Antimicrobial Therapy in Veterinary Medicine

Table 36.4. Antimicrobial treatment in mice. Caution: Most uses and dosages are extra-label.

Site Clinical Signs/Diagnosis Common Infecting Organisms Comments Suggested Drugs

Integument Scabbing over dorsum and perineum; Staphylococcus aureus, Proteus Secondary to fighting/bite wounds or Ampicillin, chloramphenicol, tetracyclines
Respiratory dermatitis; abscesses spp., Streptococcus spp. self-trauma due to acariasis.
Gastrointestinal Trim toenails. Ampicillin, chloramphenicol,
Urogenital Mastitis S. aureus fluoroquinolones
Lance and drain in addition to
Pruritis, weight loss, hyperkeratosis, Corynebacterium bovis antibiotics. Ampicillin, penicillin
alopecia
Trichophyton mentagrophytes, Affects immunocompromised mice. Low Griseofulvin (avoid in pregnant animals)
Alopecia, erythema, crusting on face, Microsporum gypseum mortality. Treatment not curative.
head, neck, tail (less frequently) Tylosin, fluoroquinolones, tetracyclines;
Uncommon, zoonotic. enrofloxacin PLUS doxycycline for its
Rhinitis, dyspnea, otitis media, upper Mycoplasma pulmonis, immunomodulating effect
respiratory tract disease, pneumonia Staphylococcus aureus, Often concurrent with Sendai virus or
Streptococcus spp. CAR bacillus; decrease intracage Chloramphenicol, fluoroquinolones,
Dacryoadenitis, sneezing, dyspnea, ammonia levels. tylosin, aminoglycosides
pneumonia Pasteurella pneumotropica,
Klebsiella pneumonia, Often concurrent with Sendai virus or Sulfamerazine, ampicillin, trimethoprim-
Pneumonia Bordetella bronchiseptica CAR bacillus; decrease intracage sulfa
ammonia levels.
Stunted growth, diarrhea, rectal CAR bacillus Tetracyclines, neomycin, metronidazole
prolapse, death; transmissible murine Primary or opportunist with other
colonic hyperplasia Citrobacter rodentium, respiratory pathogens. Amoxicillin (1.5–3 mg/30 g/d) PLUS
Clostridium piliforme metronidazole (0.69 mg/30 g/d)
Liver disease, death, chronic active Genotype, age, and diet influence PLUS bismuth subsalicylate
hepatitis, rectal prolapse Helicobacter hepaticus course and severity of disease. (0.185 mg/30 g/d), combined PO

Anorexia, dehydration, diarrhea, death Clostridium piliforme Concurrent fluid therapy essential. Tetracyclines
(Tyzzer’s disease)
Salmonella enteriditis, Zoonotic; recommend culling infected Treatment not recommended
Anorexia, weight loss, lethargy, dull S. typhimurium animals.
coat Tylosin, fluoroquinolones,
Mycoplasma pulmonis, tetracyclines
Oophoritis, salpingitis, metritis, Pasteurella pneumotropica,
infertility, abortions Klebsiella oxytoca (continued )

Table 36.4. Antimicrobial treatment in mice. Caution: Most uses and dosages are extra-label (continued ).

Site Clinical Signs/Diagnosis Common Infecting Organisms Comments Suggested Drugs
CNS
General Urethral gland obstruction, preputial Pasteurella pneumotropica, Chloramphenicol, fluoroquinolones,
gland abscesses Staphylococcus aureus aminoglycosides

Head tilt, torticollis Mycoplasma pulmonis, Chloramphenicol, tylosin,
Streptococcus spp. fluoroquinolones
Eye abscesses, Tetracyclines, aminoglycosides
conjunctivitis, panophthalmitis Pasteurella pneumotropica
Septicemia, death; mice that survive Ampicillin, tetracycline
Streptobacillus moniliformis Zoonotic potential.
acute infection may have chronic
arthritis, limb deformity, limb Corynebacterium kutscheri Antibiotic treatment not curative.
amputation; streptobacillosis
Rough hair coat, hunched posture,
inappetence, nasal and ocular
discharge, arthritis

Table 36.5. Antimicrobial treatment in hamsters. Caution: Most uses and dosages are extra-label.

Site Clinical Signs/Diagnosis Common Infecting Organisms Comments Suggested Drugs

Integument Cheek pouch abscesses, bite wound Staphylococcus aureus, Streptococcus Drain and flush; complete excision of Chloramphenicol, tetracyclines,
Respiratory abscesses spp., Pasteurella pneumotropica, abscess beneficial. fluoroquinolones
Actinomyces spp.
Swollen lymph nodes, lymphadenitis Glands warm and swollen. Supportive Chloramphenicol, tetracyclines,
Staphylococcus aureus, treatment; self-limiting infection. fluoroquinolones
Mastitis Streptococcus spp.
Zoonotic. Sometimes pruritic; improve Griseofulvin (avoid in pregnant animals)
Alopecia, dry skin, yellow flaky Beta-hemolytic streptococci cage ventilation.
seborrhea Chloramphenicol, tetracyclines,
Trichophyton mentagrophytes Secondary to poor nutrition and fluoroquinolones
Sneezing, dyspnea, upper respiratory husbandry.
tract disease, pneumonia Pasteurella pneumotropica, Sulfamerazine, sulfonamides
Streptococcus pneumonia; Opportunist with other respiratory
Gastrointestinal Diarrhea, stained perineum, lethargy, pathogens. Chloramphenicol, tetracyclines,
anorexia, rectal prolapsed, Streptococcus spp. fluoroquinolones, trimethoprim-sulfa.
proliferative ileitis (“wet tail”) CAR bacillus Especially in 3-to 10-week-olds; difficult Start with double the recommended
to treat successfully; concurrent fluid dose for 1 day
Enteritis Lawsonia intracellularis therapy, analgesics, supportive care.
Fluoroquinolones, metronidazole,
Anorexia, dehydration, diarrhea, E. coli, Clostridium difficile Concurrent fluid therapy, analgesics, tetracyclines,
death, Tyzzer’s disease supportive care essential.
Clostridium piliforme Tetracyclines
Catarrhal enteritis in weanlings Concurrent fluid therapy, analgesics,
CNS Squinting, rubbing eye, corneal Giardia muris supportive care essential. Metronidazole
Pasteurella spp., Streptococcus spp. Chloramphenicol, tetracyclines
ulceration Topical treatment. Prone to proptosis.

610 Section IV. Antimicrobial Drug Use in Selected Animal Species

Table 36.6. Antimicrobial treatment in gerbils. Caution: Most uses and dosages are extra-label.

Site Clinical Signs/Diagnosis Common Infecting Organisms Comments Suggested Drugs

Integument Red, crusty nares, staining on Staphylococcus aureus, Secondary to irritation due to Chloramphenicol, trimethoprim-
forepaws, nasal dermatitis Staphylococcus spp., Harderian gland secretions. sulfa, fluoroquinolones
Respiratory (“sore nose” or “red nose”) Streptococcus spp.
Gastrointestinal Zoonotic. Chloramphenicol, trimethoprim-
Mid-ventral marking gland Staphylococcus aureus, sulfa, fluoroquinolones
infection, dermatitis Streptococcus spp.
Griseofulvin (avoid in pregnant
Alopecia, hyperkeratosis Trichophyton animals)
mentagrophytes,
Sneezing, dyspnea, weight Microsporum gypseum Rare; concurrent therapy with Fluoroquinolones,
loss oxygen, mucolytics, oxytetracycline, sulfonamides
Beta-hemolytic streptococci, bronchodilators may help.
Lethargy, anorexia, diarrhea, Pasteurella pnuemotropica Tetracyclines
death, Tyzzer’s disease Highly susceptible.
Clostridium piliforme
Diarrhea, salmonellosis Zoonotic; recommend culling Chloramphenicol,
symptoms, death Salmonella enteriditis, affected animals. Fluid fluoroquinolones
S. typhimurium therapy is essential if
Enteritis, diarrhea, dehydration treatment attempted. Chloramphenicol,
E. coli fluoroquinolones

relatively long, narrow oral cavity, large tongue, and bility of the food or water, uneven distribution of the
small gape. Ferrets have the wider gape characteristic of drug, and possible water-quality effects on the chemical
most carnivores, but generally dislike having their composition of the compound.
mouths pried open, and may bite. In ferrets, rabbits, and
some larger rodents, administration of pills and capsules Injectable antimicrobials are most often adminis-
can be accomplished with careful use of a pilling-device tered to small mammals subcutaneously in the loose
designed for cats. Guinea pigs and chinchillas have fleshy skin over the shoulders. The procedure is quick and
cheek invaginations just behind the incisors that act as minimally stressful when performed correctly.
“one-way valves.” Small pills or pill pieces can be pushed Concurrent fluid therapy can also be given in this
past theses invaginations with the fingers (through the large space, provided the two compounds are
diastema). The presence of the substance in the mouth compatible. Small rodents can be restrained with one
stimulates a chewing response that aids in intake, espe- hand and injected with the other. The rodent is
cially if the medication is somewhat palatable. In rabbits firmly grasped by the scruff, and either left standing,
and rodents, liquids can be given using a small syringe or partially lifted off the exam table, while the injec-
inserted partway into the mouth to avoid dribbling and tion is administered. Positive re-inforcement follow-
stimulate a swallowing response. Gentle restraint and ing the procedure facilitates repeat treatments.
careful cleaning of the face and chin will help minimize Larger rodents and rabbits can be wrapped in a towel
stress and prevent skin irritation. or restrained by an assistant to facilitate injection.
Ferrets should be securely grasped by the scruff, or
Distribution of antimicrobial medication in the food around the neck in a “turtle-neck” hold, to prevent
or water is generally reserved for treatment of large excessive wriggling. Careful restraint is particularly
numbers of animals, such as in research facilities, rab- necessary for rabbits, to prevent thrashing and spinal
bitries, chinchilla farms, and pet-breeding operations, fractures; for chinchillas, to prevent damage to the
where individual dosing would be time-consuming and fur (“furslip”); for gerbils, to prevent degloving of
impractical. Problems inherent with mass-medication the tail; and for ferrets and hamsters, to minimize the
include variable intake by sick animals, reduced palata- risk of bites.

Table 36.8. Antimicrobial treatment in guinea pigs. Caution: Most uses and dosages are extra-label.

Site Disease/Clinical Signs Common Infecting Organisms Comments Suggested Drugs

Integument Enlarged lymph nodes; cervical Streptococcus zooepidemicus; also May cause septicemia; complete Chloramphenicol, fluoroquinolones
lymphadenitis Streptococcus moniliformis and surgical excision of infected
Respiratory Yersinia pseudotuberculosis lymph nodes beneficial. Fluoroquinolones, trimethoprim-
Gastrointestinal Abscesses sulfa, chloramphenicol,
Staphylococcus aureus, Streptococcus Secondary to bite wounds azithromycin, metronidazole
Mastitis spp., Pseudomonas aeruginosa, (especially males), trauma,
Pasteurella multocida, dental disease.
Swollen, ulcerated foot; ulcerative Corynebacterium pyogenes
pododermatitis; osteomyelitis Hot compresses; milk out infected Chloramphenicol, trimethoprim-
Klebsiella spp., Staphylococcus spp.,
Streptococcus spp., Pasteurella spp., glands. sulfa
E. coli, Proteus spp.
Secondary to inappropriate bedding, Chloramphenicol, fluoroquinolones,
Staphylococcus aureus, hypovitaminosis C, trauma. trimethoprim-sulfa, azithromycin,
Actinomyces spp. metronidazole
Zoonotic.
Circular areas of alopecia, crusts; Trichophyton mentagrophytes, Microsporum Fluconazole, itraconazole,
Bordetella bronchiseptica commonly ketoconazole, terbinafine,
pruritis canis carried by dogs and rabbits; some griseofulvin (avoid in pregnant
success with Bordetella bacterins. animals)
Rhinitis, tracheitis, otitis media, Bordetella bronchiseptica, Streptococcus
oculonasal discharge, upper zooepidemicus, Streptococcus pneumoniae, Amikacin, fluoroquinolones,
respiratory tract disease and/ Streptococcus zooepidemicus chloramphenicol
or pneumonia
S. pneumoniae, S. zooepidemicus, K. pneumoniae
Amikacin, fluoroquinolones,
Anorexia, diarrhea, enteritis, Clostridium difficile, Salmonella typhimurium, Concurrent fluid therapy essential; chloramphenicol
death Salmonella enteriditis, E. coli, Yersinia amikacin best for
pseudotuberculosis, Pseudomonas aeruginosa, P. aeruginosa. Chloramphenicol, systemic amikacin
Diarrhea, dehydration, bloating, Listeria monocytogenes or gentamicin
death
Clostridium difficile, E. coli Spontaneous, or following Metronidazole, chloramphenicol,
Anorexia, ascites, diarrhea, death; administration of antibiotics. control pain
Tyzzer’s disease Clostridium piliforme
Recent weanlings, predisposed by Tetracyclines
Diarrhea; coccidiosis Eimeria caviae crowding, poor sanitation.
Failure to gain, weight loss, Cryptosporidium wrairi Sulfonamides
Most common in juveniles. Sulfonamides
diarrhea, death; cryptosporidiosis In humans, newer macrolides such

as roxithromycin and azithromycin
have shown some efficacy.

Table 36.7. Antimicrobial treatment in rats. Caution: Most uses and dosages are extra-label.

Site Clinical Signs/Diagnosis Common Infecting Organisms Comments Suggested Drugs

Integument Abrasions/ulcerations over shoulders Staphylococcus aureus Secondary to primary wounds caused Ampicillin, chloramphenicol,
Respiratory and back; ulcerative dermatitis P. pneumotropica, by self-trauma. Trim toenails.
Chloramphenicol, fluoroquinolones,
Gastrointestinal Abscesses, furunculosis K. pneumoniae Secondary opportunist; drain and flush aminoglycosides
Urogenital P. pneumotropica, abscesses.
CNS Mastitis Chloramphenicol, fluoroquinolones,
Staphylococcus aureus Hot compress, drainage. aminoglycosides
Alopecia, pruritis Microsporum spp.
Snuffling, sneezing, dyspnea, vestibular Mycoplasma pulmonis Zoonotic. Griseofulvin (avoid in pregnant animals)
Common; improve nutrition, husbandry; Combination enrofloxacin 10 mg/kg &
disease, depression CAR bacillus
chromodacryorrhea, upper respiratory decrease intracage ammonia levels. doxycyline 5 mg/kg beneficial;
tract disease and/or pneumonia; tetracycline, tylosin
murine respiratory mycoplasmosis
(MRM)

Serosanguinous to mucopurulent nasal Streptococcus pneumoniae Often concurrent with mycoplasmas or Sulfamerazine, ampicillin,
discharge, rhinitis, conjunctivitis, Corynebacterium kutscheri viruses. chloramphenicol, enrofloxacin
otitis media Pasteurella pneumotropica
Clostridium piliforme Immunocompromised animals at Oxytetracycline
Rough coat, hunched, oculonasal Salmonella enteriditis greatest risk.
discharge, dyspnea, granulomatous
pneumonia; pseudotuberculosis Immunocompromised animals at Ampicillin, chloramphenicol,
greatest risk; antibiotics will not tetracyclines
Conjunctivits, panophthalmitis, eliminate infection.
oculonasal discharge, dyspnea, Enrofloxacin
head tilt Immunocompromised animals at
greatest risk.
Diarrhea, dehydration, anorexia, death;
Tyzzer’s disease Tetracyclines

Diarrhea, dry coat, unthriftiness, death Zoonotic; recommend culling affected
animals.

Infertility, oophoritis, salpingitis, metritis, Mycoplasma pulmonis Tylosin, fluoroquinolones, tetracyclines
pyometra
P. pneumotropica, Chloramphenicol, fluoroquinolones
Preputial gland abscess Staphylococcus aureus
Fluoroquinolones, chlormaphenicol,
Head tilt, circling, torticollis, otitis Mycoplasma pulmonis ± tylosin
interna secondary bacterial invaders

Urogenital Metritis, pyometra, abortions, Bordetella bronchiseptica, Ovariohysterectomy recommended Fluoroquinolones, trimethoprim-
stillbirths Streptococcus spp., Corynebacterium pyogenes, in non-breeding sows. sulfa, chloramphenicol
Eye Staphyloccus spp., E. coli
Ear Orchitis, epididymitis Urinary calculi often present. Chloramphenicol, systemic amikacin
General Bordetella bronchiseptica, Topical treatment; often secondary or gentamicin
Cystitis Streptococcus spp.
to hypovitaminosis C. Trimethoprim-sulfa,
Ocular discharge; conjunctivitis Staphylococcus pyogenes, fluoroquinolones
Staphylococcus spp., fecal coliforms Zoonotic; recommend culling
Head tilt, otitis media/interna infected animals. Tetracyclines, fluoroquinolones,
Chlamydophila caviae, Bordetella bronchiseptica, chloramphenicol
Anorexia, soft stools, dyspnea, Streptococcus pneumoniae
hepatitis, lymphadenitis, Fluoroquinolones, trimethoprim-
septicemia, death Streptococcus pneumoniae, sulfa, chloramphenicol,
Streptococcus zooepidemicus, Bordetella metronidazole
bronchiseptica, Staphylococcus aureus
Treatment not recommended
Salmonella typhimurium, Salmonella enteriditis

Table 36.9 Antimicrobial treatment in ferrets. Caution: Most uses and dosages are extra-label.

Site Disease/Clinical Signs Common Infecting Organisms Comments Suggested Drugs

Integument Dermatitis, abscesses Staphylococcus spp., Streptococcus Secondary to bite wounds; debride and Ampicillin, chloramphenicol,
spp., Corynebacterium spp.,
Pasteurella spp., Actinomyces spp., flush. fluoroquinolones
E. coli
Cervical masses with sinus tracts Debride and flush. Clavulanic acid–amoxicillin,
containing thick yellow-green pus, Actinomyces spp. chloramphenicol
actinomycoses
Respiratory Staphylococcus spp., coliforms Immediate surgical excision of infected Clavulanic acid–amoxicillin,
Skin black, dam ill, dehydrated; acute gland; contagious between dams. chloramphenicol
gangrenous mastitis Staphylococcus spp., E. coli Treatment generally ineffective
Contagious between dams; appears
Glands firm, scarred, not painful or Trichophyton mentagrophytes, insidiously when kits 3 weeks old. Itraconazole, griseofulvin (avoid in
discolored; chronic mastitis Microsporum canis pregnant animals)
Zoonotic.
Alopecia, crusts, hyperkeratosis, broken Streptococcus zooepidemicus, Secondary to influenza virus, respiratory Ampicillin, tetracyclines, fluoquinolones
hair shafts Streptococcus pneumoniae, E. coli,
Klebsiella pneumoniae, Pseudomonas syncytial virus, canine distemper Trimethoprim-sulfamethoxazole
Dyspnea, cyanosis, upper respiratory aeruginosa, Bordetella bronchiseptica, virus. Amikacin, fluoroquinolones,
tract disease and/or pneumonia Listeria monocytogenes
Improve diet; dentistry. chloramphenicol
Gastrointestinal Dental tartar, gingivitis, periodontal Pneumocystis jiroveci
disease S. pneumoniae, Metronidazole

Inappetance, vomiting, bruxism, S. zooepidemicus,
diarrhea, melena, hypersalivation, K. pneumoniae
anemia, gastritis, gastric/duodenal Multiple etiologies
ulceration; Helicobacter mustelae
gastritis Helicobacter mustelae Rule out foreign body, lymphoma, Amoxicillin 10 mg/kg PLUS
Aleutian disease, coronavirus. metronidazole 20 mg/kg PLUS
bismuth subsalicylate 17 mg/kg
(1 ml/kg) combined and given PO,
q 12 h for 14–21 days OR
Clarithromycin 25 mg/kg PLUS
omeprazole 1 mg/kg PO, q 24 h
OR enrofloxacin 4 mg/kg PLUS
colloidal bismuth subcitrate 6 mg/kg
PO, q 12 h

Diarrhea, wasting, tenesmus, prolapsed Lawsonia intracellularis Chloramphenicol, tylosin
rectum; proliferative bowel disease
Clostridium perfringens Treat as for bloat in canine patients. Metronidazole
Acute gastric distension, dyspnea,
cyanosis, sudden death; gastric bloat Salmonella newport, Zoonotic; recommend culling infected Treatment not recommended
S. typhimurium, S. choleraesuis animals.
Fever, bloody diarrhea, lethargy
Mycobacterium spp. Zoonotic potential—consider culling.
Weight loss, diarrhea, vomiting,
Urogenital granulomatous inflammation; Coccidia spp. Urolithiasis often present. Sulfonamides
mycobacteriosis Giardia spp. Metronidazole
Staphylococcus spp., Proteus spp. Fluoroquinolones, ampicillin,
Diarrhea; coccidiosis
Diarrhea; giardiasis sulfonamides
Straining, hematuria, cystitis

Table 36.10. Antimicrobial treatment in chinchillas. Caution: Most uses and dosages are extra-label.

Site Disease/Clinical Signs Common Infecting Organisms Comments Suggested Drugs

Integument Abscesses Staphylococcus aureus, Secondary to wounds; complete Chloramphenicol, tetracyclines,
Streptococcus spp., surgical excision beneficial. fluoroquinolones
Pseudomonas spp.
Patches of alopecia, scales on nose, Zoonotic. Griseofulvin (avoid in pregnant animals),
ears, and feet Trichophyton mentagrophytes
itraconazole, fluconazole
Anorexia, upper respiratory tract Pasteurella multocida, Bordetella spp.,
Respiratory disease, dyspena and/or pneumonia Streptococcus. Pneumoniae, Overcrowding, high humidity, poor Fluoroquinolones, trimethoprim-sulfa,
Pseudomonas aeruginosa
ventilation are presdisposing factors. chloramphenicol, amikacin
Yersinia enterocolitica, Clostridium
perfringens, E. coli, Proteus spp., Amikacin best for Pseudomonas
Salmonella typhimurium, Salmonella
enteriditis, Pseudomonas aeruginosa.
aeruginosa, Listeria monocytogenes,
Gastrointestinal Anorexia, decreased fecal output, Corynebacterium spp. Concurrent fluid therapy essential; Chloramphenicol, trimethoprim-sulfa,
diarrhea, enteritis, sudden death
Clostridium spp., E. coli sulfonamides best for Listeria fluoroquinolones, metronidazole (use

Giardia spp. monocytogenes. with caution)

Urogenital Diarrhea, dehydration, bloating, death Listeria monocytogenes Spontaneous, or following Metronidazole (use with caution),
E. coli, Pseudomonas spp., administration of antibiotics. chloramphenicol, trimethoprim-sulfa
Otic Diarrhea ± rectal prolapse; giardiasis
CNS Staphylococcus spp., Highly susceptible. Fenbendazole, metronidazole (use with
General Depression, abortions Streptococcus spp. caution)
Metritis, fever, purulent vaginal Pseudomonas aeruginosa, Listeria
monocytogenes, anaerobes Sulfonamides, tetracyclines
discharge Listeria monocytogenes Aminoglycosides, fluoroquinolones

Vestibular signs, head tilt, anorexia; Streptococcus spp., Enterococcus spp., Highly susceptible. Fluoroquinolones, trimethoprim-sulfa,
otitis media and/or interna Pasteurella multocida, Klebsiella chloramphenicol
pneumoniae, Actinomyces spp.,
Depression, ataxia, convulsions, Fusobacterium necrophorum Trimethoprim-sulfa, tetracyclines
sudden death
Zoonotic; recommend culling infected Chloramphenicol, fluoroquinolones
Septicemia, death animals.

Table 36.11. Antimicrobial treatment in rabbits. Caution: Most uses and dosages are extra-label.

Site Disease/Clinical Signs Common Infecting Organisms Comments Suggested Drugs

Integument Abscesses Pasteurella multocida, Staphylococcus Can be located anywhere on body; Chloramphenicol, tetracyclines,
Respiratory aureus, Pseudomonas spp.,
Ulcerative podocermatitis; “sorehock” Streptococcus spp., Bacteroides spp. complete surgical excision beneficial. fluoroquinolones
Dermatitis
Staphylococcus aureus, Pasteurella Often secondary to inappropriate Chloramphenicol, tetracyclines,
multocida, substrate. fluoroquinolones

Staphylococcus aureus Usually secondary to poor husbandry. Chloramphenicol, tetracyclines,
fluoroquinolones
Ulceraton/necrosis of face, feet; dental Fusobacterium necrophorum Associated with poor hygiene and
and internal abscesses (Schmorl’s husbandry. Cephalosporins, chloramphenicol,
disease) Pseudomonas aeruginosa, tetracyclines, metronidazole
Streptococcus spp.,
Wet chin, dewlap (“slobbers”) or urine Staphylococcus spp. Secondary to moist skin. Fluoroquinolones, amikacin, gentamicin
scald (“hutch burn”); exudative P. aeruginosa may turn fur green.
dermatitis Correct underlying cause (dental Amikacin, fluoroquinolones,
disease, obesity, inappropriate chloramphenicol, tetracyclines
Mastitis Staphylococcus aureus, Pasteurella spp., waterers).
Streptococcus spp. Griseofulvin (avoid in pregnant animals),
Alopecia, scaling, crusting on eyelids, Hot compresses; milk out affected itraconazole, ketoconazole, terbinafine
at base of ears, and muzzle Trichopyton spp., Microsporum spp. glands often.
Parenteral penicillin, cephalexin,
Crusty lesions on nose and lips ± Treponema cuniculi Zoonotic. tetracyclines, chloramphenicol
concurrent genital lesions
Pasteurella multocida Very common; treatment rarely Parenteral penicillin, fluoroquinolones,
Snuffling, oculonasal discharge, curative. tetracyclines, amikacin, gentamicin
conjunctivitis, upper respiratory tract Bordetella bronchiseptica,
disease and/or pneumonia Staphylococcus aureus,
Pseudomonas aeruginosa
Usually secondary to Pasteurella Amikacin, fluoroquinolones, tetracyclines
multocida.

(continued )

Table 36.11. Antimicrobial treatment in rabbits. Caution: Most uses and dosages are extra-label (continued)

Site Disease/Clinical Signs Common Infecting Organisms Comments Suggested Drugs
Gastrointestinala Diarrhea, death; iota-enterotoxemia Clostridium spiroforme
Spontaneous, or following Metronidazole, chloramphenicol
Diarrhea; coccidiosis Eimeria spp. administration of antibiotics.
Sulfonamides
Diarrhea, death; colibacillosis E. coli Hepatic or intestinal; improve
sanitation. Sulfonamides, fluoroquinolones,
Diarrhea, death Salmonella spp., Pseudomonas spp. amikacin
Diarrhea, death; Tyzzer’s disease Clostridium piliforme Especially neonates 1–14 days old
Reddening, edema to dry, scaly, slightly Treponema paraluiscuniculi and weanlings. Chloramphenicol, fluoroquinolones
Tetracyclines
raised areas of external genitalia; Listeria monocytogenes, Pasteurella Concurrent fluid therapy essential. Parenteral penicillin, tetracyclines,
veneral spirochetosis (“rabbit multocida
Urogenital syphilis”) chloramphenicol
Abortion E. coli, Pseudomonas spp.
Trimethoprim-sulfa, chloramphenicol,
Cystitis tetracyclines

Ocular Orchitis, metritis, uterine abscesses Pasteurella multocida, Staphylococcus Contact with wild rodents; diagnosis Trimethoprim-sulfa,
CNS aureus by serology. fluoroquinolones
Polydypsia, polyuria, depression, Chloramphenicol, tetracycline,
General anorexia, renal failure Leptospira spp. Treat topically; flush tear ducts.
gentamicin
Clear to white discharge from one or Pasteurella multocida, Staphylococcus Usually due to otitis media. Parenteral penicillin
both eyes, conjunctivitis aureus
Chloramphenicol, tetracycline,
Head tilt, nystagmus, torticollis; Pasteurella multocida aminoglycosides
“wry neck”
Encephalitozoon cuniculi Chloramphenicol, fluoroquinolones
Ataxia, torticollis, tremors, convulsions Pasteurella multocida, Listeria
Lethargy, anorexia, pyrexia, septicemia Diagnosis by clinical signs and serology. Fenbendazole, albendazole, tetracyclines
monocytogenes Fluoroquinolones, aminoglycosides,
tetracyclines, chloramphenicol

aWhere applicable, provide aggressive supportive care, including fluids (SC, IV, intraosseous), analgesics, high-fiber diet (via syringe or naso-gastric tube if necessary), cisapride or
metaclopramide, excellent nursing care; cholestyramine at 2 g per 20 ml water q 24 h by gavage may bind bacterial toxins.

Chapter 36. Antimicrobial Drug Use in Rabbits, Rodents, and Ferrets 619

Intraperitoneal injection is suitable for smaller Nebulization of antimicrobial drugs is sometimes
rodents, and is a common route of drug administration used to treat upper and lower airway disease in small
in laboratory animals. The procedure is quick and easy mammal pets. A mask may be tolerated by some ani-
to perform, which minimizes patient discomfort. The mals, or a small chamber, such as an anesthesia induc-
rodent is firmly scruffed and turned upside down to tion chamber, can be used. Patients should be supervised
expose the abdomen. Injections are given in the mid- to at all times during confinement to detect undue stress,
lower-right quadrant, to avoid puncturing the cecum. overheating, or other problems.
Intraperitoneal injection in animals with voluminous
intestines, such as guinea pigs and rabbits, is not Gavage is used primarily in experimental studies,
recommended. where accurate administration of the drug is critical. In
rabbits and ferrets, soft plastic feeding tubes or catheters
Small rodents generally lack sufficient muscle mass to can be introduced into the esophagus through a specu-
accommodate intramuscular injections. Soft tissue lum. The barrel of a 3 cc syringe with the end cut off
trauma and irritation, leading to self-mutilation, may works well in rabbits. In rodents, curved, ball-ended
occur, and drug uptake can be unreliable. In larger metal or plastic feeding needles are commercially
rodents, rabbits, and ferrets, intramuscular injections available for oral dosing. Correct restraint and gentle
can be given in the lumbar, gluteal, or quadriceps mus- insertion, allowing gravity and the swallowing reflex to
cles, taking care not to penetrate the bone or sciatic pass the tube into the esophagus, are critical for success,
nerve. Alternate routes of drug administration are gen- but once the technique is mastered, it is quick and
erally easier and safer, and therefore preferable. relatively stress-free for the animal.

Topical antimicrobial preparations, especially those Administration of oral antimicrobials in very
containing corticosteroids, should be used sparingly debilitated patients can also be accomplished through
and cautiously in rabbits, and rodents. Due to their fas- placement of a nasogastric tube (in rabbits) or esophago-
tidious grooming habits, ingestion of amounts of drug stomy tube (in rabbits, larger rodents, and ferrets),
sufficient to cause undesirable systemic effects may especially if repeated administrations are necessary and
result. In addition, use of oil-based products should be the animal becomes unduly stressed by oral manipula-
avoided if possible, especially in chinchillas and gerbils, tions, or in animals that also require nutritional
which require dust-baths to keep their fur healthy. supplementation. Nasogastric tube placement in rabbits
is not technically difficult to perform and several
Ophthalmic preparations are less concentrated than descriptions of the procedure are available in the litera-
other topical medications, and are useful not only for ture. Esophagostomy tube placement requires general
the eyes, but for other parts of the body too. These anesthesia; however, post-operative animal comfort is
preparations can also be injected into the naso-lacrimal greater than with nasogastric tubes, breathing is not
ducts of rabbits following flushing, or instilled into compromised, and tubes are rarely pulled out.
the nares.
Antimicrobial-impregnated implants are used
The intravenous route of antimicrobial administra- primarily for treatment of facial and tooth-root abscesses
tion is not used routinely and is usually reserved for ini- in rabbits. In biomedical research, small mammal mod-
tial treatment of critically ill patients. In ferrets and els have been used to study the elution kinetics and
rabbits, a catheter can be placed in the cephalic vein for other effects on bone formation and implant integration
administration of fluids and other drugs, and the ear of various antimicrobial-coated orthopedic implants for
vein is sometimes catheterized in rabbits, but may result use in people.
in subsequent ear necrosis. Injections can be attempted
directly into the ear, cephalic, lateral saphenous, medial Animal Numbers and Use
saphenous, femoral, or tail vein of some small mam-
mals, but this requires a large amount of skill and often The number of animals requiring treatment, and their
anesthesia of the patient. In severely debilitated patients intended use must always be kept in mind when
in which venous access is not possible, placement of an prescribing antimicrobial medications in rabbits,
intraosseous catheter in the tibia or femur may be
indicated.

620 Section IV. Antimicrobial Drug Use in Selected Animal Species

rodents, and ferrets. The method of treating a single animal residue avoidance databank (in Canada: www.
small mammal patient will often differ significantly cgfarad.usask.ca; in the United States: www.farad.org).
from that of treating hundreds of animals being bred for
the pet trade, used as research subjects, being farmed for Enhancing Therapeutic Success
fur, or, in the case of rabbits, being raised for meat. The
cost and feasibility of treatment, the effect of the drug on Treatment of small mammal patients usually involves
the animal, the deleterious effects that handling may more than just choosing the correct antimicrobial agent.
have on the animal, and the possibility of the animal Many infections are secondary to a compromised
being consumed by humans are some of the factors that immune system caused by stress or inadequate nutrition
will affect the choice of antimicrobial, its formulation, and/or husbandry. A thorough history is necessary to
and the method of administration. detect preexisting problems that may be unknown to the
client. For example, guinea pigs are unable to synthesize
Veterinary treatment of animal colonies used for vitamin C and require supplementation of 10–25 mg
biomedical research must be compatible with the daily. Undersupplementation is very common in these
intended scientific use of the animals, so as not to animals, leading to subclinical hypovitaminosis C,
render them useless. A colony-treatment approach, altered immune function, and secondary bacterial
rather than an individual animal approach, is com- infections. Although ascorbic acid is present in guinea
monly implemented and medications are generally pig food, the stability varies, and the actual amount
incorporated into feed or water. Particular attention available depends on the milling date and storage condi-
must be paid to treatment of genetically modified tions. Owners may not be aware that most chows should
animals; not only are they usually very valuable and be used within 90–180 days of being milled. Other
often irreplaceable, they sometimes do not metabo- options for provisions of vitamin C include water sup-
lize drugs in a predictable way due to their altered plementation, flavored tablets, or daily feeding of small
genetic background. With particularly valuable ani- amounts of vitamin C-rich fruit or vegetables, such as
mals, treatment of a small number and observation kale, parsley, beet greens, kiwi fruit, broccoli, orange, or
for deleterious side effects may be indicated, prior to cabbage. Oversupplementation of this water-soluble
treating the larger population. Several companies vitamin is generally not a concern since excess amounts
specialize in incorporating test compounds or medi- are eliminated from the body.
cal therapies into palatable diets, treats, or feed for a
wide variety of animals used in biomedical research. Altered immune function can also occur due to stress.
Prey species, such as rabbits and rodents, are particu-
A number of antimicrobials are prohibited for use in larly susceptible to stressors and the effects can be long-
food-producing animals. One of these is chlorampheni- lasting. Studies in laboratory animals have shown that
col, a drug that is frequently used in rabbits and rodents transport, separation from cage mates, and confinement
due to its effectiveness and relative safety, but has been in an unfamiliar container can affect the cardiovascular,
associated with irreversible aplastic anemia in humans. endocrine, immune, central nervous and reproductive
Strategic and tactful questioning must sometimes take systems, and it can take at least 2 days for rabbits to
place to determine whether the patient might eventually acclimate to a new environment after travel. Noise and
be used as a food source for humans. odors are also stressful to rabbits and rodents, and their
heart and respiratory rates can increase rapidly in
Extra-label medications are occasionally used in meat response to catecholamine release. Prey species are par-
rabbits, for example, antimicrobial mixtures labeled for ticularly sensitive to predator odors so an attempt should
prevention of necrotic enteritis in chickens are some- be made to minimize exposure of rabbits and rodents to
times added to commercial rabbit feed to manage enter- dogs, cats, and ferrets, and their vocalizations and
itis problems. Both the producer and the veterinarian smells, while in the clinic.
are responsible for ensuring no drug residues are pre-
sent in meat produced for human consumption; how- Prey species instinctively mask any signs of weakness
ever, withdrawal times are not available for these drugs or illness. In addition, their quiet nature, secretive habits,
when used extra-label. In these situations specific with-
drawal recommendations can be obtained from a food

Chapter 36. Antimicrobial Drug Use in Rabbits, Rodents, and Ferrets 621

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Antimicrobial Drug Use in Reptiles 37

Ramiro Isaza and Elliott R. Jacobson

Antimicrobial therapy is an important component in Gram-negative bacterial infectious diseases are also
clinical management of reptiles affected with bacterial reported in wild populations of reptiles. For instance,
or mycotic disease. Selecting the appropriate antimicro- die-offs of American alligators (Alligator mississippiensis)
bial agent for reptiles is based on similar principles and have been associated with Aeromonas hydrophila infec-
considerations common to antimicrobial selection in tions (Shotts et al., 1972).
domestic species. However, this process is more compli-
cated in reptiles because of the number and diversity of In addition to Gram-negative bacteria, a wide variety
species, their unique anatomic and physiological features, of other bacteria are becoming recognized as either
the diversity of infectious agents, and even behavioral primary or secondary pathogens of reptiles (Jacobson,
characteristics that make safety an important factor in 2007). Stewart (1990) found a variety of anaerobic
drug and route considerations. Once a candidate antimi- bacteria in a series of reptile cultures. In other studies,
crobial is selected, the process is further complicated by bacterial pathogens such as mycoplasma, Chlamydophila,
the relatively few pharmacokinetic studies performed and mycobacteria were reported in reptiles (Homer
in  reptiles. This chapter will focus on the process of et al., 1994; Jacobson and Telford, 1990; Jacobson et al.,
antimicrobial selection in reptiles while highlighting the 1989; Jacobson et al., 2002; Jacobson, 2007; Soldati et al.,
unique differences and challenges associated with select- 2004). It is apparent that as methods of detection are
ing antimicrobial agents for these species. improved and applied in reptile samples, the range of
bacterial pathogens will continue to expand.
Reptile Infectious Agents
Mycotic infections are also common in captive
Bacterial and fungal infections are important causes of reptiles (Paré et al., 2006). Mycotic infections of the
morbidity and mortality in captive reptiles (Austwick integumentary and respiratory systems are particularly
and Keymer, 1981; Clark and Lunger, 1981; Cooper, common (Austwick and Keymer, 1981; Migaki et al.,
1981; Hoff et al., 1984; Jacobson, 1999; Jacobson, 2007). 1984). For example, the Chrysosporium anamorph of
From the literature, it appears that Gram-negative Nannizziopsis vriesii (CANV) is an important fungal
bacterial infections are common in captive reptiles pathogen of reptiles (Paré et al., 1997; Paré et al., 2003;
(Paré, et al., 2006). Although not as well documented, Bertelsen et al., 2005).

Other pathogens, including protozoal, helminth, and
viral agents have been described in reptiles and subse-
quently well reviewed in the literature (Jacobson, 2007).

Antimicrobial Therapy in Veterinary Medicine, Fifth Edition. Edited by Steeve Giguère, John F. Prescott and Patricia M. Dowling.
© 2013 John Wiley & Sons, Inc. Published 2013 by John Wiley & Sons, Inc.

623

624 Section IV. Antimicrobial Drug Use in Selected Animal Species

Studies evaluating the pharmacokinetics of antimicrobial isolate from routine cultures and also often difficult to
drugs active against these pathogens are currently limited see in standard histopathological preparations. Special
(Gaio et al, 2007; Allender et al., 2012). Due to the lack of histological stains, immunohistochemical stains, and
pharmacokinetic studies, this chapter will not discuss molecular techniques are sometimes necessary to
these pathogens further, instead focusing on bacterial detect their presence (Bodetti et al., 2002; Jacobson
and mycotic pathogens. et  al., 2004; Johnson et al., 2007). Soldati (2004) pro-
vides an example of this aggressive diagnostic approach
With the increasing numbers of studies describing using both immunoperoxidase staining and PCR
reptile pathogens, some species and groups of reptiles are amplification to detect mycobacteria and chlamydia in
becoming associated with specific bacterial and mycotic a retrospective study of 90 reptiles with granulomatous
pathogens. Tables  37.1–37.3 provide a partial listing lesions.
of  these disease associations and provide the clinician
with  a preliminary guide for selecting antimicrobials. In reptiles suspected of being septic, the clinician
Examples of these species associations include: Neisseria should routinely perform blood cultures. Jacobson
iguana isolated from both the normal oral cavity and bite (1992a, 2007) describes techniques for collecting percu-
wounds of captive green iguanas (Iguana iguana; taneous blood specimens from reptiles. The interpreta-
Plowman et al., 1987; Barrett et al., 1994); Mycoplasma tion of blood culture results can be challenging, as
agassizii associated with chronic upper respiratory dis- certain bacteria such as Clostridium spp. have been cul-
ease in both the desert tortoise (Gopherus agassizii) and tured from the blood of clinically healthy reptiles (Hanel
the gopher tortoise (Gopherus polyphemus; Jacobson et al., 1999). Furthermore, if the clinician fails to collect
et  al., 1991; Brown et al., 1995; Brown et al., 1999); the percutaneous blood sample correctly, bacteria from
Mycoplasma crocodyli as the cause of polyarthritis cutaneous contamination are commonly isolated.
in  Nile  crocodiles (Crocodylus niloticus) in Zimbabwe Collecting a truly uncontaminated ante-mortem blood
(Kirchoff et al., 1997; Mohan et al., 1995); and Mycoplasma sample from a reptile is far more difficult than it appears
alligatoris associated with arthritis and pneumonia in the to be (Jacobson, 1992a). Thus blood culture results must
American alligator (Alligator mississippiensis; Brown be interpreted in the context of other health assessment
et al., 2001; Clippinger et al., 2000). tests and consideration of sample quality.

Identifying Reptile Infectious Agents As in domestic species, selecting the appropriate
antimicrobial agent is ideally based on the results of a
Once a bacterial or mycotic infection is suspected in a rep- quantitative susceptibility panel. Once the primary
tile patient, the accurate identification of the primary pathogen is isolated and identified, the clinician should
pathogen is an essential step when choosing the most request an antimicrobial sensitivity panel from the labo-
appropriate antimicrobial. If a discrete lesion is present, a ratory. The clinician may need to request a custom
biopsy specimen is ideally obtained for both cytologic and quantitative susceptibility panel that includes antimi-
histologic examination. Concurrent with the morphologi- crobials commonly used in reptiles.
cal assessment, a specimen of the lesion is also submitted
for culture. It is important to inform the laboratory that the Husbandry and Immunological
culture specimen is from a reptile and may need special Considerations
laboratory handling to isolate the pathogen (Origgi et al.,
2007). Ideally, a portion of the biopsied sample is also The next consideration in the process of antimicrobial
retained for further molecular assessments, such as poly- selection should be an understanding that captive hus-
merase chain reaction. This aggressive diagnostic approach bandry and the immunological status of the reptile are
is recommended to accurately interpret the significance of important. Bacterial and mycotic infections tend to
the microorganisms cultured from reptile lesions. become more invasive and clinically apparent in captive
reptiles when husbandry conditions are suboptimal
Some reptile pathogens such as Chlamydophila, (Cooper, 1981). For example, maintaining reptiles below
Mycoplama, and mycobacteria are relatively difficult to their optimal temperature range may induce an

Chapter 37. Antimicrobial Drug Use in Reptiles 625

Table 37.1. Antimicrobial drug selection in chelonian infections.

Site or Type Diagnosis Common Infecting Organisms Suggested Drugs
Skin, shell, and subcutis Epidermitis/Dermatitis
Citrobacter freundii Amikacin
Serratia Ceftazadime
Proteus morganii Ticarcillin
Providencia rettgeri Enrofloxacin
Pseudomonas aeruginosa
Penicillin G
Dermatophilus chelonae Ampicillin
Tetracycline
Oral cavity Subcutaneous abscesses Mycobacterium chelonei Amikacin
Respiratory tract Stomatitis Clarithromycin
Pneumonia Mucor Immersions in malachite green solution
Gastrointestinal tract Aspergillus Fluconazole
Rhinitis Amikacin
Enteritis Pasteurella testudinis Enrofloxacin
Liver Abscesses Escherichia coli
Septicemia Providencia Metronidazole
Penicillin G
Bacteroides Amikacin
Fusobacterium Ceftazidime
Aeromonas hydrophila Ticarcillin
Pseudomonas aeruginosa Enrofloxacin
Vibrio Marbofloxacin
Amikacin
Pseudomonas aeruginosa Ceftazidime
Morganella morganii Ticarcillin
Serratia marcescens Enrofloxacin
Acinetobacter calcoaceticus Marbofloxacin
Metronidazole
Bacteroides
Fusobacterium Ketoconazole
Itraconazole
Aspergillus Fluconazole
Geotrichum candidum
Beauvaria Enrofloxacin
Penicillium lilacinum Clarithromycin
Paecilomyces fumoso-roseus Enrofloxacin

Pasteurella testudinis Metronidazole
Mycoplasma agassizii
Salmonella Amikacin
Aeromonas hydrophila Ticarcilllin
Flavobacterium meningosepticum Enrofloxacin
Marbofloxacin
Salmonella
Bacteroides
Clostridium
Fusobacterium

Salmonella
Aeromonas hydrophila
Pseudomonas aeruginosa

(continued )

626 Section IV. Antimicrobial Drug Use in Selected Animal Species

Table 37.1. Antimicrobial drug selection in chelonian infections. (continued)

Site or Type Diagnosis Common Infecting Organisms Suggested Drugs
Skeletal
Osteomyelitis/ Pseudomonas Amikacin
arthritis Klebsiella Ceftazidime
Mycobacterium cheloniei
Amikacin
Nocardia Clarithromycin
Various fungi
Azithromycin
Eye and adnexa Conjunctivitis Mycoplasma agassizii
Ear Otitis interna Fluconazole
Pseudomonas Sulfonamides
Escherichia coli Doxycycline
Proteus Enrofloxacin
Pasteurella testudinis Clarithromycin
Amikacin
Bacteroides Ceftazadime
Fusobacterium Ticarcillin
Enrofloxacin

Metronidazole

immunocompromised condition in the patient. Anatomical and Physiological
Furthermore, Vaughn et al. (1974) demonstrated that Considerations
some lizard experimentally infected with Gram-negative
voluntarily selected higher ambient temperatures. This The clinician needs to be aware that reptile anatomy
behavior was interpreted as an induced fever, and is and  physiology differs significantly from domestic
thought to help the lizards fight bacterial infections. mammals. Reptiles have several unique features that can
Given that reptile body temperature affects immune potentially influence the pharmacokinetics of antimi-
system function, it is imperative to maintain the ill crobials and the subsequent response to treatment.
reptile under optimum environmental conditions as an
important part of the therapeutic plan. The carapace and plastron forms the characteristic
shell of chelonians. This unique anatomic feature is
Our understanding of reptile bacterial and mycotic composed of an outer keratinized epidermis overlying
infections has advanced to recognize that reptiles a base of dermal cartilage and bone. The dermal bone is
become more susceptible to bacterial diseases when highly vascularized and considered a metabolically
exposed to other pathogens. For example, primary viral active tissue (Jacobson, 2007). The relative metabolic
infections, such as ophidian paramyxovirus pneumonia activity and blood perfusion of the chelonian shell has
and herpes virus stomatitis of tortoises, are associated led to the recommendation that antimicrobials should
with severe secondary bacterial infections (Jacobson, be dosed based on their entire body weight and not
1992b; Origgi et al., 2004). The clinician should consider adjusted to subtract the weight of the turtle shell.
exposure to contaminated environments and a lack of
proper quarantine program as important risk factors for An anatomical feature of all snakes with eyes and
infection with multiple pathogen. Thus the clinician’s some lizards is the transparent palpebral spectacle
recognition of both husbandry mistakes and the proper (Millichamp et al., 1983). This spectacle embryologi-
diagnosis of co-infections are important aspects of anti- cally represents a fusion of the upper and lower eyelids
microbial selection for reptiles. that permanently covers the cornea leaving a potential
subspectacular space. Infections of this subspectacular

Chapter 37. Antimicrobial Drug Use in Reptiles 627

Table 37.2. Antimicrobial drug selection in crocodilian infections.

Site or Type Diagnosis Common Infecting Organisms Suggested Drugs
Oral cavity Stomatitis Aeromonas hydrophila
Tetracycline
Skin Epidermitis/ Candida Amikacin
Dermatitis Ceftazidime
Dermatophilus
Respiratory tract Pneumonia Nystatin
Morganella morganii
Yolk infection Omphalitis Pseudomonas aeruginosa Procaine penicillin G
Liver Hepatitis Serratia Tetracycline
Klebsiella
Eye Uveitis Amikacin
Aspergillus Ceftazidime
Trichophyton
Trichosporon Ketoconazole
Itraconazole
Aeromonas hydrophila Fluconazole
Citrobacter freundii
Morganella morganii Amikacin
Providencia rettgeri Ceftazidime
Escherichia coli Enrofloxacin
Salmonella
Ketoconazole
Beauvaria Itraconazole
Fusarium Fluconazole
Mucor
Paecilomyces Enrofloxacin
Oxytetracyline
Mycoplasma alligatoris
Tetracycline
Aeromonas hydrophila Amikacin

Escherichia coli Amikacin
Salmonella Ceftazidime
Aeromonas hydrophila Enrofloxacin

Aeromonas hydrophila Oxytetracycline
Enrofloxacin
Aeromonas hydrophila
Amikacin
Cardiovascular Septicemia Salmonella Ceftazidime
Serosa/joints Polyserositis/arthritis Aeromonas hydrophila Tetracycline

Mycoplasma alligatoris Amikacin
Ceftazidime
Enrofloxacin

Enrofloxacin
Oxytetracyline

Table 37.3. Antimicrobial drug selection for infections in snakes and lizards.

Site or Type Diagnosis Common Infecting Organisms Suggested Drugs

Oral cavity Stomatitis Pseudomonas aeruginosa Amikacin
Aeromonas hydrophila Ceftazidime
Piperacillin
Skin and subcutis Abscesses Proteus Enrofloxacin
Providencia Marbofloxacin
Respiratory tract Bacterial dermatitis Pseudomonas
Mycotic dermatitis Salmonella Amikacin
Pneumonia Serratia Ceftazidime
Clostridium Piperacillin
Gastrointestinal tract Enteritis Pseudomonas aeruginosa Azithromycin
Enrofloxacin
Hepatitis Fusobacterium
Bacteriodes Metronidazole
Skeletal Osteomyelitis Citrobacter
Eye Klebsiella Amikacin
Subspectacle Pseudomonas Ceftazidime
infections Neisseria Enrofloxacin
Uveitis Geotrichum
Conjunctivitis Fusarium Ketoconazole
Chrysosporium Itraconazole
Fluconazole
Pseudomonas aeruginosa
Pseudomonas maltophilia Amikacin
Providencia rettgeri Ceftazidime
Aeromonas hydrophila Ceftiofur
Morganella morganii Piperacillin
Enrofloxacin
Pseudomonas aeruginosa Marbofloxacin
Aeromonas hydrophila Azithromycin
Escherichia coli
Salmonella Trimethoprim/sulfadiazine
Ciprofloxacin
Pseudomonas aeruginosa Metronidazole
Morganella morganii
Providencia rettgeri Amikacin
Aeromonas hydrophila Ceftazidime
Escherichia coli Cefoperazone
Salmonella Enrofloxacin

Clostridium Metronidazole

Salmonella Amikacin
Escherichia coli Ceftazidime
Pseudomonas aeruginosa Piperacillin
Enrofloxacin
Pseudomonas aeruginosa Marbofloxacin
Providencia rettgeri
Proteus Ophthalmic gentamicin

Pseudomonas aeruginosa Amikacin
Serratia Ceftazadime
Klebsiella Piperacillin
Amikacin
Pseudomonas aeruginosa Enrofloxacin

Chapter 37. Antimicrobial Drug Use in Reptiles 629

space have been reported and are difficult to treat mas, or near the capsule of the chronic granulomas.
with topically applied antimicrobial agents that do not Granulomas can limit the penetration of many antimi-
appear to penetrate this barrier (Millichamp et al., crobial agents into the sites of infection. When possible,
1983). In treating reptiles with subspectacular infec- surgical removal of the granulomatous masses prior
tions, a wedge is carefully excised from the lower half of to  antimicrobial therapy can improve the chances of a
the spectacle and the appropriate antimicrobial drug positive therapeutic outcome.
applied directly through the wedge shape hole onto the
surface of the cornea. Physiological and husbandry factors can also influence
drug pharmacokinetics and therefore drug selection in
Most species of reptiles have a renal portal system reptiles. The ambient temperature of the reptile enclosure
that can shunt blood from the caudal half of the directly affects the pharmacokinetics of antimicrobials.
body through the kidneys before reaching the systemic Mader (1985) studied gopher snakes (Pituophis melano-
circulation. This blood flow pattern can potentially alter leucus catenifer) given amikacin and housed at ambient
the pharmacokinetics of drugs and is the basis for rec- temperatures of either 25°C or 37°C. When housed at
ommendations that intramuscular and subcutaneous 37°C, the apparent volume of distribution was larger and
injections be given in the cranial half of the reptile body. body clearance of amikacin was faster. In another study
However, few studies have tested this hypothesis. Holz of gopher tortoises (Gopherus polyphemus), the mean
(1997a) reported that in red-eared sliders (Trachemys residence time of amikacin was significantly shorter in
scripta elegans) the blood from the caudal region of the tortoises acclimated to 30°C than those kept at 20°C, and
body did not necessarily flow through the kidney via clearance at 30°C was approximately twice that in the
the renal portal system. Instead, the blood draining the tortoises kept at 20°C (Caligiuri et al., 1990). In contrast,
caudal portion of the body perfused both the liver and Johnson et al. (1997) found no significant pharmacoki-
the kidneys, indicating that the renal portal shunt was netic differences among the snakes given amikacin and
only partially functional. In a related study, Holz (1997b) housed at 25°C and 37°C. No explanation for this
also found that red-eared sliders receiving gentamicin discrepancy was offered, suggesting that the effect of
either in a forelimb or hind limb had no significant dif- temperature on drug pharmacokinetics is either species-
ferences in the pharmacokinetic parameters, indicating specific or requires further evaluation.
a minimal pharmacokinetic effect from the renal portal
system. In contrast, the same study noted that red-eared Behavioral and Safety Considerations
sliders receiving carbenicillin in the hind limb had
significantly lower blood concentrations for the first The size and temperament of a reptile can influence
12  hours post-injection than those that received the antimicrobial drug selection and the route of adminis-
same dose in a forelimb. Despite this finding for carben- tration. Some reptiles are extremely timid and nervous,
icillin, the authors concluded that this difference was not and may not be suitable for repeated handling and intra-
clinically important and questioned the necessity of muscular injections. In such cases the antimicrobial
forelimb injections (Holz et al., 1997b). Because, the must be administered orally, preferably in food if the
renal portal system varies in development, anatomy, and animal is still eating. Most species of reptiles weigh less
function between various groups of reptiles and the than 100 g and many lizards are under 30 g as adults. The
pharmacokinetic evidence is conflicting, many clini- clinician may be limited to those antimicrobials that can
cians still recommend injecting potentially nephrotoxic easily be diluted to a concentration that can be precisely
drugs and drugs eliminated primarily through the renal and safely injected. At the other end of the spectrum,
system in the cranial half of the body. some reptiles are quite large in size and dangerous to
approach. In such cases the clinician may have to choose
In contrast to mammalian pus, reptiles infected with a drug that can be administered in a relatively small
bacterial and mycotic pathogens tend to develop solid volume via remote injection dart or orally in food.
exudates within discrete granulomatous lesions (Montali, Venomous snakes present a similar treatment challenge,
1988, Jacobson, 2007). These pathogens are located since they are dangerous to handle and manipulate for
within the necrotic center of heterophilic granulomas,
within histiocytes (macrophages) in histiocytic granulo-

630 Section IV. Antimicrobial Drug Use in Selected Animal Species

administration of drugs. For these dangerous species medicating reptiles not feeding is often difficult. In giant
drugs that can be administered every few days are pre- tortoises, extracting the head beyond the shell margins
ferred over drugs that must be administered each day. and then forcing the mouth open is usually impossible.
Furthermore, these overzealous efforts to force the
Routes of Antimicrobial Administration mouth open can injure the keratinized epidermal hard
parts over the mandibles and dentary bones. In general,
The authors generally reserve the use of oral antimicro- giant tortoises must be anesthetized and a pharyngos-
bials to those cases where the primary infection is in the tomy tube inserted for oral medication. Pharyngostomy
gastrointestinal tract, the species is not tolerant of tubes are easy to insert and routinely used in tortoises
injections, the selected antimicrobial is only available in and other chelonians (Norton et al., 1989).
an oral formulation, or when safety considerations make
injections dangerous. An additional indication for oral As a generalization, non-venomous snakes are the
medication is when large numbers of reptiles are infected easiest group of reptiles to medicate orally. The mouth
and must be treated simultaneously. In these situations of most snakes is simple to open and the glottis is easy to
the individual administration of drugs is not practical see and avoid. In these snakes a lubricated French cath-
and the usage of medicated food may be warranted. eter or nasogastric tube is passed down the esophagus
with minimal resistance. Since the cranial esophagus
Several problems exist with oral medication of rep- is  extremely thin in most snake species, the end of
tiles. First, very few pharmacokinetic studies have been the  catheter should be round and smooth. The use of
performed on drugs administered orally to reptiles. excessively rigid catheters should be avoided as they
Thus, for the vast majority of antimicrobials the dose may penetrate the esophageal mucosa. While the stom-
selected will not be based on existing literature. ach of most snakes is located from one-third to half the
Secondly, the gastrointestinal transit time varies greatly distance from the head to the cloaca, it is not necessary
among the various reptile species. Transit time is usu- to pass a catheter this far. In most situations, passing the
ally slowest in the large herbivorous reptiles. For exam- catheter halfway between the stomach and oral cavity is
ple, the transit time in large tortoises may be as much as satisfactory.
21 days. Even in some carnivorous reptiles, the transit
time may be quite prolonged. Carnivorous reptiles, such Most of the injectable antimicrobials commonly
as pythons, are adapted to infrequent meals and increase used in reptiles are injected intramuscularly, subcuta-
their gastric and intestinal mucosa in response to feed- neously and occasionally intraceolomically. The problem
ing (Secor, 2008). This massive change in gastrointestinal with intravenous administration in reptiles is that
metabolism is likely to influence antimicrobial absorp- peripheral vessels are difficult to catheterize (Jacobson
tion and treatment frequency. Thus, in reptiles it may be et al., 1992a). While blood can be collected from a
difficult to achieve optimum and consistent therapeutic number of vascular sites in different species of reptiles,
concentrations of antimicrobials in blood following most of this sampling is “blind” and is not suitable for
oral administration. Martelli (2009) published a phar- repetitive intravenous infusions (Olson et al., 1975;
macokinetic study of enrofloxacin in estuarine croco- Samour et al., 1984).
diles (Crocodylus porosus) where delayed absorption
and subtherapeutic drug concentrations were measured The intramuscular and subcutaneous injections are
with the oral route. In contrast, repeated twice-weekly practical and provide the most predicable drug absorp-
oral doses of clarithromycin in desert tortoises tion. Snakes and lizards are the easiest reptiles to inject
(Gopherus agassizii) attained target drug concentrations intramuscularly because of the large epaxial dorsal mus-
(Wimsatt et al., 2008). Clearly, oral absorption in rep- cles of the body associated with the ribs and vertebrae.
tiles is species- and drug-specific and requires further In lizards, the forelimb muscle masses are usually small
investigation. limiting injection volumes. The best site for intramuscu-
lar injections in chelonians is the pectoralis musculature
While clinicians can often administer oral antimicro- located, medial and caudal to the base of the forelimbs
bials in the food of reptiles actively feeding, orally just within the cranial margins of the shell.

Despite the ease of intramuscular and subcutaneous
drug administration, the authors tend to avoid placing

Chapter 37. Antimicrobial Drug Use in Reptiles 631

Table 37.4. Conventional dosage regimens for antimicrobial drugs in reptiles.

Drugs Species Route of Dose Dose Interval References
Administration
96 h Jacobson, 1988
Amikacin American Alligator IM 2.25 mg/kg 48 h Caligiuri, 1990
Gopher Tortoise IM 5 mg/kg 1st loading dose; Mader, 1985
Azithromycin Snakes IM 5 mg/kg;
Carbenicillin thereafter 72 h Johnson, 1997
Ceftazidime Ball python IM 2.5 mg/kg No given Coke, 2003
Ceftiofur Ball python PO 3.5 mg/kg 2 to 7 days Lawrence, 1984a
Chloramphenicol Snakes IM 10 mg/kg 24 h Lawrence, 1986
Tortoises IM 400 mg/kg 48 h Lawrence, 1984b
Snakes IM 400 mg/kg 72 h Stamper, 1999
Loggerhead Sea Turtle IM; IV 20 mg/kg 72 h Adkesson, 2011
Snakes IM 20 mg/kg 120 h Clark, 1985
Snakes SQ 15 mg/kg 12–72 h depending
50 mg/kg Wimsatt, 1999
on species Wimsatt, 2008
Clarithromycin Desert Tortoise Oral 15 mg/kg 48–72 h Prezant, 1994
Enrofloxacin Oral gavage 15 mg/kg 84 h Raphael, 1994
Gopher Tortoise IM 5 mg/kg 24–48 h Jacobson, 2005
Fluconazole Star Tortoise IM 5 mg/kg 12–24 h James, 2003
Itraconazole Loggerhead Sea Turtle PO 20 mg/kg Not given
Ketoconazole Red-eared slider IM 5 mg/kg Not given Helmick, 2004
Marbofloxacin PO 10 mg/kg Not given Martelli, 2009
Metronidazole American Alligator IV 5 mg/kg 36 h Maxwell, 2007
Estuarine Crocodile PO, IM, IV 5 mg/kg Not given Young, 1997
Oxytetracycline Green Iguana IM 5 mg/kg 24 h Mallo, 2002
Piperacillin Burmese Python IM 10 mg/kg 48 h
Ticarcillin Loggerhead Sea Turtle SQ 21 mg/kg; 1st dose; Manire, 2003

Kemp’s Ridley Sea Turtle PO 10 mg/kg thereafter 5 days Gamble, 1997
15 mg/kg 72 h Page, 1991
Spiny Lizard PO 5 mg/kg 24 h Lai, 2009
Tortoise PO 23.5 mg/kg Daily Martin, 2009
Loggerhead Sea Turtle IM, IV 15–30 mg/kg 24 h Coke, 2006
PO 2 mg/kg 24 h Kolmstetter, 1998
Ball Python Not given Kolmstetter, 2001
Green Iguana PO 10 mg/kg 48 h Bodri, 2006
Yellow Rat Snake PO 20 mg/kg 48 h Innis, 2007
Red Rat Snake PO 20 mg/kg 48 h Helmick, 2004
Red-eared Slider Turtle IC 50 mg/kg 48 h Harms, 2004
American Alligator IV 20 mg/kg 48 h
Loggerhead Sea Turtle IM 10 mg/kg 5 days Hilf, 1991
41 mg/kg; 1st dose; Manire, 2005
Snakes IM
Loggerhead Sea Turtle IM 21 mg/kg thereafter 72 h
100 mg/kg 24 h
50 mg/kg 24 h
100 mg/kg 48 h

large volumes of irritating drugs such as enrofloxacin authors have also seen severe necrosis of pectoralis mus-
into reptile muscles. The authors have had several snakes culature in sea turtles injected with enrofloxacin. In one
develop necrotizing skin lesions following injection of case, a gopher tortoise that received an intramuscular
more than 1 ml of enrofloxacin at a single site. The injection of enrofloxacin in a forelimb eventually had to

632 Section IV. Antimicrobial Drug Use in Selected Animal Species

have the necrotic limb surgically amputated. Because of Despite the lack of pharmacokinetic studies, the cli-
this, the authors do not recommend enrofloxacin be nician must still select antimicrobials based on the best
administered by injection to reptiles. available evidence. Several reptile medicine textbooks,
formularies, and review articles provide extensive lists
Injectable drugs with a prolonged elimination are of antimicrobials recommended for reptiles (Funk and
potentially useful in reptiles that are difficult or dangerous Diethelm, 2006). These sources often include recom-
to handle. Adkesson (2011) reported that a long-acting mendations that have not been well evaluated for safety
formulation of ceftiofur maintained adequate plasma or efficacy, yet are commonly used empirically with
concentrations for 5 days in ball pythons (Python regius). apparent clinical success. An example is the trimetho-
However, in another study of subcutaneous cefovecin, a prim combinations that are commonly listed in
long-acting antibiotic used in dogs and cats, at a 14-day formularies for a wide variety of reptiles, but apparently
interval had an unexpectedly short half-life of only 3.9 lack pharmacokinetic studies in reptiles (Funk and
hours in green iguanas (Thuesen et al., 2009). Diethelm, 2006).

The use of intraceolomic injections to administer anti- Allometric Scaling to Estimate
microbials is infrequently used and rarely described in Drug Dosages
pharmacokinetic studies. Innis et al. (2007) studied the
pharmacokinetics of intraceolomic metronidazole in red- Clinicians faced with the lack of pharmacokinetic
eared sliders (Trachemys scripta elegans). The  potential studies and even the paucity of empirical dosage recom-
injury from inappropriately placed or an irritating drug in mendations are often forced to extrapolate drug dosages
the ceolomic space requires further investigation. from domestic mammals. In practice, clinicians use
three methods to estimate proper therapeutic drug dos-
Antimicrobial Drug Selection ages (Hunter and Isaza, 2008).

Ideally the clinician should select drugs for a reptile The first method is to use an established drug dose
based on published pharmacokinetic studies conducted derived from pharmacokinetic studies in other species.
on that particular species, or at least a closely related By this method, a 20 mg/kg dose of amoxicillin in dogs
species. Pharmacokinetic studies provide the clinician is applied across all reptile species regardless of size.
with a recommended drug dose and interval of drug Using a set dose results in a linear increase in the amount
administration that should provide therapeutic blood of drug administered as body weight increases. Although
concentrations necessary to treat the target pathogen. common, this method tends to overdose larger animals
Table 37.4 is a partial listing of published antimicrobial and underdose smaller animals.
pharmacokinetic studies in various reptile species.
The second method is similar to the first except that it
Of the 7,500 species of reptiles, pharmacokinetic takes the established dosage in a specific species and
studies have been reported for a few drugs in a small makes an additional assumption that links the dosage to
number of species commonly kept in captivity. As in the metabolic rates of both species. Using this method,
most scientific literature there is a publication bias the established drug dosage from one species is adjusted
toward reporting pharmacokinetic studies that lead to based on the ratio of the calculated metabolic rate of the
dosage recommendations, versus those that fail to patient over the calculated metabolic rate of the target
produce useful recommendations (Stamper et al., 2003; species,
Thuesen et al., 2009). Studies focused on the metabo-
lism, tissue concentrations, and potential toxicity of Patient Dose = Set dose(species X) * Pmet(patient) /
antimicrobials in reptiles are rare in the literature Pmet(species X)
(Hunter et al., 2003). This lack of pharmacokinetic
research is not surprising, in view of the relatively few This method, termed metabolic scaling, is popular in
researchers interested in pharmacokinetics of antimi- zoological medicine and described for use in reptiles
crobials in reptiles and the lack of research support (Pokras et al., 1992; Mayer et al., 2006). Unfortunately,
available for such studies.

Chapter 37. Antimicrobial Drug Use in Reptiles 633

this method of allometric scaling is controversial In the third method, the allometric scaling of measured
because formulas to estimate reptile metabolic rates are pharmacokinetic parameters is used for extrapolation of
inconsistent between reptile species. For many mam- drug doses between species. This method is commonly
mals the following allometric equation is considered the used in the pharmaceutical industry to extrapolate phar-
best estimate of the basal metabolic rate, macokinetic parameters between laboratory mammal
species to humans (Hunter and Isaza, 2008). Using known
Pmet = 70(Kg)0.75 pharmacokinetic parameters as the basis for extrapola-
tion has theoretical advantages over calculated metabolic
where Pmet is the minimum energy costs (Kleiber, rates. However, when Maxwell and Jacobson (2007)
1961). In contrast, a similar allometric equation compared the pharmacokinetics of enrofloxacin over a
wide range of green iguana sizes, they found that clearance
Pmet = 10(Kg)0.75 and other pharmacokinetic parameters did not scale
adequately allometrically. Thus this method of allometric
is suggested for use in all reptile species (Pokras et al., scaling using pharmacokinetic parameters also needs
1992; Mayer et al., 2006). However, when Jacobson further investigation in reptiles.
(1996) reviewed the subject, this single reptile equation
was not considered appropriate for all reptiles, since the Conclusion
constant varied from 1 to 5 for snakes and 6 to 10 for
lizards, with no values for chelonians or crocodilians The information and discussion contained in this chap-
available. Additionally, he noted significant data varia- ter provide initial suggestions for differential diagnosis
bility in those groups where scientific studies have been that should always be followed with attempts to obtain a
performed. For instance, Bartholomew and Tucker definitive diagnosis. This diagnostic process includes a
(1964) measured the metabolic rate in lizards ranging in culture and antimicrobial sensitivities for the isolated
size from 0.002 to 4.4 kg and calculated the allometric pathogens. Once an antimicrobial therapeutic plan is
equation to be Pmet = 6.84(Kg)0.62. This is different from selected, the clinician needs to consider the various
findings by Bennet and Dawson (1976) for 24 species of anatomical and practical aspects of antimicrobial usage
lizards, ranging from 0.01 to 7 kg, for which the in reptiles. Finally, the clinician needs to review the
equation available pharmacokinetic studies in reptiles and care-
fully consider the most appropriate antimicrobial drug
Pmet = 7.81(Kg)0.83 selection given the available evidence.

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half-life and dosage regimen of amikacin in the gopher eases of reptiles. In: Mader DR (ed). Reptile Medicine and
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loggerhead sea turtles (Caretta caretta) after single intrave- in iguanas (Cyclura cornuta and Iguana iguana) associated
nous and subcutaneous injections, and multiple subcuta- with a Neisseria species. J Zoo Anim Med 18:86.
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turtles, Lepidochelys kempi. J Zoo Wildl Med 34:171. Prezant RM, et al. 1994. Plasma concentrations and disposi-
Manire CA, et al. 2005. Pharmacokinetics of ticarcillin in the tion kinetics of enrofloxacin in gopher tortoises (Gopherus
loggerhead sea turtle (Caretta caretta) after single intrave- polyphemus). J Zoo Wildl Med 25:82.
nous and intramuscular injections. J Zoo Wildl Med 36:44. Raphael BL, et al. 1994. Pharmacokinetics of enrofloxacin
Martelli P, et al. 2009. Pharmacokinetics behavior of enro- after a single intramuscular injection in Indian star tor-
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Samour HJ, et al. 1984. Blood sampling techniques in rep- Stewart JS. 1990. Anaerobic bacterial infections in reptiles.
tiles. Vet Rec 114:472. J Zoo Wildl Med 21:180.

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Shotts EB, et al. 1972. Aeromonas induced death among fish Vaughn LK, et al. 1974. Fever in the lizard Dipsosaurus
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Wimsatt J, et al. 1999. Clarithromycin pharmacokinetics in
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Wimsatt J, et al. 2008. Long-term and per rectum disposition
Stamper MA, et al. 1999. Pharmacokinetics of ceftazidime in of clarithromycin in the desert tortoises (Gopherus agas-
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Young LA, et al. 1997. Disposition of enrofloxacin and its
Stamper MA, et al. 2003. Pharmacokinetics of florfenicol in metabolite ciprofloxacin after IM injection in juvenile
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nous and intramuscular injections. J Zoo Wildl Med 34:3. Med 28:71.

Antimicrobial Drug Use 38
in Zoological Animals

Ellen Wiedner and Robert P. Hunter

Although the scope and breadth of zoo and wildlife Antimicrobial Breakpoint Interpretation
medicine has grown enormously over the past 2 in Zoological Medicine
decades, a large number of challenges remain. At the
most basic level, when working with non-domestic Global events and perceptions regarding the use of
species, determining whether an animal is actually ill, antimicrobial agents in animals have placed even more
let alone affected with a potentially treatable infectious importance on the essential role of antimicrobial suscepti-
organism, can be remarkably difficult. Wild animals bility testing of bacterial isolates from animals (chapter 2).
conceal disease extremely well, and sometimes only However, little information is available on microorgan-
through necropsy will a clinician become aware ism/antimicrobial/host interactions with zoo species.
that  the animal had been harboring a long-standing
infection. Results of in vitro susceptibility tests are typically pre-
sented to the veterinarian by designating the pathogen as
If a diagnosis is made, determining what antimicro- susceptible, intermediate, or resistant. This designation
bials are appropriate becomes the next challenge. Pharma- is based on breakpoints established by the Clinical and
cological studies relevant to zoo and wildlife species Laboratory Standards Institute (CLSI). A breakpoint is
continue to be scant. This is due, in part, to the technical the concentration above and below which specific
difficulty of performing drug studies in wild animals, as bacterial isolates are categorized as susceptible, interme-
well as to the perceived risks to the subject species, many diate, or resistant to a given antimicrobial agent. Clinical
of which are rare or endangered. Unfortunately, without breakpoints take an antimicrobial’s minimum inhibitory
this data, the clinician is required to extrapolate drugs concentration (MIC) into consideration but are based
and doses from studies performed in domestic animals also on additional interpretive criteria, such as concen-
or even in humans, which creates a new set of trations of the drug that can be achieved in a given
problems. animal species (pharmacokinetics), the best presentation
of the drug to the bacteria in the host (pharmacodynam-
Finally, the technical aspects of providing a course of ics), and, when available, results of clinical trials in the
antimicrobial therapy to wild animals, most of whom target species that is the ultimate standard of efficacy.
are uncooperative and many of whom can be dangerous,
even if sick, provide a final level of complexity. All of Clinical breakpoints are species-specific and relevant
these issues are discussed below. only for the specific bacteria, specific drug, and specific

Antimicrobial Therapy in Veterinary Medicine, Fifth Edition. Edited by Steeve Giguère, John F. Prescott and Patricia M. Dowling.
© 2013 John Wiley & Sons, Inc. Published 2013 by John Wiley & Sons, Inc.

637

638 Section IV. Antimicrobial Drug Use in Selected Animal Species

body system infected only. An important limitation in information. Because of the monetary value of these
interpreting the results of in vitro susceptibility data is animals or their status as endangered species, the
that there are no breakpoints established specifically for method of “trial and error” for antimicrobial dosage
zoological species. For all antimicrobials, the results selection is inappropriate.
of  antimicrobial susceptibility testing from samples
obtained from zoo animals are reported based on In zoological medicine, various methods have been
breakpoints that have been established for people or used in an attempt to extrapolate or predict safe and
other domestic animal species. A result indicating sus- effective dosage regimens (Hunter and Isaza, 2008). The
ceptibility is unquestionably preferable to one indicating simplest and typical method of extrapolating a dosage to
resistance. However, there are no data correlating the a non-domestic species is to use a mg/kg dose estab-
results to clinical efficacy and there is no guarantee that lished for another domestic species or humans. However,
the breakpoint is valid for a given pathogen or site of this calculation results in a linear increase in the amount
infection in a given animal species. of drug administered as body weight increases. Although
common, this method tends to overdose large animals
Given the limited number of antimicrobial agents and underdose small animals. A second method is
approved for use in zoological animal species, “extra- similar, except that it takes the approved dose in a spe-
label” use of antimicrobial agents is typically practiced. cific species and makes an additional assumption that
The U.S. Congress, in the Animal Medicinal Drug Use links the dosage to a physiologic function or anatomic
Clarification Act (AMDUCA), has defined extra-label feature. Examples are the use of basal metabolic rate or
use as the “actual use or intended use of a drug in an body-surface area as the basis for dosage extrapolation.
animal in a manner that is not in accordance with the Allometric scaling of pharmacokinetic parameters is the
approved labeling.” This includes, but is not limited to: final method of dosage extrapolation between species.
use in species or for indications (disease or conditions) This is commonly used in the pharmaceutical industry
not listed in the labeling; use at a dosage level higher to establish the first dosage in human drug investiga-
than those stated in the label; and use of routes of tions. Adaptation of this method for zoological medicine
administration other than those stated in the labeling. is believed to enhance the ability to estimate therapeutic
This type of use has regulatory acceptance in many dosages for non-domestic species. However, relatively
countries (chapter 26). recent data (Hunter et al., 2008; Mahmood et al., 2006;
Martinez et al., 2006) question the practical use of this
Intra- and Interspecies Dose Extrapolation approach.

Species differences in drug absorption, distribution, Allometric scaling of pharmaceuticals to predict
metabolism, and excretion (ADME) for numerous pharmacokinetics in zoo/exotic animals has considera-
pharmaceutical agents have been well documented for ble benefit for zoological veterinarians. This tool, when
domestic species; however, there is limited information used appropriately, can provide an estimate for design-
concerning the ADME of drugs in non-domestic species ing dosage regimens. The example of differences in
(Hunter, 2009). Lack of approved pharmaceutical agents ketoprofen inversion across species emphasizes the
and/or pharmacokinetic data in the literature for zoo need to understand and be aware of the assumptions
species is a major issue for veterinarians attempting to when designing treatment regimens based on allomet-
treat these animals. Zoological medicine practitioners ric scaling data. Just as mammals can range from a few
take approved agents (veterinary or human) and extrap- grams to thousands of kilograms, reptiles and birds can
olate their use to non-approved species. The range of also vary in body weight across a wide range. It has been
animals a zoo veterinarian cares for varies from very suggested that it is impossible to derive a single equa-
small invertebrates (honeybees) to megavertebrates tion correlating body mass to metabolic rate for all 6,000
such as elephants and whales. The decision on dose, species of reptiles (Funk, 2000). Without knowledge as
duration, and treatment interval is often made with lim- to the extent and route of elimination of an adminis-
ited species-specific (pharmacokinetic and/or efficacy) tered pharmaceutical agent, extrapolation of dosage
regimens from one class to another is difficult, if not
impossible, with any certainty.

Chapter 38. Antimicrobial Drug Use in Zoological Animals 639

Before extrapolation of any drug dose, the veterinarian Table 38.1. Breakpoints for select antituberculous drugs
should appreciate not only the mathematical assump- used in elephants.
tions but also the limitations that are associated
with  allometry. Careful consideration of the available Breakpoint Concentration (μg/mL)
literature to understand the route of elimination and the
extent of metabolism of therapeutic agents will greatly Agent 7H10 agar 7H11 agar
assist in determining allometric relationships of phar-
macokinetic parameters. There is a continuing need to Isoniazid 0.2 0.2
consider and apply methods for reducing the size and Rifampin 1.0 1.0
risk of extrapolation error, as this can affect both target Ethambutol 5.0 7.5
animal safety and therapeutic response. Data from at 10 NR
least one large animal (non-human and a body Pyrazinamide NR NR
weight > 70 kg) should be included to reduce potential Levofloxacin 1.0 ND
error (Mahmood et al., 2006). Moxifloxacin 0.5 0.5
Ofloxacin 2.0 2.0
A Practical Example of Allometry Streptomycin 2.0 2.0
and Breakpoints 10 10

An example of how the above information can be inter- NR=not recommended; ND=not determined. Where multiple values are
preted and potentially misused is the case of provided, the second is when resistance has occurred and the drugs are
Mycobacterium tuberculosis susceptibility testing and used as “second-line therapies” (modified from M24-A2; CLSI, 2011).
the treatment of this bacterial disease in elephants
(Loxodonta africana and Elephas maximus). Unlike cat- There are published reports on the “population”
tle and other livestock, which are more apt to be infected pharmacokinetics of several antituberculous drugs in
with M. bovis and are euthanized if positive, in the African and/or Asian elephants that were used to
United States, elephants are recognized for their rarity develop the multidrug treatment protocols for elephants
and value and are treated rather than culled. Mandatory published in the USDA elephant TB guidelines and were
testing and treatment of elephants with TB is overseen modeled after the disease in people (Peloquin et al.,
by the U.S. Department of Agriculture (USDA), and 2006). The issues with these types of extrapolation have
guidelines for drug administration in pachyderms have been previously discussed (Hunter and Isaza, 2008).
been derived from those established for humans Using the human breakpoints for isoniazid established
(USDA, 2008). Susceptibility testing for this pathogen is by the CLSI and the plasma concentrations reported
described in detail, for human isolates, in the CLSI by  Maslow et al. (2005) one could conclude that the
M24-A2 document. The results of in vitro susceptibility likelihood for efficacy is high with all reported con-
testing of these agents appear to correlate well with the centrations > 0.2 μg/mL for the doses and routes of
clinical effectiveness of these agents in human patients. administration evaluated, but many concentrations
The interpretive criteria, or breakpoints, are provided were greater than 5 times, which seems excessive and
in Table 38.1. could be contributing to the adverse events reported by
some clinicians. Maslow et al. (2005) suggest that area
In elephant, the pharmacodynamics and pharma- under the curve (AUC) may be the driving pharmaco-
cokinetics of antituberculous drugs differ considerably dynamic parameter, which is not surprising given the
compared to people. In addition, the metabolic state of slow growth of the target pathogen, but the target PK/
Mycobacterium tuberculosis significantly affects its PD relationship is currently unknown in elephants, and
susceptibility to antimicrobials. Optimization of dosage is very likely to be different than that reported for
of antituberculous drugs is necessary to achieve maxi- humans. This idea is further supported when the fluoro-
mum drug exposure at the site of infection in order to quinolones are evaluated. While in human medicine an
maximize reduction in M. tuberculosis viable organisms AUC/MIC ratio of ≥ 125 for fluoroquinolones has been
and to minimize the emergence and selection of resist- shown to eradicate a particular bacterial disease, this
ance (de Steenwinkel et al., 2010). ratio cannot be directly extrapolated across species,
indication, or pathogen, nor has it been determined for

640 Section IV. Antimicrobial Drug Use in Selected Animal Species

antituberculous drugs. The effective AUC:MIC ratio has such as a meatball for a carnivore or a watermelon for an
been reported to be different between species (Aliabadi elephant. Non-human primates are often more willing
et al., 2003). Opinions also differ within the human to take medication if it is mixed with sweet substances
literature, where some report that a ratio > 25 is best, such as jams or juices. Compounding pharmacies that
while others state that the ratio must be greater than 350 make flavored medications for children can be helpful in
(Barger et al., 2003). This is complicated by the fact that developing mixtures that are appealing to captive
for the fluoroquinolone ciprofloxacin, 100% of success- primates who require oral medication
fully treated patients had an AUC:MIC ratio > 3.6
(Barger et al., 2003). It should be remembered that the in It is unknown whether drug bioavailability is affected
vivo antimicrobial effect is the result of dynamic expo- by its concealment in food. Another issue is that
sure of the pathogen to the antimicrobial and the host zoo  animals often become very adept at identifying
immune system. The comments and issues raised here “doctored” food items, and will pick carefully around
also apply to rifampin (Peloquin et al., 2006) and etham- drugs hidden in grain balls, meat balls, and similar, leav-
butol (Maslow et al., 2005). ing the medication untouched. Thus, it is important for
the animals’ caretakers to observe ingestion of the
Unfortunately, numerous serious adverse effects have medication.
occurred in the majority of elephants undergoing
treatment. In many cases, these were severe enough that Pachyderms can be trained to accept oral medications
treatment needed to be discontinued, at least temporarily. using a bite block. Even using this device, however, ele-
Reported adverse effects include anorexia, depression, phants often learn to hide medications within their mas-
diarrhea, kidney and liver insults, blepharospasm, and sive mouths for hours, only to spit them out hours later
death. The high incidence of severe adverse effects sug- when they are unobserved (Isaza and Hunter, 2004).
gests that the doses of drugs required to achieve serum
levels comparable to those targeted in people, may, in Injectable Administration
fact, be toxic to elephants (Wiedner and Schmitt, 2007).
Most injectable antimicrobials are given via the intra-
Techniques of Administration muscular route in zoo and wildlife species. Although
under anesthesia, both the intravenous or subcutaneous
Administration of medications to zoo and wildlife routes are possible for a single dose, anesthetizing a sick
species can be made considerably easier by training the animal repeatedly for the purpose of administering a
animals to accept them. Such training has increasingly course of antimicrobials is generally not desirable. In
become part of the general animal care routine at many some situations, an intraosseous (IO) or intravenous
zoological institutions. A remarkable variety of species (IV) catheter can be placed. Reptiles, birds and severely
have been taught to tolerate injections, swallow tablets, debilitated animals that will be housed in a hospital
and accept various other forms of drug administration. environment are best suited for this. In determining
Such training requires a significant time commitment whether a particular patient is an appropriate candidate
both for teaching the behaviors as well as for ongoing for an indwelling catheter, the clinician should assess
practice to maintain them, using placebos when the the  ease of maintaining patency and cleanliness of the
animal is healthy. catheter, and the likelihood of the animal’s removing it.
If these are concerns, a catheter is generally not suitable.
Oral Administration In several groups of animals, anatomical and/or living
situations make indwelling catheters inappropriate or
Oral medication can be hidden in feed. Generally, this extremely difficult. These include very small animals,
requires that the patient be physically separated from its such as songbirds, animals with extremely thick skins
social group for feeding. For some species, such as large such as hippos and aquatic animals that cannot be
carnivores, this is routine. For others, separation from dry-docked.
conspecifics can cause stress. Typically, the medication
is hidden in something the animal particularly enjoys In some situations, intramuscular injections can be
given via hand injection into animals trained to present
body parts against the pen, chute, or cage bars (flank or
thigh muscles for large carnivores; neck for hoofstock;

Chapter 38. Antimicrobial Drug Use in Zoological Animals 641

limbs, back, or flat palms of hands or feet for primates). reasons, the largest animal will receive a subtherapeutic
A squeeze cage can be used for uncooperative animals, dose. In addition, the social behavior of the animals to
although ideally the animal should have received be medicated must be noted. In hierarchical species
some  training to enter the squeeze. In some species, such as wild equids and some ruminants, higher ranked
manual  restraint by experienced personnel is possible. animals will have increased access to any feed materials
Repeatedly restraining the animal, however, can be dan- and will eat considerably more than those lower in rank.
gerous and stressful to both handler and animal, and is This, of course, means that these animals will also ingest
not recommended for long courses of antimicrobial larger amounts of medication than those lower in rank.
treatment. Mass medication of zoo megavertebrates in feed and
water is not done commonly, and there are scant reports
For untrained or uncooperative patients, intramuscu- of this technique.
lar drugs can be administered using remote delivery
techniques, that is, darting equipment. While a discus- Specific Examples of Antimicrobial Use
sion of darting techniques is beyond the scope of this in Zoo and Wildlife Species
chapter, any veterinarian planning to work with wildlife
and zoological species should have an understanding of Prophylactic antibiotic treatment against pneumonia in
darting equipment and techniques, and its risks, which groups of free-ranging bighorn sheep (Ovis canadensis;
include stress to the animal, accidental bone fractures or Weiser et al., 2009) as well as reindeer (Rangifer tarandus;
penetration of internal organs and equipment failure, Pietsch et al., 1999) continues to be used in the manage-
that is, the dart fails to inject its contents either partially ment of these animals in North America. Following
or entirely into the animal. The use of long-lasting depot capture by various methods, the animals are physically
formulations can decrease the frequency that the animal examined, then hand-injected with oxytetracycline or
needs to be darted. florfenicol prior to release or translocation. The goal of
these one-time antibiotic injections is to decrease the
Other Routes of Administration likelihood of stress-induced respiratory disease; how-
ever, it has been difficult to confirm the efficacy of this
Great apes with air sacculitis have been successfully approach.
trained to tolerate routine nebulization with antibiotics
(Gresswell and Goodman, 2011). Rectal administration Tetracycline baits represent another use of antimicro-
of certain antimicrobials has been used successfully in bials in wildlife species. When ingested, tetracycline is
elephants. Antibiotic impregnated beads, placed under incorporated into bones and teeth. Under ultraviolet
anesthesia, have been used in the treatment of mandib- light, the teeth fluoresce. The drug can also be detected
ular osteomyelitis in tammar wallabies (Macropus euge- in histological sections from tooth and bone in necropsy
nii; Hartley and Sanderson, 2003). The use of an specimens. Tetracycline baits have been used for mark-
osmotic pump was tested for amikacin delivery in a capture population studies of American black bear
corn snake (Elaphe guttata; Sykes et al., 2006). Although (Ursus americanus: Peacock et al., 2011), polar bears
complications, such as migration of the pump, were (Ursus arctos; Taylor and Lee, 1994), and feral swine
noted with this technique, it eliminated repeated (Reidy et al., 2011), as well as for determining the use of
handling of an animal needing medication and its use supplemental feed in herds of white-tailed deer
warrants further investigation. (Odocoileus virginianus; Bastoskewitz et al., 2003).

Treating Groups of Animals Tetracycline is also a component of oral rabies vaccines
that are scattered as baits in areas inhabited by vector spe-
Medicating herds or flocks of animals requires special cies such as raccoons (Procyon lotor) and skunks (Mephitis
consideration. If the animals are to be medicated in feed mephitis). To determine with what frequency the vac-
and water, a total dosage of medication for all animals cines are being ingested by target species, the animals are
needs to be calculated, but if the individual dose is based captured a period of time after the vaccine baits are
on the size of the smallest animal in the group for safety distributed. Under anesthesia, a tooth is removed and

642 Section IV. Antimicrobial Drug Use in Selected Animal Species

analyzed for evidence of tetracycline deposition to (Aegypius monachus) and Egyptian vultures, Neophron
provide an estimate of the performance of the baits and percnopterus, avian scavengers that feed on carcasses.
thus of vaccine efficacy (Fehlner-Gardiner et al., 2012). Affected nestlings showed liver and kidney damage as well
as compromised immune systems that could be directly
An interesting area of antimicrobial research involves correlated with the antibiotic residues (Blanco et al., 2009).
wildlife species that actually produce their own antimicro- In another study, it was demonstrated that fluoroquinolo-
bial substances. The Nile hippopotamus (Hippopotamus nes that could be tracked back to livestock operations were
amphibious) releases a red sweat from its skin that has causing embryonic death in the eggs of griffon vultures
been found to have antimicrobial properties. At low con- and red kites (Milvus milvus; Lemus et al., 2009).
centrations (lower than those actually occurring on the
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Antimicrobial Drug Use in Aquaculture 39

Renate Reimschuessel, Ron A. Miller, and Charles M. Gieseker

As aquaculture has become a more prominent source of ture. A number of textbooks that include formularies for
food fish, use of therapeutics, especially antimicrobials, doses and treatment regimens for fish have been pub-
to treat these animals has increased, especially as fish lished (Stoskopf, 1993; Noga, 1996; Carpenter, 2005). In
farming has become more intensive. Because of this, pub- addition, an extensive review of literature pertaining to
lic health agencies have raised concerns worldwide about fish pharmacokinetics (Phish-Pharm) has been published
the impact of antimicrobial use in aquaculture on envi- as a database, available free in a web-based journal and
ronmental bacteria and, potentially, on human pathogens an on line resource (Reimschuessel et al., 2005, 2011).
(Serrano, 2005; Weir et al., 2012). Nevertheless, fish are The information in these texts and in the database is,
vertebrates that should receive humane care, including however, skewed toward the species and drugs that are
treatment with antimicrobials when appropriate. Ideally, most commonly used. What is still largely missing is
before an antimicrobial is appropriately prescribed as information on the many exotic and ornamental fish
treatment the following factors should be considered: fish species, as well as the “niche” food-fish species.
physiology; information regarding the pharmacokinetics of
the antimicrobial in fish; the availability of an antimicrobial Treating fish with antimicrobials is somewhat more
as an approved drug for use in fish (Food and Drug complex than treating terrestrial animals, but the basic
Administration [FDA], 2005; American Fisheries Society, principles for antimicrobial use are really the same
2011) and in vitro antimicrobial susceptibility testing (chapter 6). Five main aspects must be considered:
to provide information on the likelihood of therapeutic (1)  choice of an appropriate drug at an effective dose;
success (Clinical and Laboratory Standards Institute [CLSI], (2) avoidance of toxicity in the animal; (3) the safety of
2006a, 2006b, 2010). In many cases, the practitioner must humans administering the antimicrobial or consuming
often interpret test results generated by a laboratory that has the fish; (4) avoidance of non-target species and envi-
no standardized testing protocol as a reference, and then ronmental effects; and (5) legal restrictions.
must prescribe a drug (either labeled or as an extra-label
prescription) for which there is little or no literature detail- Choosing the Appropriate Drug
ing pharmacokinetic data in the fish species being treated.
The Pathogen
Over the last decade, however, researchers and fish
health practitioners worldwide have made considerable Picking an effective drug requires that the clinician
progress toward obtaining and making available make an accurate diagnosis (chapter 6). A definitive
information about therapeutic treatments in aquacul- diagnosis requires isolation and identification of the

Antimicrobial Therapy in Veterinary Medicine, Fifth Edition. Edited by Steeve Giguère, John F. Prescott and Patricia M. Dowling.
© This chapter is public domain. Published 2013 by John Wiley & Sons, Inc.

645

646 Section IV. Antimicrobial Drug Use in Selected Animal Species

causative organism, preferably from three to five infected Table 39.1. Frequently isolated bacterial pathogens of fish.
fish (Hawke and Thune, 1992; Office International des
Epizooties, 2003; American Fisheries Society, 2005). A Bacterial Pathogen Disease
list of some of the more frequently isolated aquatic
bacterial pathogens from diseased fish is provided in Aeromonas caviae Motile aeromonad septicemia
Table 39.1. In aquaculture, especially in intensive rear- Aeromonas hydrophila
ing facilities, timely institution of treatment is often Aeromonas sobria Furunculosis, ulcer disease, carp
critical. Therefore, many practitioners rely on clinical Aeromonas salmonicida erythrodermatitis
signs and past experience when faced with a population
of moribund fish. It is, however, prudent to take multi- Aerococcus viridans Gaffkemia
ple samples for culture prior to administering the anti- Edwardsiella ictaluri Enteric septicemia of catfish
biotic empirically. This allows confirmation later that the Edwardsiella tarda Red pest disease, Edwardsiella
appropriate drug was used or, if necessary, subsequent
change of the treatment based on the organism isolated Flavobacterium branchiophilum septicemia
and its antimicrobial susceptibility profile. Since antimi- Flavobacterium columnare Bacterial gill disease
crobial susceptibility changes with antibiotic use, it is Flavobacterium psychrophilum Columnaris disease
important for the veterinarian to monitor the isolates Cold-water disease, rainbow
from their aquaculture clients so that future outbreaks Francisella spp.
are not treated empirically with the incorrect drug. Lactococcus garvieae trout fry syndrome
Francisellosis
Evaluating the antimicrobial susceptibility of aquatic Lactococcus piscium Lactococcosis, Lactococcus
bacterial isolates has been problematic prior to 2006, Moritella viscosa
since there were no standardized methods for testing Mycobacterium spp. septicemia
organisms that grow at lower temperatures. CLSI Photobacterium damselae
published guidelines (2006a, 2006b, 2010) for testing Winter ulcer disease
aquatic bacteria at different temperatures. Specific subsp. damselae Mycobacteriosis
methods that should be used for testing aquatic bacteria Photobacterium damselae Vibriosis
may be found in these documents, along with clinical
breakpoints and epidemiological cut-off values. It is subsp. piscicida Photobacteriosis, fish
essential that these standardized methods be used to pasteurellosis,
ensure reliable results and allow comparisons between Piscirickettsia salmonis pseudotuberculosis
laboratories (chapter 2).
Plesiomonas shigelloides Piscirickettsiosis, salmonid
The Host Pseudomonas spp. piscirickettsial septicemia
Pseudomonas anguilliseptica
Choosing the correct drug depends in part on such fac- Renibacterium salmoninarum Winter disease
tors as age, size, and housing of the animal. Treatment Streptococcus agalactiae Pseudomoniasis
options will be different for animals that are held in net Streptococcus dysgalactiae Red spot disease
pens at sea, as opposed to those held in an indoor facility Streptococcus iniae Bacterial kidney disease
or aquarium. A treatment must also be feasible. An Streptococcus phocae Group B streptococcosis
appropriate treatment route for aquarium fish or Tenacibaculum maritimum Group C streptococcosis
selected brood-stock individuals may be cost- or labor- Streptococcosis
prohibitive in commercial aquaculture. The stress asso- Vagococcus salmoninarum Warm-water streptococcosis
ciated with treatments must be balanced with the need Vibrio salmonicida Salt-water columnaris, marine
for and expected benefits of treatment.
Vibrio spp. flexibacteriosis
Drug dosage regimens also are host-dependent. Fish Yersinia ruckeri Cold-water streptococcosis
species reared in warm water may absorb, metabolize Cold-water vibriosis, Hitra
and excrete drugs at a different rate (often faster) than
those in cold water. The salinity of the holding water disease
Vibriosis
Enteric redmouth disease

Reprinted with permission from the Clinical and Laboratory Standards
Institute.

also affects drug kinetics. Fish kept in saltwater drink
the water whereas freshwater fish do not. Thus, antimi-
crobials in the gastrointestinal tract of fish species held
in saltwater may bind cations that can reduce their

Chapter 39. Antimicrobial Drug Use in Aquaculture 647

uptake. This is especially true for antimicrobials, such as The  half-lives listed in the Phish-Pharm database
the tetracyclines, that have low bioavailability even in (Reimschuessel et al., 2005, 2011) may help with such
freshwater fish (Elema et al., 1996). Uptake of oral decisions. Temperature as a variable in pharmacokinet-
difloxacin by Atlantic salmon is ten-fold less in saltwater ics has been reported for a number of drugs. For
than freshwater (100 vs. 1000 ng/ml in plasma; Elston example, Bowser et  al. (1992) examined the half-life of
et al., 1994). The elimination rate of oxolinic acid (oral enrofloxacin in rainbow trout at 10 and at 15°C. The half-
or injected) is also faster in rainbow trout held in saltwa- life at 10°C was 30 hours, whereas at 15°C the half-life
ter than freshwater (Ishida, 1992). It is therefore impor- was 56 hours. In a study of flumequine in rainbow trout,
tant to obtain information on the pharmacokinetic however, researchers found that half-lives decreased
parameters of the drugs in the host species. This is, of with rising temperature: 3°C—569 hours, 7°C—300
course, easier said than done. An extensive review of the hours, and 13°C—137 hours (Sohlberg et al., 1990, 1994).
literature has been incorporated into the Phish-Pharm Bjorklund and Bylund (1991) found longer half-lives at
database (Reimschuessel et al., 2005, 2011), which 5 and 10 than at 16°C in rainbow trout fed oxytetracycline,
makes much of the published data rapidly searchable. whereas Chen et al. (2004) found minimal differences in a
However, even with such a tool, there are many species number of fish species held at different temperatures.
and drugs for which there are no published studies. The There is considerable pharmacokinetic data in the Phish-
veterinarian is thus often in the position of making a Pharm database, and Table 39.3 summarizes half-life
best guess based on data from other species held, hope- ranges of antimicrobial drugs in different fish species that
fully, under similar conditions. Half-lives of drugs in have been extracted from the database.
fish are highly dependent on the dosage regimen, the
route, and temperature. Therefore, these parameters are The Treatment Route
included in the Phish-Pharm database and should be
considered when administering antimicrobials to fish. Waterborne Treatments
Waterborne antimicrobial treatments will vary depend-
The Dosage ing on the animal and holding conditions. Treating fish
by applying the drug to the water avoids stressing the
Table 39.2 shows drug dosages that have been reported fish by handling. Three main methods are employed: (1)
for fish. These dosages are compiled from a number of baths (and dips), in which the drug is added to a holding
formularies (Stoskopf, 1993; Noga, 1996; Carpenter, system; (2) flushes, used in flow-through systems, add-
2005) and research reports. It is important to realize that ing the entire dose in a short period (1–2 minutes) then
the dosages listed in Table  39.2 may not have been allowing the system to flow, thereby diluting the dose;
shown to be safe or effective in all fish species. The table and (3) constant flow, also used in flow-through systems
also lists the interval that was reported in the original by continuously pumping in a stock solution with a
citation, but it is important to remember that successful chemical dosimeter.
therapy often depends on maintaining adequate blood
levels over a course of 7–10 days. In some cases, only the The disadvantages of waterborne treatments include
dose used for experimental purposes is listed. It is advis- expense, waste, and potential environmental contamina-
able to consider the half-life of the drug in that species tion. Biological filters may also be compromised due to
when determining the length and frequency of treat- killing the filter bacteria. A rapid rise in ammonia has
ments. In a few species (the aglomerular fish in particu- been seen using therapeutic concentrations of erythro-
lar), half-lives of drugs excreted by the kidney are quite mycin in a catfish recirculating system, but chloram-
prolonged (Jones et al., 1997) and must be considered phenicol, nifurpirinol, oxytetracycline, and sulfamerazine
when treating these animals. did not affect the filter function (Treves-Brown, 2000).

Temperature is a very important factor in deciding It is also important to consider the ability of a drug to
the dose and treatment intervals. Knowledge of drug be absorbed from the water. Lipophilic compounds
half-lives calculated from exposures at different under a molecular weight of 100 will be more likely to
temperatures can help the clinician choose intervals diffuse across the gills. Antimicrobials that are absorbed
that  will maximize chances for successful therapy. from the water include chloramines, dihydrostreptomy-
cin, enrofloxacin, erythromycin, flumequine, furpyrinol,

Table 39.2. Antimicrobial dosages used in fish.

Drug Dosage Interval Route Comments
Amikacin
Amoxicillin 5 mg/kg q 12 h IM Rarely used due to few Gram-positive pathogens
Ampicillin 5 mg/kg q 72 h × 3 IM
25 mg/kg q 12 h PO Sharks
Aztreonam 40–80 mg/kg q 24 h 10 d PO Sharks
Azithromycin 10 mg/kg q 24 h IM
Ceftazidime 10 mg/kg q 12 h 7–10 d PO Used by koi hobbyists
Cefquinome 50–80 mg/kg q 24 h 10 d PO
Chloramine-T 100 mg/kg q 24 h 7d IM/IP Dose used for determining PK
30 mg/kg q 24 h 14 d PO
Ciprofloxacin 22 mg/kg q 72–96 h × 3–5 IM/IP Disinfectant control bacterial gill disease and parasites
Difloxacin 5–20 mg/kg single dose IP
Dihydrostreptomycin 20 mg/L 1h 4 d BATH Dose used for determining PKa
2.5–20 mg/L flush (various) BATH Dose used for determining PKa
Enrofloxacin 5–10 mg/L 1h BATH Dose used for determining PK
15 mg/kg single dose IM/IV Dose used for determining PK
Erythromycin 10 mg/kg single dose PO Sharks
0.125 mg single dose IM/IV
Florfenicol 10 mg single dose PO a
10 mg/kg q 24 h IM
Flumequine 2.5–5.0 mg/L 5 h q 24 h 5–7 d BATH a
30–50 mg/L 4–24 h (various) BATH
Fumagillin 5–50 mg/kg q 24 h × 5–10 d PO Dose used for determining PK
Furpyrinol 2.5–10 mg/kg single dose IM/IP/IV For BKD before spawning
Gentamicin 10–20 mg/kg single dose IP
Kanamycin 50–100 mg/kg q 24 h 10–21 d PO For BKD in eggs
2 mg/L 1h BATH Salmon
5–20 mg/kg q 24 h 10 d PO Dose approved by U.S. FDA for select species
10–15 mg/kg q 24 h 10 d PO Red pacu
40–50 mg/kg q 12–24 h PO, IM, IP
25–50 mg/kg single dose IM Increase dose in saltwatera
10–500 mg/L 1–72 h BATH
5–50 mg/kg q 24 h 5–10 d PO a
30 mg/kg single dose IM/IP
2–25 mg/kg single dose IV IP (and IM) dose levels remain at effective levels for 10da
30–60 mg/kg single dose PO Dose used for determining PK
3–6 mg/kg single dose IV Dose used for determining PK
4–32 mg/L 5h BATH Dose used for determining PK
3 mg/kg q 72 h IM
6 mg/kg each week IM Very nephrotoxic to aglomerular fish. Bath exposure does not achieve blood levels
50–100 mg/L q 72 h 5 h × 3 BATH Sharks
Nephrotoxic some species. Change water 50% between treatments

Lincomycin 50 mg/kg q 24 h PO Nephrotoxic some species
Marbofloxacin 10–20 mg/kg q 24 h PO Sharks
Miloxacin 20 mg/kg q 72 h × 5 IP Nephrotoxic some species
Nalidixic acid 40 mg/kg q 24 h PO Japan
10 mg/kg q 24 h 1–3 d PO Dose used for determining PK
60 mg/kg q 24 h 6 d PO Japan
13 mg/L 1–4 h BATH
20 mg/kg q 24 h PO, IM, IV Other doses used for PK studies

Neomycin 66 mg/L q 3 d×3 BATH Toxic to nitrifying bacteria in filter
Norfloxacin 20 mg/kg single dose PO Sharks to prevent bloat, poorly absorbed from gut
Oxolinic acid 30–50 mg/kg q 24 h 5 d PO
25 mg/L 0.25 h q 12 h × 3 BATH Dose used for determining PK
Oxytetracycline 0.15–1.5 mg/L 10 d BATH Freshwater species
50–200 mg/L 1–72 h BATH Saltwater species
Piromidic acid 5–25 nf.j single dose IV For superficial infections
Sarafloxacin 10 mg/kg q 24 h 10 d PO Change 50–75% water between treatments
Sulfadiazine-Trimethoprim 25–75 mg/kg q 24 h 10 d PO Dose approved by U.S. FDA for select species
Sulfadimethoxine-Ormetoprim 10–50 mg/L 1h BATH Produces high levels for several days when given IM
Sulfamerazine 20–50 mg/L 5–24 h q 24 h 5–6 d BATH Red pacu
Sulfamethoxazole- 55–83 mg/kg q 24 h 10 d PO Japan
25–50 mg/kg q 24 h 5–7 d IM/IP
Trimethoprim 3 mg/kg q 24 h IV a
Tetracycline 10 mg/kg q 24 h 5–10 d PO
Thiamphenicol 10–30 mg/kg q 24 h 10 d PO Dose approved by U.S. FDA for select species
Vetoquinol 30–50 mg/kg q 24 h 7–10 d PO
Virginiamycin 125 mg/kg IP Change 50–75% water between treatments
50 mg/kg q 24 h 5d PO
220 mg/kg q 24 h 14 d PO Japan
200 mg/kg q 24 h 10 d PO
20 mg/L 5–12 h q 24 h 5–7 d BATH

30 mg/kg q 24 h 10–14 d PO
80 mg/kg single dose PO
20 mg/L 1h BATH
50 mg/kg q 24 h 7–10 d PO
25–40 mg/kg single dose PO
40 mg/kg q 24 h 15 d PO

aExtra-label use of fluoroquinolones in food animals is prohibited by the U.S. FDA.
Data obtained from many authors.

Table 39.3. Half-lives of antibiotics in fish.

Drug Species t1/2-hr Dosage Route °C

Amoxicillin Atlantic salmon 120 12.5 mg/kg sd* IM 13
Chloramphenicol Atlantic salmon, Seabream 14–72 40–80 mg/kg sd IV/PO 16–22
Ciprofloxacin Carp 48–72 40 mg/kg sd IP 9
Difloxacin Carp, Rainbow trout, African catfish 11–15 15 mg/kg sd IM/IV 12–25
Enrofloxacin Atlantic salmon 16 10 mg/kg sd PO 11
Erythromycin Carp 58, 114 20 mg/kg 3 d PO 10, 20
Florfenicol Atlantic salmon, Rainbow trout, Brown trout, Sea bass 25–105 5–10 mg/kg sd IM/IV/PO 10–15
Carp, Red pacu, Seabream 16–26 5–10 mg/kg sd IM/IV/PO 25–28
Flumequine Chinook salmon 120 0.1 g/kg 21 d PO 10
Carp, Gourami, Tilapia 4–16 10–50 mg/kg sd IM/PO 22–24
Furazolidone Atlantic salmon 12–30 10 mg/kg sd IV/PO 10–11
Gentamicin Cod 39–43 10 mg/kg sd IV/PO 8
Miloxacin Eel 255 9 mg/kg sd IM 23
Nalidixic acid Atlantic halibut, Brown trout, Corkwing wrasse, Atlantic halibut, Atlantic 21–96 5–25 mg/kg sd IP/IV/PO 5–25
Nifurstyrenate
Norfloxacin salmon, Cod, Goldsinny wrasse, Sea bass, Seabream, Turbot 208–314 10 mg/kg sd IV/PO 23
Ormetoprim Eel 285–736 5 mg/kg sd IV/PO 13 vs 3
Oxolinic acid Rainbow trout 1–24 1 mg/kg sd IV/PO 24
Channel catfish 12–54 1–3.5 mg/kg sd IC/IM 20–25
Oxytetracycline Channel catfish, Brown shark, goldfish 602 3.5 mg/kg sd IM 19
Toadfish 35 30–60 mg/kg sd IV/PO 27
Eel 21–46 5–40 mg/kg sd IV/PO 14–15
Rainbow trout, Amago salmon 2 100 mg/kg sd PO 23
Yellowtail 97–192 30–50 mg/kg 5d PO
Halibut, Japanese Seabass, Seabream 4–25 4–50 mg/kg sd IV/PO 10–28
Atlantic salmon, Channel catfish, Rainbow trout, Hyb. Striped bass 15–87 4–20 mg/kg sd IP/IV 8–24
Atlantic salmon, Corkwing wrasse, Channel catfish, Cod, Rainbow trout,
82–146 25–75 mg/kg sd PO 5–8
Red seabream, Sea bass 13–48 10–40 mg/kg up to 10 d PO 9–19
Atlantic salmon, Cod, Rainbow trout
Atlantic salmon, Gilthead seabream, Rainbow trout, Sharpsn. Seabream, 63–95 5–60 mg/kg sd IM 12–25
6–167 5–60 mg/kg sd IV 8–25
Turbot
African catfish, Carp, Rainbow trout, Red pacu, Sockeye salmon
African catfish, Atlantic salmon, Ayu, Carp, Chinook salmon, Eel, Rainbow

trout, Red pacu, Sea bass, Seabream, Sharpsnout seabream

Arctic charr 266–327 10–20 mg/kg sd IV 6
Atlantic salmon, Ayu, Black seabream, Carp, Channel catfish, Eel, Perch, 43–268 10–100 mg/kg up to 10d PO 7–27

Piromidic acid Rainbow trout, Sea bass, Seabream, Hyb. Striped bass, Summer flounder, 428–578 10–100 mg/kg sd PO 6–11
Sarafloxacin Tilapia, Walleye 24 5 mg/kg sd PO 26
Streptozotocin Arctic charr, Sockeye salmon, Chinook salmon 12–45 10–15 mg/kg sd IV/PO 8–24
Sulfachlorpyridazine Eel, Goldfish 24 50 uCi IV
Sulfadiazine Atlantic salmon, Cod, Eel 4–5 60 mg/kg sd IC/PO 22
Sulfadimethoxine Toadfish 26–96 25–200 mg/kg sd IV/PO 8–24
Sulfadimidine Channel catfish 7–48 25–200 mg/kg sd IV/PO 10–27
Sulfamethoxypyridazine Atlantic salmon, Carp, Rainbow trout 18–57 100–200 mg/kg sd IV/PO 10–20
Sulfamonomethoxine Atlantic salmon, Channel catfish, Rainbow Trout, Hyb. Striped bass 72 200 mg/kg sd PO 13
Sulfanilamide Carp, Rainbow trout 5–33 100–400 mg/kg sd IV/PO 15–22
Sulfathiazole Rainbow trout 36 200 mg/kg sd PO 13
Tetracycline Rainbow trout, Yellowtail 60 200 mg/kg sd PO 13
Thiamphenicol Rainbow trout 17, 44 4, 80 mg/kg sd IV/PO 27
Tobramycin Rainbow trout 21 30 mg/kg 5 d PO 19
Trimethoprim Channel catfish 48 1–2.5 sd IM 25
Vetoquinol Sea bass 21–48 5–20 mg/kg sd IV/PO 10–24
Brown shark 79 25 mg/kg sd PO 8
*sd, single dose Atlantic salmon, Carp, Rainbow trout 16 40 mg/kg sd PO 10
Cod
Atlantic salmon

652 Section IV. Antimicrobial Drug Use in Selected Animal Species

kanamycin, oxolinic acid, oxytetracycline, nifurpirinol, indicate that the antimicrobial appears to help actively
sulfadimethoxine, sulfadimidine, sulfamonomethoxine, feeding healthy fish fight off the infection, whereas fish
sulfanilamide, sulfapyridine, sulfisomidine and trimeth- with clinical signs are anorexic and therefore not receiv-
oprim. Antimicrobials that are absorbed poorly or not at ing the antimicrobial. Variable intake can also occur if
all include chloramphenicol and gentamicin (Treves- fish vary in size. The larger fish will probably consume
Brown, 2000; Reimschuessel et al., 2005). more of the medicated feed than their smaller and less
vigorous counterparts. Palatability, especially of the sul-
Dipping treatments are a shorter and more controlled fonamide products, can also be a problem.
method of administering bath treatments. The advan-
tages of this type of treatment are reduced waste (thus Absorption from the intestinal tract may vary from spe-
reduced expense) and less environmental contamina- cies to species. As mentioned, saltwater fish will drink and,
tion. The disadvantage of this type of approach is the therefore, drugs may bind cations in the water in their
increased stress to the animals through handling. intestinal tracts, affecting bioavailability. The formulation
Therefore most dip treatments are done when fish are of the drug may either enhance or decrease absorption.
small or in pet/aquarium cases, but commercial
aquaculture producers have used tarpaulins to contain Various methods for administering oral medication
the drug (Vavarigos, 2003) and more recently, well boats include commercial medicated feed, custom surface-
to more effectively contain treatments (Burka et al., coated feeds, custom feeds (e.g., gelatin diets), medicated
2012). Localized topical treatment, often under light live feeds (e.g., Artemia grown in or fed antimicrobials),
anesthesia, has been recommended for small external injecting food (e.g., small fish used for food) and tube
lesions in pet fish (Stoskopf, 1993; Noga, 1996). feeding (Noga, 1996; Treves-Brown, 2000). Obviously,
some of these techniques are appropriate only for pet/
Some studies have used either hyperosmotic infiltra- aquarium fish.
tion (first high osmolarity, > 1200 mOsm/L, then lower
osmolarity containing the drug) or ultrasound treatments Injectable Treatments
to try to improve permeability across the gills. Drug Treating fish with injectable antimicrobials causes
absorption and elimination can be affected by salinity handling stress and can be a massive undertaking for
under normal conditions, and the effects of hyperosmotic commercial producers. Advantages include assuring
treatments have not been adequately studied. Certain that all animals receive the drug at the desired dose. The
drugs that bind divalent cations (such as the tetracyclines) route of administration is often intramuscular, but
may have their bioavailability compromised by the sometimes intraperitoneal, intravascular, or intradorsal
addition of salts. Ultrasound treatments to enhance sinus (caudal to the dorsal fin) routes are used.
absorption may be feasible in a small aquarium setting Intramuscular treatments are usually administered in
but have not been studied extensively. Both hyperosmotic the epaxial muscles, above the lateral line and near the
and ultrasound treatments are fairly stressful. They are caudal fin. Since there is a renal portal vascular system
mainly used for vaccination rather than antimicrobial in fish, it is best to inject aminoglycosides cranial to the
treatment (Treves-Brown, 2000; Navot et al., 2004). dorsal fin to avoid large doses entering the kidney.

Oral Treatments In pet/aquarium fish, most injections are given man-
Oral treatments are the most feasible methods for large ually. Automatic injectors, such as those used in poultry
commercial aquaculture systems because they are the operations, can be used in commercial aquaculture.
least stressful for the animals. However, sick fish may Although this seems a formidable task, vaccinations are
not eat. This was shown in a study where the concentra- given by injection, often manually, to many net-pen
tion of oxolinic acid was examined in Atlantic salmon reared fish (Noga, 1996; Vavarigos, 2003).
treated during an outbreak of winter ulcer disease
(Moritella viscosa). Oxolinic acid was detected in plasma Avoiding Toxicity in the Target Animal
and tissues of healthy fish, whereas levels were below the
limit of detection in moribund and dead fish (Coyne Even though fish drug metabolism can be affected by
et  al., 2004a). The moribund and dead fish also had environmental salinity and temperature, it is remarkably
no  food in their gastrointestinal tracts. These results similar to mammalian drug metabolism. Both groups

Chapter 39. Antimicrobial Drug Use in Aquaculture 653

have similar metabolic systems: phase 1 systems, includ- dramatically. Since their kidneys can undergo nephron-
ing the heme protein monooxygenase (cytochrome neogenesis, fish can sometimes survive such a toxic epi-
P450) and the flavin monooxygenase (FMO) systems, sode and regenerate their kidneys. The risks and benefits
and the phase 2 conjugation systems. The P450 systems of treatment must be carefully considered before using
have been identified in over 150 fish species (Whyte these antimicrobials.
et al., 2000). FMO activity, however, is lacking in some
fish species, e.g., channel catfish (Schlenk et al., 1995). Renal damage has also been associated with the use of
This difference can affect the metabolism of drugs, result- erythromycin and sulfamerazine. A number of antimi-
ing in either enhanced or reduced toxicity, depending crobials, including erythromycin, nalidixic acid, and
on the chemical. For example, in the case of the herbi- sulfonamides, can cause anorexia, especially if adminis-
cide aldicarb, catfish and trout take up similar amounts tered in high doses. Nalidixic acid and, to a lesser
of the parent compound, but their metabolism of the extent, oxolinic acid have induced macrocytic anemia,
compound differs (Perkins and Schlenk, 2000). potentially due to their effect on DNA synthesis.
Compared to trout, catfish are 10 times less susceptible Immunosuppression has been shown to occur with
to toxicity induced by aldicarb because they lack FMO tetracyclines (Rijkers et al., 1980).
activity. Trout (like mammals) metabolize the parent
drug to a toxic sulfoxide (Montesissa et al., 1995) that is Ensuring Safety for Humans
responsible for most of the toxic effects (Perkins et al.,
1999). Such differences in metabolism must be consid- Considerations for safety to humans include potential
ered when choosing antimicrobials. In general, however, hazards associated with: (1) administration of the drug;
most antimicrobials given by the oral route will not (2) exposure of individuals from environmental con-
cause toxicity because fish rarely overdose by eating tamination; and (3) consumption of the fish with respect
excessive amounts of medicated feed, and overmedi- to residues and antimicrobial resistance. Most hazards
cated feed is often not palatable and thus rejected. associated with administration of the drug can be man-
aged by adequate training, specialized equipment, and
Drugs administered via bath treatments can cause personal protective clothing. Basic veterinary practices
toxicity if grossly overdosed, especially if they are used to reduce hazards to personnel and the environ-
absorbed by the gills. In addition, saltwater fish will ment when treating terrestrial animals generally apply
drink the water and thus probably get an oral dose as to treating fish.
well. Drugs may have an effect on the water pH, which
can affect the osmoregulation of the animal. High doses Food safety concerns, for the most part, relate to resi-
of tetracyclines, which are used for immersion treat- dues of the drug used (or its metabolites) in the food
ments, can affect the pH of the water, inducing toxicity product (chapter 26). To prevent harmful residues,
(Treves-Brown, 2000). Drugs can also irritate the skin or governmental agencies establish required withdrawal
gills. Waterborne irritants can affect the gills by increas- periods. These periods are designed to ensure that the
ing mucus production and thus decreasing gaseous food product will have residue levels below the toler-
exchange. ance (United States) or maximum residue limit (MRL;
outside the United States) established by the governing
The main antimicrobial toxicity seen in fish is that body. Tolerances and MRLs are based on the potential
of  aminoglycoside-induced nephrotoxicosis. Amino- toxicity of the compound and an assessment of poten-
glycosides, such as gentamicin, which cannot be excreted tial exposure levels, including consideration of the
through filtration in aglomerular fish (including toad- general risk to the consumer. The basic principles are,
fish, goosefish and seahorses), can cause extensive renal again, similar to those used when treating terrestrial
necrosis in these fish at doses that are therapeutic (and food animals. Withdrawal periods for fish, however,
non-toxic) in other fish species (Reimschuessel et al., can incorporate water temperature as part of the equa-
1996). The half-life of gentamicin in toadfish is approxi- tion, sometimes in the form of “degree days” (the °C
mately 2 weeks, compared to 2 days in goldfish. Since multiplied by the number of days, e.g., 50 days at
fish eliminate nitrogenous waste through the gills, they 10°C = 500 degree days, as does 25 days at 20°C;
can survive with compromised renal function as long as Alderman, 2000; European Medicines Agency, 2005;
the osmolarity of their environment does not change

654 Section IV. Antimicrobial Drug Use in Selected Animal Species

FDA, 2005). The European Union (EU) regulations in sediments; (4) presence in drinking water; and (5)
have included the concept of degree days in their sug- alterations in the ecosystem’s microbial community,
gested generic withdrawal period of 500 degree days for including antimicrobial resistance. Local effluent dis-
compounds for which no specific withdrawal period charge regulations must be considered both by the clini-
has been set. Knowledge of the pharmacokinetics and cian and the owner of the aquaculture facility.
depuration patterns of different drugs in different fish
species is essential for both those establishing such Toxicity to non-target species depends on the dose
periods and clinicians using the drugs. When evaluat- and the route of administration of the drug (Isidori
ing data reporting depuration periods and residue lev- et al., 2005). For example, furazolidone, which is usually
els, one should also consider what detection method administered by bath treatment, is extremely toxic to
was used. Analytical methods have changed over the crustaceans (Macri et al., 1988). Bioaccumulation of
years, in general becoming more sensitive. As a result, antimicrobials in edible food sources can occur in non-
residues determined to be “below the level of detection” target species, including fish, crustaceans, and plants
in the 1980s may actually be detectable using improved (Samuelsen et al., 1992a; Delepee et al., 2003; Migliore
detection systems, and could be considered unaccepta- et  al., 2003). Accumulation in the sediment has also
ble today. It is important for clinicians prescribing been documented for a number of antimicrobials,
aquaculture drugs to be aware of the regulations in their including flumequine, furazolidone, ormetoprim, oxo-
country to protect the safety of the consumer. linic acid, and oxytetracycline (Bjorklund et al., 1991;
Samuelsen et al., 1991; Capone et al., 1996; Lalumera et
Another concern for agencies regulating food safety is al., 2004). Antimicrobials and other pharmaceuticals,
the development of antimicrobial resistance among including those from human and terrestrial agricultural
potential zoonotic bacteria in or on food-fish, as a result use, have been detected in receiving waters (Hirsch et
of antimicrobial use in aquaculture (Heuer et al., 2009). al., 1999; Kümmerer, 2001; Rooklidge, 2004). Recently,
The United States Food and Drug Administration’s researchers showed that exposure of various bacterial
Center for Veterinary Medicine assesses the level of risk genera to sublethal antimicrobial concentrations led to
associated with a proposed use by a qualitative antimi- mutant strains sensitive to the applied antimicrobial but
crobial resistance risk assessment (FDA, 2003). Recently, resistant to other antimicrobials (Kohanski et al., 2010).
the U.S. FDA (2012a) issued guidance outlining their These findings have important implications for the
concerns regarding the development of antimicrobial widespread use of antimicrobials in aquatic environ-
resistance in human and animal bacterial pathogens ments. Such changes in the antimicrobial susceptibility
when medically important antimicrobials are used in following antibiotic use in the aquatic setting have been
food-producing animals in an injudicious manner. Two reported in the past (Samuelsen et al., 1992b; Angulo,
principles guiding appropriate or judicious use of medi- 1999; Guardabassi et al., 2000; Chelossi et al., 2003).
cally important antimicrobials include limitation of Recent standardized methods for assessing anti-
medically important antimicrobial drugs to uses in ani- microbial susceptibility of bacteria isolated from aquatic
mals that are considered necessary for assuring animal animals should help efforts to monitor changes in sus-
health, and include veterinary oversight or consultation ceptibility following antimicrobial exposure of patho-
(Codex Alimentarius Commission, 2005, 2011; FDA, genic bacteria and some less fastidious environmental
2012b). isolates (Miller et al., 2003, 2005; CLSI 2006a, 2006b).

Environmental Effects and Non-target Legal Considerations
Species
Veterinarians dealing with food animals, either terrestrial
Treating fish with antimicrobials, especially in large com- or aquatic, must be familiar with the regulations regard-
mercial systems, can affect the environment in a number ing antimicrobial use in their country as well as in coun-
of ways. These include: (1) toxicity to non-target species; tries that may import the product (chapter 26). These
(2) accumulation by non-target species; (3) accumulation regulations include: (1) prohibitions from use, for exam-

Chapter 39. Antimicrobial Drug Use in Aquaculture 655

ple, chloramphenicol (local and abroad); (2) residue tol- Association (2003). They are, in general, similar to guide-
erance levels in the United States, or other regulatory lines proposed for antimicrobial use in terrestrial animals.
levels, such as MRLs in the EU; (3) effluent and discharge The Codex Alimentarius Commission, charged to protect
regulations; and (4) general prescription regulations. the health of consumers while ensuring fair practices in
the food trade, recently published Guidelines for Risk
Such laws vary greatly from country to country, from Analysis of Foodborne Antimicrobial Resistance (Codex
almost no regulation to restrictive regulation. For exam- Alimentarius Commission, 2011).
ple, the U.S. FDA has only approved four classical anti-
microbials (florfenicol, ormetoprim/sulfadimethoxine, The clinician must keep abreast of recent develop-
oxytetracycline, and sulfamerazine) for use in fish reared ments in both national and international regulations
for food purposes. Canada has approved the first three regarding antimicrobial use in aquatic species. The
antimicrobials, as well as sulfadiazine and trimetho- aquaculture producer must also be conversant in these
prim. Approximately ten antimicrobials have received areas to assure that the therapies recommended by the
authorization for use in certain EU member states, clinician are appropriately implemented.
including quinolone antimicrobials such as flumequine,
oxolinic acid, and sarafloxacin. Japan has approved Antimicrobial Susceptibility Testing
approximately thirty antimicrobials for use in aquacul- of Aquatic Bacteria
ture (Treves-Brown, 2000; Schnick, 2001; FDA, 2005).
Many developing countries are beginning to formulate Defining conditions for antimicrobial susceptibility
regulations regarding antimicrobial use in aquaculture. testing has been difficult because aquatic bacteria vary
greatly in their optimal in vitro growth requirements.
Many countries are also developing provisions for Temperature optimums of various aquatic bacteria can
using therapeutic agents that are not approved (extra- or range from 15°C to 35°C. Some aquatic bacteria prefer
off-label use) in minor species. Some countries, such as or require supplementation to the basal medium, while
the United States, have established specific rules for others need a low-nutrient or diluted basal medium.
extra-label use of approved drugs by veterinarians. In Nevertheless, standardized testing protocols are essen-
the United States, the FDA lists some substances as “low tial to obtain results that are reproducible within and
regulatory priority”; these substances are not legal for among laboratories (chapter 2). Such test protocols are
use, but it has been determined that under certain standardized through extensive multilaboratory valida-
conditions no regulatory action is likely. Such substances tion studies, and are used to establish quality control
include sodium chloride, sodium bicarbonate, and urea. (QC) ranges to monitor performance and reproduci-
Although not classical antimicrobials, these chemicals bility (CLSI, 2008).
might be used in conjunction with other treatments.
Also, the U.S. Minor Use and Minor Species Animal The CLSI has published two guidelines, M42-A and
Health Act (MUMS) provides regulatory authority to M49-A, which describe standardized methods for disk dif-
the U.S. FDA to add certain drugs to an index of legally fusion and broth dilution susceptibility testing of some bac-
marketed but unapproved new animal drugs for use in terial isolates from aquatic animals (CLSI, 2006a, 2006b).
minor species (FDA, 2004). MUMS provides more flex- Because of their complexity and length, full details are not
ibility for veterinarians prescribing medicines to aquatic given here. Specialists in the area should consult the CLSI
animals. The European Medicines Agency, which regu- current guidelines, and those published in the future.
lates antimicrobial use in the EU, is considering institut-
ing similar policies (EMA, 2005). The ultimate goal of any susceptibility test is to obtain
a result that can be used to predict therapeutic efficacy
In addition to prescription regulations, many countries (clinical application), detect shifts in susceptibility over
are developing guidelines for stewardship or judicious use time (surveillance application), or both. Currently, the
of antimicrobials in order to prevent antimicrobial resist- only fish pathogen that has these interpretive tools avail-
ance from developing in pathogenic and environmental able is Aeromonas salmonicida. These minimal inhibi-
bacteria (chapter 7). In the United States, such guidelines tory concentration (MIC) and zone diameter clinical
have been proposed by the American Veterinary Medical breakpoints and epidemiological cutoff values will be
Association (2002) and the National Aquaculture

656 Section IV. Antimicrobial Drug Use in Selected Animal Species

Table 39.4. Standard methods for disk diffusion Table 39.5. Antimicrobial agents used in global
susceptibility testing of aquatic bacterial pathogens aquaculture and status of quality control for disk diffusion
susceptibility testing.

Organisms Medium Incubation

Group 1: Non-fastidious bacteria MHA 22°C (24–28 h Zone Diameter
Enterobacteriaceae and/or 44–48 h) QC Ranges for
Aeromonas salmonicida or 28°C Antimicrobial Agents Suggested
(24–28 h) Disk Content Testing at:
(nonpsychrophilic strains)
Aeromonas hydrophila and other 22°C 28°C 35°C

mesophilic aeromonads Drugs Used in Global Aquaculture with CLSI-Approved QC Ranges for Disk Ampicillin 10 μg × × ×
Pseudomonas spp. Diffusion Testing of Aquatic Isolates ×
Plesiomonas shigelloides Chloramphenicol 5 μg × × ×
Shewanella spp. Clindamycin 2 μg × × ×
Vibrionaceae and related bacteria Doxycyclinea 30 μg × × ×
Enrofloxacin 5 μg × × ×
(nonobligate halophilic strains) Erythromycin 15 μg ×
Florfenicol 30 μg × × ×
Reprinted with permission from the Clinical and Laboratory Standards Fosfomycinb 200 μg × × ×
Institute. Gentamicin 10 μg × × ×
Kanamycin 30 μg ×
published in the next edition of CLSI’s M49-A guideline Minocyclinea 30 μg × × ×
for dilution susceptibility testing. Nalidixic acid 30 μg ×
Nitrofurantoin 300 μg
Disk Diffusion Susceptibility Testing Ormetoprim- 1.25 μg/ ×
×
Since the Kirby-Bauer disk diffusion method is sulfadimethoxinec 23.75 μg ×
frequently  used in aquatic animal disease diagnostics, Oxolinic acid 2 μg ×
many studies have been published using different types of Oxytetracyclinea 30 μg ×
basal media for testing a cornucopia of aquatic pathogens Penicillin 10 units ×
(Bauer et al., 1966; Dalsgaard, 2001). Barker and Kehoe Rifampin 5 μg
(1995) and Dalsgaard (2001) both found Mueller-Hinton Sulfisoxazole 250 or 300 μg
agar (MHA) to be the best medium for disk diffusion Tetracyclinea 30 μg
testing, based upon its consistent performance with a Tiamulin 30 μg
wide range of aquatic pathogens. An international col- Trimethoprim- 1.25 μg/
laborative study in 2003 conducted in accordance with
existing CLSI guidelines (CLSI, 2008) standardized the sulfamethoxazole 23.75 μg
disk diffusion testing method for non-fastidious aquatic
isolates that grow well on MHA (Table 39.4; Miller et al., aDrugs in the tetracycline group are closely related and, with few
2003). These aquatic bacteria have been labeled Group 1 exceptions, only oxytetracycline may need to be tested routinely.
isolates by the Aquaculture Working Group of the CLSI bThe 200 μg fosfomycin disk contains 50 μg glucose 6-phosphate.
Subcommittee on Veterinary Antimicrobial Susceptibility cTraditionally, trimethoprim-sulfamethoxazole may be used to predict
Testing. Organisms in Group 1 prefer growth on MHA at susceptibility to ormetoprim-sulfadimethoxine; however, this has not
22°C or 28°C (CLSI, 2006a). been confirmed at 22 ± 2°C or 28 ± 2°C.
Note: Laboratories may also include disks containing other antimicrobial
Disk diffusion zone diameter QC ranges were agents. The inclusion of disks outside the recommended set can be
established for two control organisms, Escherichia coli valuable if a laboratory has data relating to its clinical significance.
ATCC25922 and Aeromonas salmonicida subsp. However, quality control data generated with disk contents other than
salmonicida ATCC33658, testing on MHA at both 22°C those with quality control range established should not be reported as
and  28°C (Table  39.5). Ranges were established for being in compliance with CLSI standards established in this guideline.
ampicillin, enrofloxacin, erythromycin, florfenicol, gen- Variations must be reported with results.
tamicin, ormetoprim/sulfadimethoxine, oxolinic acid,
Reprinted with permission from the Clinical and Laboratory Standards
Institute.

oxytetracycline, and trimethoprim/sulfamethoxazole
(Miller et al., 2003; CLSI, 2006a).

Chapter 39. Antimicrobial Drug Use in Aquaculture 657

Table 39.6. Potential modifications for disk diffusion susceptibility testing of aquatic bacterial pathogens.

Organisms Medium Incubation

Group 2: Vibrionaceae and Photobacteriaceae MHA + 1% NaCl 22°C (24–28 h and/or 44–48 h) or
(obligate halophilic strains) Diluted MHA (4 g/L) 28°C (24–28 h and/or 44–48 h)

Group 3: Gliding bacteria 28°C (44–48 h)
Flavobacterium columnare 18°C (92–96 h)
Flavobacterium psychrophilum
Flavobacterium branchiophilum MHA + 5% sheep blood 22°C (44–48 h + CO2 if necessary for growth)
MHA + 5% sheep blood 28°C (24–28 h and/or 44–48 h + CO2 if
Group 4: Streptococci
Lactococcus spp., Vagococcus salmoninarum MHA necessary for growth)
Streptococcus spp., Carnobacterium maltaromaticum, MHA + supplementationa
Diluted MHA (1:7) + inorganic ion 15°C (44–48 h)
and other streptococci 15°C (6 days)
supplementation 25°C (24–28 h)
Group 5: Other fastidious bacteria Unknown
Psychrophilic Aeromonas salmonicida strains See CLSI standard M24 15°C
Vibrio salmonicida and Moritella viscosa Chocolate MHA See CLSI standard M24
Tenacibaculum maritimum 35 ± 2°C

Renibacterium salmoninarum
Mycobacterium spp. and Nocardia seriolae
Erysipelothrix rhusiopathiae

aRecommended supplementation cannot be made at this time, but may include cations, horse or fetal calf serum, or NaCl.
Reprinted with permission from the Clinical and Laboratory Standards Institute.

Aquatic pathogens in Groups 2–5 may require media inoculation systems for broth microdilution suscepti-
other than MHA (Table  39.6). There are currently no bility testing, discussed in chapter 2, have fostered its
quality control (QC) parameters in place to control their growing popularity in many aquatic animal medicine
tests. In these cases, the clinician should perform the research laboratories.
following: (1) identify the isolate; (2) determine to which
“Group” the isolate belongs; (3) test the isolate on the Standardized broth dilution susceptibility testing
suggested media; (4) use a QC organism under stand- methods have been developed for non-fastidious
ardized conditions in parallel with the test isolate; (5) aquatic bacteria in Group 1 at 22°C and 28°C (Miller
determine whether the test was within QC; (6) if a test et al., 2005; CLSI, 2006b). Group 1 bacteria are tested
result is not consistent by QC, determine the cause and in undiluted cation-adjusted Mueller-Hinton broth
repeat as necessary. (CAMHB).

Clinicians should consult CLSI guideline M42-A Recently, a standardized broth dilution suscepti-
(CLSI, 2006a), for suggested conditions to test the more bility  testing method was developed for the gliding
fastidious aquatic bacterial genera (Groups 2–5). bacteria  (Group 3), Flavobacterium psychrophilum and
F. columnare, at 18°C and 28°C, respectively, in diluted
Dilution Susceptibility Testing CAMHB (4 g/L; Gieseker, 2011; Gieseker et al., unpub-
lished). These gliding flavobacteria form aggregates,
Both broth dilution and agar dilution antimicrobial sus- which must be allowed to settle out of suspension so
ceptibility testing methods are used in aquatic animal that only the free-floating cells are tested. Laboratories
disease diagnostics. Results of dilution susceptibility should conduct preliminary cell enumerations to
tests provide data in the form of an MIC, which has confirm target cell concentrations prior to working with
greater clinical relevance than a zone diameter value, flavobacteria. The CLSI guideline M49-A (CLSI, 2006b)
since it can be correlated with serum concentrations will be updated with QC ranges for various antimicro-
in  the animal (chapter 2). Advances in automated bial agents in diluted (4 g/L) CAMHB.