Tuberculosis treatment protocols Tuberculosis treatment protocols and complications for elephantsand complications for elephants

Genevieve Dumonceaux, DVMGenevieve Dumonceaux, DVMPalm Beach Zoo, FloridaPalm Beach Zoo, Florida

Susan Mikota, DVMSusan Mikota, DVMElephant Care InternationalElephant Care International

Mycobacteria tuberculosis Mycobacteria tuberculosis complexcomplex

M. tuberculosis (M.tb)M. tuberculosis (M.tb) M. bovisM. bovis M. microtiM. microti M. africanumM. africanum M. kinettiM. kinetti M. capraeM. caprae M. pinnipedi M. pinnipedi

Any species not in the M. tb complex is Any species not in the M. tb complex is not truly tuberculosis.not truly tuberculosis.

Infection from these are classified as Infection from these are classified as mycobacteriosis.mycobacteriosis.

In people and elephants the most In people and elephants the most frequently identified tuberculosis frequently identified tuberculosis causing agent is M. tuberculosis.causing agent is M. tuberculosis.

Elephant management Elephant management optionsoptions

IsolationIsolation EuthanasiaEuthanasia TreatmentTreatment

Most Effective TherapyMost Effective Therapy

Prompt diagnosisPrompt diagnosis Culture and Sensitivity Culture and Sensitivity 3-4 first line agents3-4 first line agents Adequate plasma drug levelsAdequate plasma drug levels Adequate length of treatmentAdequate length of treatment Close monitoring of hemogram and Close monitoring of hemogram and

organ function. organ function. Close monitoring of the patientClose monitoring of the patient

Routes of administrationRoutes of administration

Over the feed – not recommended, Over the feed – not recommended,

poorly accepted, poorly effectivepoorly accepted, poorly effective Directly oral – preferred, best Directly oral – preferred, best

absorptionabsorption Rectally – good alternative to direct Rectally – good alternative to direct

oral for some medsoral for some meds

Direct oralDirect oral

Deposit in back of throat behind base Deposit in back of throat behind base

of tongueof tongue Use large 400 cc syringe with Use large 400 cc syringe with

modified extended tip or stiff tubing.modified extended tip or stiff tubing. Train to take a bite blockTrain to take a bite block

RectallyRectally

Large animal syringe 400cc - multipleLarge animal syringe 400cc - multiple Flexible tubingFlexible tubing SuppositoriesSuppositories Lecithin – may increase Lecithin – may increase

absorption, increases absorption, increases

volumevolume

GuidelinesGuidelines

First developed in 1998First developed in 1998 Modified several times to reflect Modified several times to reflect

experience and investigational experience and investigational

resultsresults

First line drugsFirst line drugs

Isoniazid (INH)Isoniazid (INH) Pyrazinamide (PZA)Pyrazinamide (PZA) Rifampin (RIF)Rifampin (RIF) Ethambutol (ETH)Ethambutol (ETH) Streptomycin (STR)Streptomycin (STR)

INHINH Peripheral neuropathyPeripheral neuropathy Optic nerve toxicityOptic nerve toxicity Nausea, vomiting, anorexiaNausea, vomiting, anorexia PicaPica, epigastric distress, epigastric distress Elevated liver enzymesElevated liver enzymes, hepatitis., hepatitis. Agranulocytosis, Agranulocytosis, anemiaanemia Skin eruptions, fever, vasculitisSkin eruptions, fever, vasculitis Pyridoxine deficiency, Rheumatic syndromePyridoxine deficiency, Rheumatic syndrome Systemic lupus erythematosis-like Systemic lupus erythematosis-like

syndromesyndrome

PZAPZA

Hyperuricemia Hyperuricemia gouty arthritis gouty arthritis Hepatocellular damage, elevated Hepatocellular damage, elevated

enzymesenzymes Nausea, vomiting, Nausea, vomiting, anorexiaanorexia Arthralgia, myalgiaArthralgia, myalgia PhotosensitivityPhotosensitivity Porphyria, feverPorphyria, fever

RIFRIF

AnorexiaAnorexia, nausea, vomiting, nausea, vomiting ThrombocytopeniaThrombocytopenia Muscle weakness, ataxia, Muscle weakness, ataxia, limb limb

painpain Headaches, visual disturbancesHeadaches, visual disturbances Elevated BUN and serum uric acidElevated BUN and serum uric acid Pruritis, urticaria, Pruritis, urticaria, rashrash ConjunctivitisConjunctivitis

ETHETH

Optic neuropathyOptic neuropathy Acute renal failureAcute renal failure

PZA/EnrofloxacinPZA/Enrofloxacin

Group of female AsiansGroup of female Asians Varying degrees excessive Varying degrees excessive

epiphora, blepharitis.epiphora, blepharitis. Some with stiffness/soreness of one Some with stiffness/soreness of one

or more limbs.or more limbs.

Multi-drug resistanceMulti-drug resistance

MDR TBMDR TB Typically resistance to INH and Typically resistance to INH and

RIFRIF Employ second line drugs for Employ second line drugs for

therapytherapy Some second line drugs more Some second line drugs more

toxic than first line agents.toxic than first line agents.

Second line drugsSecond line drugs

AmikacinAmikacin EthionamideEthionamide QuinolonesQuinolones CapreomycinCapreomycin

AminoglycosidesAminoglycosides

Amikacin, CapreomycinAmikacin, Capreomycin Potential side effectsPotential side effects

OtotoxicityOtotoxicity NephrotoxicityNephrotoxicity

EthionamideEthionamide

Digestive problemsDigestive problems Psychotic Psychotic

disturbancedisturbance DizzinessDizziness Liver problemsLiver problems PhotosensitivityPhotosensitivity ThrombocytopeniaThrombocytopenia

QuinolonesQuinolones

Nausea, abdominal painNausea, abdominal pain Vomiting, diarrheaVomiting, diarrhea Dizziness, seizuresDizziness, seizures RashRash CrystalluriaCrystalluria PhototoxicityPhototoxicity, tendinopathy, tendinopathy

LiteratureLiterature

Physicians’ Desk Reference, 2006…, 60Physicians’ Desk Reference, 2006…, 60thth ed. ed. Thomson PDR, Montvale, New Jersey 07643-Thomson PDR, Montvale, New Jersey 07643-1742, USA1742, USA

The International Journal of Tuberculosis and The International Journal of Tuberculosis and Lung Disease. 2005 Dec. V 9, N 12: 1373-7. Lung Disease. 2005 Dec. V 9, N 12: 1373-7. Side effects Associated with the Treatment of Side effects Associated with the Treatment of Multidrug-Resistant Tuberculosis. Torun, T., Multidrug-Resistant Tuberculosis. Torun, T., Gungor, G., Ozmen, I., Bolukbasi, Y., Maden, Gungor, G., Ozmen, I., Bolukbasi, Y., Maden, E., Bicakci, B., Atac, G., Sevim, T., and E., Bicakci, B., Atac, G., Sevim, T., and Tahaoglu, K.Tahaoglu, K.

American Journal of Veterinary American Journal of Veterinary Research. 2005, Nov; 66(11):1948-Research. 2005, Nov; 66(11):1948-53. Pharmacokinetics of a single 53. Pharmacokinetics of a single dose of enrofloxacin administered dose of enrofloxacin administered orally to captive Asian elephants orally to captive Asian elephants ((Elephas maximusElephas maximus). Sanchez, CR., ). Sanchez, CR., Murray, SZ., Isaza, R., Papich, MG.Murray, SZ., Isaza, R., Papich, MG.

Southern Medical Journal. 1994. Southern Medical Journal. 1994. Sep;87(9):869-74. Neurotoxicity of Sep;87(9):869-74. Neurotoxicity of antibacterial therapy. Thomas, RJ.antibacterial therapy. Thomas, RJ.

Annals of Pharmacotherapeutics. Annals of Pharmacotherapeutics. 2007. Nov;41(11):1859-66. Safety 2007. Nov;41(11):1859-66. Safety concerns with fluoroquinolones. concerns with fluoroquinolones. Mehlhorn, AJ., Brown, DA.Mehlhorn, AJ., Brown, DA.

Seminars in Ophthalmology. 2007, Jul-Seminars in Ophthalmology. 2007, Jul-Sep;22(3):141-6. Ethambutol Sep;22(3):141-6. Ethambutol neuroretinopathy. Vistamehr, S., neuroretinopathy. Vistamehr, S., Walsh, TJ., Adelman, RA.Walsh, TJ., Adelman, RA.

Expert opinions of drug safety. 2006, Expert opinions of drug safety. 2006, Sep;5(5):615-8. Update on ethambutol Sep;5(5):615-8. Update on ethambutol optic neuropathy. Graunfelder, FW., optic neuropathy. Graunfelder, FW., Sadun, AA., Wood, T.Sadun, AA., Wood, T.

Mayo Clinic Proceedings. 2003, Mayo Clinic Proceedings. 2003, Nov;78(11):1409-11. Ocular Nov;78(11):1409-11. Ocular ethambutol toxicity. Melamd., A, ethambutol toxicity. Melamd., A, Kosmorsky, GS., Lee, MS.Kosmorsky, GS., Lee, MS.

Altered regimenAltered regimen

Diminishing side effects in elephantsDiminishing side effects in elephants

Withdraw medications 1-2 days a weekWithdraw medications 1-2 days a week

Give double the dose of meds on every Give double the dose of meds on every

other day schedule = Pulse therapyother day schedule = Pulse therapy

Success of treatment ------Success of treatment ------ Not 100%.Not 100%. Many elephants “apparently” treated Many elephants “apparently” treated

successfully to date. (rectal, oral, successfully to date. (rectal, oral, suppositories)suppositories)

Some have not had infection successfully Some have not had infection successfully eliminated. (based on necropsy findings)eliminated. (based on necropsy findings)

One Asian euthanized due to MDR and One Asian euthanized due to MDR and drug toxicity.drug toxicity.

Other AspectsOther Aspects

Cost of treatment $50,000 + USCost of treatment $50,000 + US Labor intensiveLabor intensive Additional costs: Blood work, serum drug Additional costs: Blood work, serum drug

level monitoring, employee time, extra level monitoring, employee time, extra materials, isolation.materials, isolation.

Limitations of drug availabilityLimitations of drug availability Success depends on all animal care staff.Success depends on all animal care staff.

Early DetectionEarly Detection

Cultures take up to 8 weeks for Cultures take up to 8 weeks for

resultsresults Additional time for sensitivitiesAdditional time for sensitivities Contamination of samplesContamination of samples Quality of sample collectionQuality of sample collection

Serological tests are rapid in Serological tests are rapid in

comparisoncomparison

Early detection cont’Early detection cont’

Rapid test – screening test Rapid test – screening test (ElephantTB STAT-PAK(ElephantTB STAT-PAK® ® Assay)Assay)

Mutiantigen Print Immunoassay Mutiantigen Print Immunoassay (MAPIA)(MAPIA)

DNA extractionsDNA extractions Immunologic markersImmunologic markers Other technologyOther technology

Resources

Most recently available guidelinesVeterinarians who have experience with this disease

in elephantsState Veterinarian

USDA Animal Care/ Elephant SpecialistInfectious disease/ tuberculosis specialists (MD, DVM,

VMD)

Thanks to all who contributed information to this effortThanks to all who contributed information to this effort Thanks to Hank Hammatt of ECI for reviewing this pptThanks to Hank Hammatt of ECI for reviewing this ppt