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Plague and other tick-borne diseases

Melina Braly, PharmD, BCPS

PGY-2 Critical Care Resident

Baptist Hospital of Miami

January 9, 2016

Objectives

� Define the locations and signs and symptoms of common tick-borne diseases.

� Understand the antibiotic treatments for common tick-borne diseases.

� Describe tick bite prevention and prophylaxis practices.

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The Plague in History1-9

Justinian Plague

6th Century

The “Black Death” or

Great Plague

14th Century

Modern Plague

19th Century

The Plague in History1-9

Justinian Plague

6th Century

The “Black Death” or

Great Plague

14th Century

Modern Plague

19th Century

The Plague in History1-9

Justinian Plague

6th Century

The “Black Death” or

Great Plague

14th Century

Modern Plague

19th Century

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The Plague in History1-9

Justinian Plague

6th Century

The “Black Death” or

Great Plague

14th Century

Modern Plague

19th Century

The Plague4

� Reported Plague Cases (2000-2009)

The Plague 4

� Plague cases/deaths, United States (2000- 2014)

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The Plague in 2015 4

� Fifteen people have been infected with bubonic plague in the U.S.

� 4 fatalities

� Locations include: Arizona, Colorado, New Mexico, Oregon, California, Utah, Georgia, Michigan

� Unknown reasons for the increase in cases

The Plague 1-9

� Causative agent: Yersina pestis

� Gram-negative coccobacillus

� Evolved from the enteric pathogen Y. pseudotuberculosis

� Bipolar staining with Giemsa, Wright’s, or Wayson staining

� Grows aerobically on most culture media

The Plague: Virulence Factors 1-9

Virulence Factors Function

Low calcium response V

antigen (LcrV)

Modulates host immune response,

essential for the production of Yops

Plasminogen activator

(Pla protease)

Dispersal within host and coagulase

and fibrinolytic activity

Yersinia outer proteins

(Yops) and pH 6 antigen

Involved in cytotoxic processes,

immune suppression, or survival within host phagocytes

Fraction 1 capsule (F1)

antigen

Enables resistance to phagocytosis,

expressed at higher temperatures

Murine toxin and pgm

locus

Responsible for pathogenicity in

mammals, and survival and transmission in vectors

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Resource #6

Resource #6

Resource #6

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Resource #6

The Plague 1-9

� Three main syndromes:

� Bubonic plague

• 80-95% of cases

� Septicemic plague

• 10-20% of cases

� Pneumonic plague

• Generally rare

• Primary or Secondary

� Other manifestations: pharyngitis, tonsillitis , meningitis

Bubonic Plague 1-9

� Transmission: flea bite

� May be overlooked

� Signs/Symptoms:

� Sudden onset of fever, chills, weakness, and headache, followed by intense pain and swelling in a lymph node bearing area (bubo)

� May become disseminated infection without treatment

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Septicemic Plague 1-9

� May be primary or secondary

� Signs/Symptoms:

� Febrile, nausea, vomiting, diarrhea and abdominal pain

� 40% mortality for treated cases

� 100% mortality for untreated cases

Pneumatic Plague 1-9

� May be primary or secondary

� Transmission: inhalation of respiratory secretions or aerosolized droplets

� Signs/Symptoms:

� Sudden onset of dyspnea, high fever, pleuritic chest pain, and cough

� 100% mortality if not treated within first 24 hours

The Plague: Diagnosis 1-9

� Clinical presentation

� High fever with lymphadenopathy

� Culture and staining

� Positive blood culture in 27-96%

� Gram-negative rods

� Serologic confirmation (F1 antigen)

� Requires acute and convalescent serum

� Single titer of >1:16 using the passive hemagglutination test is suggestive

� Rapid diagnostic test

� 100% sensitivity/specificity for F1 antigen

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The Plague: Treatment 1-9

Agent Dose Evidence

Doxycycline * 100 mg IV/PO Q12H Human data

Gentamicin * 5 mg/kg IV/IM QD OR2 mg/kg IV/IM LD, 1.7 mg/kg TID MD

Human data

Ciprofloxacin * 400 mg IVQ8-12H OR500mg PO BID

Animal dataLimited human data

Levofloxacin 500 mg IV/PO Q24H Animal data

Moxifloxacin 400 mg IV/PO Q24H Animal data

Chloramphenicol 25 mg/kg IV Q6H Human data for treatment of meningitis

* = Preferred agents in the United SatesLD = Loading doseMD = Maintenance dose

Treatment Duration = 10-14 days

Post-exposure Antibiotic Prophylaxis 1-9

� Naturally occurring plague

� Doxycycline is the preferred choice

� Alternative: Ciprofloxacin

� Biological weapon (pneumonic plague)

� Ciprofloxacin is the preferred choice

The Plague 1-9

� Resistance

� Case reports of plasmid-mediated antibiotic resistance strains

� Recent study of Y. pestis isolates in Mongolia showed naturally occurring, multi-drug resistant variants

� Vaccine

� Not available in Western world

� Recombinant vaccine in development

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Tick-Borne

Diseases

Lyme Disease Rocky

Mountain Spotted Fever

Ehrlichiosis

Tularemia

BabesiosisAnaplasmosis

Colorado tick

fever

PowassanDisease

Relapsing fever

Tick-Borne

Diseases

Lyme Disease Rocky

Mountain Spotted Fever

Ehrlichiosis

Tularemia

BabesiosisAnaplasmosis

Colorado tick

fever

PowassanDisease

Relapsing fever

Lyme Disease10,11,13

� Most common vector-borne infectious disease in the U.S.

� Causative agent: Borrelia burgdorferi

� Tick vector:

� Ixodes scapularis (“Deer tick”)

� Natural reservoirs: white-footed mouse and small mammals

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Lyme Disease: Presentation10,11,13

� Incubation period: 3-30 days

� Stage 1 (early localized):

� Erythema migrans rash at bite of bite, influenza-like symptoms, cough, lymphadenopathy

� Stage 2 (early disseminated):

� Secondary cutaneous annular lesions, fever, adenopathy, CNS symptoms

� Stage 3 (late chronic):

� Arthritis, CNS impairment, dermatitis, keratitis, and myocardial abnormalities

Lyme Disease10,11,13

� Diagnosis:

� Serologic testing insensitive within 2wks

� Two tier testing recommended:

• Enzyme immunoassay (EIA) or immunofluorescence assay (IFA)

• Western Blot

� Single positive serologic test results cannot distinguish between active and past infection

Lyme Disease: Treatment10,11,13

� Treatment of localized (early) disease

� Treatment of disseminated (late) disease

Antimicrobial Agent Dose Duration (Days)

Doxycycline 100 mg PO BID 14 (14-21)

Cefuroxime axetil 500 mg PO BID 14 (14-21)

Amoxicillin 500 mg PO BID 14 (14-21)

Late Disease with Neurologic/ Cardiac Involvement

Antimicrobial Agent Dose Duration (Days)

Ceftriaxone 2g IV QD 14-28

Cefotaxime 2g IV Q8H 14-28

Penicillin G 18-24 million units/day in divided doses (Q4H)

14-28

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Rocky Mountain Spotted Fever (RMSF)11,14

� Most common rickettsial disease in U.S.

� Causative agent: Rickettsia rickettsii

� Tick Vectors:

� Dermacentor variabilis ( “American dog tick”)

� Dermacentor andersoni (“Rocky Mountain wood tick”)

RMSF: Presentation 11,14

� Incubation: 2-14 days

� Signs/ Symptoms:

� Flu-like symptoms, GI symptoms, photophobia, focal neurological deficits

� Maculopapular rash

• Initially on extremities, then spread to trunk

� Petechial rash

• Considered a sign of progression

� Complications:

� DIC, ARF, gangrenous disorder, ARDS

RMSF: Diagnosis 11,14

� Laboratory findings:

� Thrombocytopenia, mildly elevated LFTs, hyponatremia

� Laboratory Confirmation:

� Gold standard: IFA on paired samples

• Four-fold change from week 1 to week 4 (3-5)

• Antibodies detectable 7-10 days after onset

� PCR or immunohistochemical (IHC) staining of skin biopsy

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RMSF: Treatment 11,14

� Presumed or confirmed RMSF:

� Doxycycline 100 mg PO Q12H

� Presumed Meningococcal Disease:

� Doxycycline 100 mg IV Q12H

AND

� Ceftriaxone 2g IV Q12H

� Duration:

� At least 3 days after fever subsides and until evidence of clinical improvement seen (minimum of 5-7 days, total course)

Babesiosis10,11

� Only tick-borne disease in U.S. that is caused by a protozoan

� Causative agent: Babesia microti

� Tick Vectors:

� Ixodes scapularis ticks

� Black-legged or deer ticks

Babesiosis: Presentation 10,11

� Incubation: 1-9+ weeks

� Signs and Symptoms:

� Flu-like symptoms, GI symptoms, dark urine

� Not all infected persons are symptomatic or febrile

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Babesiosis: Diagnosis 10,11

� Laboratory Findings:

� Hemolytic anemia, thrombocytopenia, elevated BUN and SCr, mildly elevated LFTs

� Laboratory Diagnosis:

� Identification of parasites within RBC

• “Maltese Cross” may be present

� Positive PCR analysis

� Isolation of parasites from a whole blood specimen

Babesiosis: Treatment10,11

� Mild disease:

� Symptomatic treatment only

� Severe disease:Regimen Drug Dose

1 Atovaquone 750 mg PO Q12H

Azithromycin Day 1: 500-1000mg PO (total dose)Subsequent days: 250-1000* mg in divided doses

2 Clindamycin 300-600 mg IV Q6H OR 600mg PO Q8H

Quinine 650 mg PO Q6-8H

* = Larger dose (600- 1000 mg) for immunocompromised patientsTreatment duration = 7-10 days

Anaplasmosis and Ehrlichiosis 10,11,15

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Anaplasmosis� Causative agent:

� Anaplasma

phagocytophilum

• Formerly known as human granulocytic anaplasmosis (HGA)

� Tick Vectors:

� Ixodes scapularis

• “Blacklegged tick”

� Ixodes pacificus

• “Western blacklegged tick “

Ehrlichiosis� Causative agents:

� Ehrlichia chaffeensis

• Human monocyticehrlichiosis (HME)

� Ehrlichia ewingii

• Human ewingiiehrlichiosis (HEE)

� Tick Vectors:

� Amblyomma

americanum

• “Lone star tick”

Resources: 10,11,15

Anaplasmosis and Ehrlichiosis 10,11,15

� Incubation:

� Anaplasmosis: 1-3 weeks

� Ehrlichiosis: 1-2 weeks

� Signs and Symptoms

� Fever, shaking, chills, headache, malaise, myalgia, GI symptoms, rash

� Conjunctival injection and confusion may occur in Ehrlichiosis

Anaplasmosis and Ehrlichiosis: Diagnosis 10,11,15

� Laboratory Findings:

� Anemia, thrombocytopenia, mildly elevated LFTs, leukopenia

� Visualization of morulae in granulocytes or monocytes

� Laboratory Diagnosis

� Gold standard: IFA on paired samples

• Four-fold change from week 1 to week 4 (3-5)

• Antibodies detectable 7-10 days after onset

� PCR of whole blood

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Anaplasmosis and Ehrlichiosis 10,11,15

� Treatment

� Doxycycline 100mg IV/PO Q12H

� Ceftriaxone may be added if meningococcal disease is suspected

� Duration

� 5 to 14 days, continuing for at least 3 to 5 days after the fever resolves

� In patients with anaplasmosis, coinfection with babesiosis or Lyme disease may occur

Flea and Tick Bite Prevention11

� Wear repellent containing at least 20% DEET or permethrin-treated clothing

� Treat dogs and cats for ticks

� Check for ticks daily, especially under the arms, in and around the ears, inside the belly button, behind the knees, between the legs, around the waist, and on the hairline and scalp

� Shower soon after being outdoors

Tick Removal11

� Use fine-tipped tweezers to grasp the tick as close to the skin’s surface as possible

� Pull upward with steady, even pressure. Don’t twist or jerk the tick; this can cause the mouth-parts to break off and remain in the skin

� After removing the tick, thoroughly clean the bite area and your hands

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Summary

� Y. pestis, Lyme disease, Rocky Mountain Spotted Fever, Babesiosis, Anaplasmosis and Ehrlichiosis have caused extensive morbidity and mortality prior to antibiotic use

� Early treatment is key in preventing morbidity and mortality from Y. pestis, Lyme disease, Rocky Mountain Spotted Fever, Babesiosis, Anaplasmosis and Ehrlichiosis

� Flea and tick bite prevention and management may also help in preventing morbidity and mortality

Assessment Questions

Assessment Questions

� Majority of tick-borne diseases occur in the Northeast United States.

� True/False

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Assessment Questions

� Majority of tick-borne diseases occur in the Northeast United States.

� True/False

Assessment Questions

� Majority of tick-borne diseases occur in the Northeast United States.

� True/False

� Ceftriaxone is the best choice for empiric treatment of a suspected tick-borne disease.

� True/False

Assessment Questions

� Majority of tick-borne diseases occur in the Northeast United States.

� True/False

� Ceftriaxone is the best choice for empiric treatment of a suspected tick-borne disease.

� True/False

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Assessment Questions

� Majority of tick-borne diseases occur in the Northeast United States.

� True/False

� Ceftriaxone is the best choice for empiric treatment of a suspected tick-borne disease.

� True/False

� Wearing repellent containing at least 20% DEET or permethrin-treated clothing can help to prevent tick bites.

� True/ False

Assessment Questions

� Majority of tick-borne diseases occur in the Northeast United States.

� True/False

� Ceftriaxone is the best choice for empiric treatment of a suspected tick-borne disease.

� True/False

� Wearing repellent containing at least 20% DEET or permethrin-treated clothing can help to prevent tick bites.

� True/ False

Resources

1. Lotfy WM. Plague in Egypt: Disease biology, history and contemporary analysis: A minireview. J Adv Res. 2015 Jul;6(4):549-54.

2. Perry RD, Fetherston JD. Yersinia pestis--etiologic agent of plague. Clin

Microbiol Rev. 1997 Jan;10(1):35-66.

3. Eisen RJ, Dennis DT, Gage KL. The Role of Early-Phase Transmission in the Spread of Yersinia pestis. J Med Entomol. 2015 Nov;52(6):1183-92.

4. CDC, Division of Vector-Borne Infectious Diseases: Plague.. CDC. Atlanta,

GA. 2003. Last updated: September 1, 2015

5. Feodorva VA, Motin VL. Plague vaccines: current developments and future perspectives. Emerg Microbes Infect. 2012 Nov;1(11):e36.

6. Gage KL, Kosoy MY. Natural history of the plague: perspectives

from more than a century of research. Annu Rev Entomol. 2005;50:505-28.

7. Stevens DL , Bisno AL , Chambers HF , et al: Practice guidelines for the

diagnosis and management of skin and soft tissue infections: 2014 update by the infectious diseases society of america. Clin Infect Dis 2014; 59(2):e10-e52.

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Resources

8. Inglesby TV, Dennis DR, & Henderson DA: Plague as a biological weapon. JAMA 2000; 283:2281-2290.

9. Butler T: Yersinia species (including plague) In: Mandell GL, Bennett JE, & Dolin R (Eds): Principles and Practice of Infectious Diseases, 5th ed. Churchill Livingston, New York, NY, 2000, pp 2406-2414.

10. Wormser GP, Dattwyler RJ, Shapiro ED, et al. The clinical assessment, treatment and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2006; 43: 1089–1134.

11. CDC, Division of Vector-Borne Infectious Diseases: Tickborne diseases of the United States. CDC. Atlanta, GA. 2015.

12. Dumler JS, Madigan JE, Pusterla N, et al: Ehrlichioses in humans: epidemiology, clinical presentation, diagnosis, and treatment. Clin Infect Dis 2007; 45(Suppl 1):S45-S51.

13. Lyme Disease. Micromedex 2.0. Truven Health Analytics, Inc. Greenwood Village, CO. Available at: http://www.micromedexsolutions.com. Accessed December, 2015.

14. Rocky Mountain Spotted Fever. Micromedex 2.0. Truven Health Analytics, Inc. Greenwood Village, CO. Available at: http://www.micromedexsolutions.com. Accessed December, 2015.

15. Ehrlichiosis; Human anaplasmosis. Micromedex 2.0. Truven Health Analytics, Inc. Greenwood Village, CO. Available at: http://www.micromedexsolutions.com. Accessed December, 2015.

Questions and Discussion

Plague and other tick-borne diseases

Melina Braly, PharmD, BCPS

PGY-2 Critical Care Resident

Baptist Hospital of Miami

January 9, 2016