Infectious Disease

Infectious Diseases Update!
Christopher Pfeiffer, MD, MHS
Hospital Epidemiologist, VA Portland HCS
OPSO CME Conference, Sun River, Oregon
Feb 21, 2016
Objectives/Outline
• Understand the changing epidemiology,
clinical manifestations, diagnosis, and
treatment of emerging, re-emerging, and preemergent infectious diseases.
• Learn about strategies and tools available for
outpatient antibiotic stewardship.
Case 1
• CC: fever, HA, myalgia in returned traveler
• 30 yo M returned to US 3d ago; ill for ~1 week.
• Travel: Trinidad 2 weeks for a friend’s 30th
birthday 2 weeks, followed by 2 weeks on island
off coast of Puerto Rico.
– +tick, mosquito bites, hiking with freshwater exposure
– denies new sexual partners, injection drug use (IDU)
• He described acute onset high fever; symmetric,
migratory myalgias and arthralgias; severe
headache. Improved after a few days but then
relapsed.
DDx
Treatable, potentially deadly, diseases:
• Malaria?? (NO: check the CDC malaria map)
• Typhoid fever
Treatable, usually more mild, infections
• Rickettsial disease: tick-bite fever, Lyme
• Leptospirosis
http://www.cdc.gov/malaria/travelers/country_table/a.html
http://wwwnc.cdc.gov/travel/destinations/list/
DDx, more
Endemic/Epidemic Viral diseases:
• Dengue
• Chikungunya
• Zika
• Yellow fever?
• West Nile virus?
-----------Other:
• HIV, CMV, EBV, parvovirus
• Measles?
Recent Viral Invasion of
Western Hemisphere!
• Dengue: stealthy over decades; more
aggressively in 90’s
• West Nile: 1999
• Chikungunya: 2013
• Zika: 2015
Fauci and Morens, NEJM 2016
http://www.cdc.gov/zika/
Pertinent Basic Virology
Flaviviruses
• Single-strand, linear, positive-sense RNA, family Flaviviridae
• Mosquito and tick-borne
• Dengue, Zika, West Nile, St. Louis, Tick-borne Encephalitis,
Powassan, Yellow fever, Japanese encephalitis
– Important: disease overlap in serologic testing!
Alphaviruses
• Single-strand, linear, positive-sense RNA, family Togaviridae
• All mosquito-borne
• 2 main clinical syndromes:
– Encephalitis: EEE, WEE, VEE
– Fever, joint pain, rash: Chikungunya (CHIK), Ross River, Barmah
Forest, Sindbis
Manual of Clnical Microbiology, 11th ed.
Dengue Virus, aka Breakbone Fever
• 4 types (DENV-1, -2, -3, -4)
– Immunity not cross-protective
– 100-fold risk of Dengue Hemorrhagic Fever (DHF) with
acquisition of secondary (2nd type of) infection!
• Transmission: Aedes mosquitos, primarily A. aegypti
• Epidemiology:
– #1 worldwide arboviral disease (~100M/yr)
– 75% in Asia/Western Pacific
– Rapidly increasing burden in Latin America and Caribbean
since 1970’s
– Key West, FL and Southern Texas have locally established
mosquito reservoirs and human infections
Dengue Map
Oregon’s Imported Cases
Dengue Fever
• Incubation 4-7d
• Classically:
– Flu-like illness, frontal headache, retro-orbital pain
– Followed by: musculoskeletal and lumbar back pain,
abdominal tenderness (liver), macular rash sparing palms,
anorexia, n/v
– Minor bleeding is common from mucosal surfaces, GI tract
• “saddleback pattern” possible
• followed by long period of fatigue +/- depression
Dengue Hemorrhagic Fever
Dengue Dx/Tx
• Diagnosis: IgM, IgG commercially available
• Treatment: supportive (aggressive for DHF)
• Prognosis for DHF
• Untreated: 50% mortality
• Treated in experienced centers: <1% mortality
Chikungunya (CHIK) Virus
• “to walk bent over”
• 1st isolated in Tanzania in 1952-3
• Transmission: Aedes mosquitos
– several mutations (2006-2011) allowed for adoption to A.
albopictus  wider spread!
• Epidemiology:
– 2006-7 Reunion Island outbreak
– 2006-2011: India (1.4M cases), other Indian
Ocean islands such as Madagascar
– 2013-current: Caribbean  Americas
Current CHIK map
http://www.cdc.gov/chikungunya/geo/
CHIK Clinical Manifestations
• Incubation 1-12 days
• Common symptoms:
– Abrupt onset high fever, chills
– Then acute onset of painful polyarthritis
• small joints and site of old injuries
• duration 1 week to several months
– Rash: neck, trunk  can include face, palms, soles
– Myalgia, photophobia, retro-orbital pain, nausea
• Atypical: meningoencephalitis, eye findings, bullous
dermatitis, hepatitis, pneumonia
CHIK, continued
• Dx: IgM, IgG commercially available and
through Oregon State Lab
• Prognosis:
– Mortality: 0.1%
– Chronic symptoms
• >50% reported persistent arthralgia and/or arthopathy
from Reunion Island @18 and 36 mths
Zika
• Originally isolated in 1952 in the Zika Forest, Uganda in
a caged, febrile rhesus monkey.
• Transmission: A. aegypti, A. albopictus mosquitos,
sexual
• Epi:
– Primarily in Africa, spread to SE Asia
– 2007 outbreak on Yap Island,
Micronesia (59 cases)
– 2015 Brazil  widespread
to Americas
http://www.cdc.gov/zika/
Current Zika Map in Americas
USA Cases:
Travel-acquired:82
-- Oregon = 1
Locally-acquired
in US Territories:
--Puerto Rico
--US Virgin Islands
As of Feb 22, 2016
Zika Clinical Manifestations
• Incubation ~3d
• ~80% cases asymptomatic
• From Yap Island outbreak:
– Rash 90%, fever 65%, conjunctivitis 55%,
headache 45%
• Newer reports include arthralgia, myalgia
• New possible associations:
– Guillian-Barre?
– Microcephaly?
Important Zika Resources
Use these for updated travel, epi, clinical, diagnosis,
and treatment guidance
• OHA:
http://public.health.oregon.gov/DiseasesConditio
ns/DiseasesAZ/Pages/zika-providers.aspx#oregon
– Current Testing: serology sent to CDC through county
health department (and State Health Lab)
• CDC: http://www.cdc.gov/zika/index.html
Most Recent from OHA
See: bitly.com/zikaoregon
• Whom to test?
– Symptomatic returned travelers
– Returned pregnant travelers with evidence of fetal
microcephaly / CNS deficits (in utero or post partum)
– Asymptomatic pregnant travelers w/in 2-12 weeks of
return
• Testing:
– Testing for Zika, Dengue, and CHIK routed through OHA
to CDC  PCR and/or serology as indicated and per a
complex algorithm determined by CDC
http://www.cdc.gov/zika/pdfs/denvchikvzikv-testing-algorithm.pdf
http://www.cdc.gov/zika/
Take Home Points (1)
Returned Traveler with Fever
• Rule out high-stakes treatable diseases
– Malaria
– Typhoid fever
– Other: Rickettsial disease, leptospirosis
• With recent travel to Caribbean, consider:
– Dengue “breakbone fever”
– Chikungunya “to walk bent over”; and
– Zika
Case 2
• 65 yo M Vietnam veteran:
– CC: My eyes are bloodshot and everything flutters
• HPI:
– 2 months ago: L eye vision w/ new black spot
• Ophthalmology Dx: iridocyclitis.
• Started prednisone (20 mg BIDx 2 weeks). Vision improved.
– 1 month prior: hair began falling out; on head 1st; then
eyelashes, eyebrows, legs, arm-pits, and back.
• Some hair returning but now white. Moustache white.
– On presentation: L eye vision worse again, described as
a blue and white "Nike symbol".
• No floaters. No flashes. Still able to read. No photophobia. No
redness or pain.
courtesy of Kevin Winthrop, MD
PMHx, SH, ROS
• PMH: hypothyroidism, DM II
• SH
– Wife swapping in Italy 15-20 years ago
– Served Vietnam: “war and women”
• ROS
– Tingly left toes (6 years prior)
– Tinnitus left ear, minimal hearing loss (1.5 years
prior)
Labs
• ESR 85, CBC and Comp WNL
• Pertinent tests: HIV Ab, Toxo Ab, Bartonella
Ag, Lyme Ab, ACE < 3, HbA1c 5.8
• CXR with slight tortuousity of aorta
• Negative PPD
Anything else???
• RPR 1:128, FTA-ABS positive
Syphilis!!!
Primary and Secondary Syphilis –
Rates by State, US and Outlying Areas, 2010
Updated map: 2013
In 2014
42% HIV+
92% male
-71% MSM
https://public.health.oregon.gov
https://public.health.oregon.gov
Infection
Stages
Mandell et al. Infectious Diseases
Clinical Manifestations
• 1°:
– “painless” chancre at site of inoculation
• highly infectious, lasts 1-5 weeks, heals spontaneously
• 2°
– >95% have a rash: maculo-papular, trunk to palms/soles
• Other: pustular, annular, scaly (psoriasis-like), mucosal
– Other: lymphadenopathy (epitrochlear), fever/malaise
– Less common: condyloma lata, alopecia, hepatitis,
synovitis, nephritis, ocular Sx, meningitis, periostitis
Mandell et al. Infectious Diseases
1° Chancre w/ Darkfield Microscopy
Typical rash of 2° syphilis
2° syphilis: less common findings
Lues Maligna
Condyloma lata
UpToDate
Mandell et al. Infectious Diseases
More Stages/Clinical Manifestations
• Latent (early <1 year; late >1 year*)
– Sub-clinically active disease
• 3°
– Late Neurosyphilis
– Cardiovascular- aortitis
– Gummatous- granulomatous, nodular lesions in a variety of
organs including skin, bones, CNS.
• Neurosyphilis
– Early: mostly meninigitis
– Late: parynchematous including tabes dorsalis & general
paresis; meningovascular; less commonly meningitis
Mandell et al. Infectious Diseases
Tertiary Syphilis
Mandell et al. Infectious Diseases
Syphilis Serologic Diagnosis
• Requires 2 positive antibody tests, generally of
different types
– Nontreponemal Abs
– Treponemal Abs
Nontreponemal Tests
• Examples: VDRL, RPR
• Principles
– Measure Ab to cardiolipin-lecithin-cholesterol Ag
– Titers correlate with disease activity
– Titers may remain low-level positive despite
successful treatment, i.e., remain “serofast”
http://www2a.cdc.gov/stdtraining/ready-to-use/syphilis.htm
Treponemal Tests
• Examples: FTA-ABS, TP-PA, EIA
• Principles
– Measure Ab directed against T. pallidum Ag
– Qualitative (+/- only)
– Usually reactive for life
http://www2a.cdc.gov/stdtraining/ready-to-use/syphilis.htm
43
Note: LOW
Sensitivity
Syphilis: Test Sensitivity
Stage of Disease (Percent Positive [Range])
Test
Primary
Secondary
Latent
Tertiary
RPR
86 (77–99)
100
98 (95–100)
73
FTA-ABS*
84 (70–100)
100
100
96
Treponemal
Agglutination*
76 (69–90)
100
97 (97–100)
94
93
100
100
EIA
EIA: higher sensitivity but lower specificity than TP-PA
*FTA-ABS and TP-PA are generally considered equally sensitive in the primary stage of disease.
http://www2a.cdc.gov/stdtraining/ready-to-use/syphilis.htm
44
Syphilis Screening Algorithm Options
Traditional
New
EIA
RPR
TPPA
Syphilis
unlikely
RPR
Syphilis
Syphilis
(past or
present)
Syphilis
unlikely
(past or Type
present) equation
Syphilis
unlikely
TP-PA
here.
Syphilis
(past)
http://www2a.cdc.gov/stdtraining/ready-to-use/syphilis.htm
Syphilis
unlikely
Which Algorithm to Use?
• Traditional
– Hands-on test
– Modest biological false-positive rate
– May miss tertiary, early primary, and succussfully
treated infections
• New, reverse-sequence
– Automated test
– Requires RPR to detect disease activity
– If RPR negative, requires 2nd treponemal test to
confirm diagnosis
http://www2a.cdc.gov/stdtraining/ready-to-use/syphilis.htm
Treatment
Primary, secondary, early latent disease
• benzathine PCN G 2.4 MU IM x1 dose
• treat all partners exposed in past 90 days
Rationale for short course: actively dividing spirochetes
Unknown duration, late-latent, or tertiary disease
• benzathine PCN G 2.4 MU IM weekly x3 doses
Rationale for longer course: slowly/non-dividing sprirochetes
Neurosyphilis
• Aqueous crystalline PCN G 18-24 MU IV daily in divided doses
q4 or continuously
Rationale for IV: need better CNS drug concentration
STD treatment guidelines, CDC.gov accessed 2016
Syphilis Prevention in Oregon, 2016
• The obvious: abstain from sex or use condoms
• Screen high-risk patients up to quarterly!
– Sexually active individuals with multiple partners,
particularly those HIV+, MSM, h/o STDs, IDUs
• Screen 3 times in pregnancy– 1st visit
– Beginning of 3rd trimester
– At delivery
https://public.health.oregon.gov
Case
• 80 yo Romanian man was hospitalized after CVA.
• After discharge, a family member living in Oregon
brought him to Oregon to care for him.
• He was re-hospitalized in Oregon for failure-tothrive, then transferred to a nursing facility.
• Urine cultures from the ED grew the following:
Klebsiella pneumoniae
• Susceptible to: amikacin only
• Resistant to: everything else!!!
– Ampicillin, Amp/Sulb, Pip/Tazo, Cefazolin, Ceftazidime,
Ceftriaxone, Cefepime
– Ertapenem (>8), Meropenem (4)
– Gentamicin, Tobramycin
– Ciprofloxacin, Nitrofurantoin, Bactrim
• Sent to State Public Health Lab for further testing:
– OXA-48 carbapenemase-positive
Overview of Commonly Encountered
Drug-Resistant Gram-Negative Rods
• Enterobacteriaceae
– Family of gut bacteria, e.g., E. coli, Klebsiella, Enterobacter
– Resistance mechanisms shared across species through plasmids
– Examples: extended-spectrum β-lactamases (ESBLs), AmpCs,
carbapenemases
• “Non-enterics”
– Pseudomonas aeruginosa
– Acinetobacter baumannii
CRE = carbapenem-resistant Enterobacteriaceae
CP-CRE = carbapenemase-producing CRE
http://www.cdc.gov/drugresistance/threat-report-2013/
The mechanism of resistance matters
1. Carbapenemase-producing CRE (CP-CRE)
 Enzymes produced that directly inactivate carbapenem
antibiotics (e.g., KPC, NDM, OXA-48, VIM, IMP)
 Rapid worldwide spread!!!
 Very uncommon in Oregon
2. Non-CP-CRE
 Multiple mechanisms required for carbapenem resistance
 Relatively stable incidence nationally
 Less uncommon in Oregon
(CP)-CRE: Clinical Impact
• ~30-50% mortality of invasive infection across
multiple studies
• Treatment options are very limited; “doublecoverage” often recommended:
–
–
–
–
–
Colistin
Tigecycline
Aminoglycoside
Fosfomycin (UTIs)
New: ceftazidime-avibactam (Avycaz; $$$; IV only;
active against KPC, possibly OXA-48, not against NDM)
Drug-Resistant Organism Prevention and Coordinated Regional
Epidemiology (DROP-CRE) Network
CRE
Initiated September 2012
DROP-CRE
• Main goals:
– Detect all cases rapidly
– Prevent Spread by responding aggressively to all
CP-CRE cases
– Educate providers and patients about CRE
Updated Oregon CRE Toolkit, 2016
• CRE definitions
• Prevention and Control
recommendations:
– Acute Care
– Skilled nursing
– Ambulatory Care, etc.
• Educational material for patients
and providers
• CRE protocols used in Oregon
CRE reported by Oregon laboratories,
Nov 2010 – Dec 2015
1
3
2
1
1
3
3
2
1
3
2
2
2
1
1
1
1
1
2
2
1
1
2 2 2
1
4
4
3
2
1
6
6
6
1
10
1
10
9
8
16
15
1
other CRE
13
13 1
14
13
1
4 4 4
4
1
CP-CRE
18
1
Dec-16
Nov-16
Oct-15
Sep-15
Aug-15
Jul-15
Jun-15
May-15
Apr-15
Mar-15
Feb-15
Jan-15
Dec-14
Nov-14
Oct-14
Sep-14
Aug-14
Jul-14
Jun-14
May-14
Apr-14
Mar-14
Feb-14
Jan-14
Dec-13
Nov-13
Oct-13
Sep-13
Aug-13
Jul-13
Jun-13
May-13
Apr-13
Mar-13
Feb-13
Jan-13
Dec-12
Nov-12
Oct-12
Sep-12
Aug-12
Jul-12
Jun-12
May-12
Apr-12
Mar-12
Feb-12
Jan-12
Dec-11
………………………………
Nov-10
CRE in Oregon by county,
Nov 2010 – Dec 2015
Oregon’s CP-CRE, n=10
• Sex: 5 (50%) males
• Age: 61- 88 years (median: 76)
• Source:
– 2 wounds, 5 urines,1 blood, 1 sputum, 1 tissue
• 6 (60%) hospitalized at collection
• 8 (80%) health care out of state (<1.5 yr prior)
61
Back to the Case
• CP-CRE identified
– Resident placed in Contact Precautions
– Public health/DROP-CRE team rapidly notified and teleconferenced facilities to review CRE Toolkit recommendations
• Patient (or resident) management: isolation, cohorting, etc.
• CRE screening for contacts: who and how
• Inter-facility transfer notification
– A contact investigation revealed no disease spread
• Fortunately, he was colonized and did not require
treatment.
CRE Education/Resources

Oregon CRE website (and Toolkit)
◦ http://public.health.oregon.gov/diseasescondition
s/diseasesaz/pages/disease.aspx?did=108

CDC CRE website (and Toolkit)
◦ http://www.cdc.gov/HAI/organisms/cre/
CRE & Primary Care?
• You may be asked about CRE by curious patients
and family
• One of your patients may become CRE
colonized/infected
• What can you do?
– Use Oregon CRE Toolkit to yourself about CRE
– Practice Antibiotic Stewardship
Reasons for Stewardship
• Prevent Unnecessary Resistance
– Gram-negative organisms (CRE, ESBLs, Pseudomonas, etc.)
– N. gonorrhoeae, MRSA, VRE, Candida, Shigella,
Salmonella, S. pneumoniae, TB
• Avoid Unnecessary Harm
– Allergic Reactions
– C. difficile infection
– Drug Interactions and Side Effects
• Save Money
http://www.cdc.gov/drugresistance/threat-report-2013/pdf/arthreats-2013-508.pdf
Where to start?
• Avoid antibiotics for:
– Asymptomatic bacteriuria
– Acute upper respiratory tract infection
– Sinusitis (prior to day 7)
• Use antibiotics wisely
– Treat using national guidelines (IDSA, etc.)
– Avoid quinolones when possible (UTIs, pneumonia)
How to Improve Your Practice?
• Implement clinical pathways or electronic clinical
decision support systems for pre-defined common
diseases (bronchitis, UTI)
• Place provider-signed letters in the clinic attesting a
commitment to judicious antibiotic prescribing
(“Nudge”)
• Antibiotic prescription performance feedback
• Use point-of-care rapid diagnostics
Gerber JS et al. JAMA. 2014;312(23):2569-70.
Meeker D et al. JAMA Intern Med. 2014;174(3):425-431
Point-of-care testing in the office
Alere™ i Influenza A & B
–
–
–
–
CLIA-waived
Nasal swabs
15 minutes
>97% sensitivity/specificity2
Alere™ i Strep A
– 8 minutes
– >98% sensitivity/specificity3
1http://www.cdc.gov/flu/professionals/diagnosis/clinician_guidance_ridt.htm
2Bell
et al., J Clin Virol. 2014 Sep;61(1):81-6. doi: 10.1016/j.jcv.2014.06.001
3Cohen et al,. J Clin Microbiol. 2015 May 13. pii: JCM.00490-15. [Epub ahead of print]
Summary (1)
• Dengue, Chikungunya, and Zika are emerging
viruses carried by Aedes mosquitos with highly
overlapping clinical presentations.
• Syphilis is back!
– Recall the unusual clinical manifestations
– Screen high-risk and pregnant patients frequently
– Understand the new screening algorithm
Summary (2)
• CRE
– Uncommon in Oregon, particularly CP-CRE
– DROP-CRE goal: prevent emergence and spread
– Use Oregon CRE Toolkit and DROP-CRE Team as
resources with any questions
• Outpatient Antibiotic Stewardship
– Prevents drug resistance, adverse events, and saves
money
– Improve your practice: set goals and select a strategy
Thank you!! Questions?
Acknowledgements
DROP-CRE Working Group
Zintars Beldavs, MS
Gen Buser, MD, MSHP
Maureen Cassidy, MT, MPH
Kate Ellingson, PhD
Ann Thomas, MD, MPH
JJ Furuno, PhD
John Townes, MD
Andy Leitz, MD
Mary Post, RN, MS, CNS, CIC
Regional Collaborators
DROP-CRE Advisory Committee
CRE Stakeholders in Oregon (IPs, labs, LTCFs)
OSPHL Personnel / Karim Morey
Oregon Patient Safety Commission
Washington State DOH
Weissman laboratory
National Collaborators
Alex Kallen, MD, MPH (CDC)
Nimalie Stone, MD (CDC)
Keith Kaye, MD, MPH (Detroit Medical Center)
Robert Bonomo, MD (Cleveland VAMC)
VA Portland and OHSU ID Division
Tom Ward, MD
Graeme Forrest, MBBS
Etc.