Transcript Antimicrobials - Stanford University

Hot Topics in Pediatric Infectious
Diseases 2011
Hayley A. Gans, MD
Assistant Professor of Pediatrics,
Stanford University School of Medicine
Stanford University
School of Medicine
Hot Topics in Pediatric Infectious
Diseases 2011
Globalization: “their disease is our disease”
Pertussis: the epidemic continues….
Tuberculosis: Old disease; new diagnostics?
Clinical Case
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5yo previously healthy male
2 days prior: rhinorrhea, congestion, croupy cough
1 day prior: attended daycare, but sent home for temp 99oF
Developed rash on face/trunk
Seen in urgent care;
 103oF, ill appearing
 Conjunctiva injection; OP petechiae on posterior buccal mucosa
 Maculopapular rash pronounced on face/trunk; sparse on LE,
included palms
 PMH: UTD on immunizations: 5 year vaccines 6 days
prior
 SH: Returned 12 days prior from 7 day trip to London
and Spain
Stanford University
School of Medicine
Clinical Case-Laboratory
Rubeola IgG of 0.56 (negative is <0.91)
Rubeola IgM of 1.15 (positive > 1.10)
Urine and nasal swabs for measles PCR were
positive for wild type measles, type D4.
Clinic shut down and public health measures
practiced for 3 weeks
No secondary cases
MRSA
Measles Is Fighting Back Against Eradication
Air travelers possibly exposed to measles
U.S. sees largest outbreak of measles in 15 years
Measles is a global problem, meaning it's everyone's problem
Measles Resurgence
 US declared measles free 2000
 Prior to vaccine
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3–4 million infected each year,
400–500 died
48,000 hospitalized,
1,000 developed chronic disability from measles
encephalitis
 Outbreak : 1989-1991
• 55,000 cases
• 100 deaths
Measles 2011
To date in 2011
-118 cases reported
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-highest case incidence
since 1996
-89% associated with
importation from other
countries: 87% from the
WHO European and SouthEast Asia regions
15% <12 mo: 20% 1-4 yrs
87% unvaccinated
40% hospitalized; all but 1 was unvaccinated
52% were < 12 mo
> 95%
coverage
required to
stop
transmission
International Travelers
50-80 million travelers annually from
industrialized countries to developing countries
• Only ½ seek medical advice prior to travel
• 22-64% report health problems
• 8-19% seek medical care
Travel Advice
Infants 6 -11 mo should have at least one dose
of measles-containing vaccine
• Does not replace routine 2 dose regimen
Children 12 mo or older should have two
doses separated by at least 28 days.
• Fulfills school entry requirement
Adults proof of protection or vaccinate
Clinical Case
 2-year-old previously healthy female
 12 days PTA: developed fevers
 10 days PTA: seen by PMD
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Temp 102-103oF at home
No rhinnorhea, cough, vomiting, diarrhea, or rash
Physical exam: well-appearing and normal
Rec: close observation; possible roseola; RTC for fevers
 7 days PTA: had been afebrile x 2 days, then fever
returned
Clinical Case
 6 days PTA: seen by PMD
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Temp 103.3oF in clinic
Otherwise asymptomatic as before
Physical exam: well appearing
UA & Ucx sent
CXR with no infiltrate
 UA was (+) and Ucx later (+) for 50-75,000 GNRs
 Treated with PO cephalexin
 Continued having fevers at home
Clinical Case
 4 days PTA: seen by PMD for WCC
• Temp 104.8oF at home
• Noted to have decreased appetite
—“Recently returned from India. Since then she has not been eating
well.” Her mother estimates she lost 2 lbs in India
• Impression: Healthy 2-year-old female growing &
developing normally except a UTI with persistent fevers
despite cephalexin. Given fever, IM ceftriaxone was given.
Will not order a BCx today as she has already been on
antibiotics and the culture will likely be sterile.
• Later that day UCx identified as ESBL E.coli
—Cephalexin changed to nitrofurantoin
Clinical Case
 1 day PTA: seen in Urgent Care Clinic
• Persistent fevers; 103.6oF in clinic
• Now with vomiting, diarrhea, and lethargy for the past 2
days
• “Weak, cranky, and limp when standing”
• Impression: acute UTI with vomiting and dehydration as
well as concern for bacteremia
• Referred to El Camino ED -> Admitted to LPCH
• BCx later grew Salmonella typhi
Clinical Case Summary
 2-year-old female with fever onset 7 days after
coming back to the U.S. from a 5 week family visit
to Mumbai, India. No typhoid vaccine was given.
She took malaria prophylaxis. BCx grew Salmonella
typhi.
 Diagnosis made after 13 days of fever and 3 days
vomiting, diarrhea (and potential red-herring UTI)
• 3 PMD visits, 1 urgent care visit
• First documentation of travel to India in 3rd PMD visit.
Typhoid Fever In-Depth Report
In-Depth From A.D.A.M.
General Health Precautions
Typhoid Fever News and Research
Typhoid Fever at Simsbury School
Warning After N.Y. Restaurant Worker Tests Positive
for Typhoid Fever
Enteric Fever
Enteric Fever Risk
150 million people live outside their country of birth
Comprise 25-40% of travelers=
Travelers visiting friends and relatives (VFR)
Enteric Fever Risk
 Highest risk for travelers to South Asia
• Other areas of risk are SE and east Asia, Caribbean, and
South & Central America.
 Travelers to South Asia also at risk for drug resistant
typhoid
 Highest risk are VFRs
 Specific Risk Factors
• Travel to rural areas
• Not following food and water precautions
• Longer duration of stay
VFRs
 VFRs = Travelers returning to their country of origin
to “visit friends and relatives”
 Risk is increased several-fold compared to tourists,
expatriates, & other travelers
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Higher risk of exposure & insufficient protection measures
Less likely to seek pre-travel health care
Less likely to be adequately vaccinated
More likely to stay in remote rural areas
More likely to consume high-risk foods/beverages
Have close contact with local populations
Immigrant VFRs are more likely to seek care only for more lifethreatening illnesses requiring hospitalization
Fever in Returned Travelers
Children are a particularly difficult age group for
evaluation of fever because they have frequent
febrile illnesses at baseline
• Many times their fever will be due to common
childhood illnesses
• In the more rare occasion that it is enteric fever or
malaria, delay in diagnosis leads to increased
morbidity and mortality
Travel history
 Sometimes difficult to elicit travel history
• The family may view travel as “vacation”
• They often do not view it as a risk factor
• It sometimes comes up in passing (ex. of becoming sick
on the plane)
 Important to not only ask about recent travel, but
in some cases past travel
 Also, ask about visiting friends/relatives
• Important for transmissible diseases (i.e. typhoid, TB,
etc)
Febrile Returning Travelers
 The “Big 3”
• Malaria
• Enteric fever (typhoid, paratyphoid)
• Dengue
 Others
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Chikungunya
Leptosporosis
Hepatitis A
Tuberculosis
Acute schistosomiasis
Brucella
Histoplasmosis
Acute HIV
Rickettsiae: African tick bite fever, scrub typhus
Viral hemorrhagic fevers
Vaccine Preventable Illness
— Meningococcal disease, Measles, Hepatitis A & B, Yellow fever, Japanese encephalitis, Rabies
Diagnosis by Travel History
N Engl J Med 2006; 354:119-130
Diagnosis by Incubation Period
 Determining the incubation period can be helpful
in ruling out possible causes of fever
 Malaria can occur during the short, intermediate,
or long incubation period & enteric fever during
the short & intermediate incubation periods
 If the fever begins >21 days after a traveler’s
return, then dengue, rickettsial infections, yellow
fever, & Lassa fever are unlikely
Short Incubation Period
N Engl J Med 2002; 347: 505-516
Intermediate Incubation Period
Long Incubation Period
Typhoid Vaccine
 Oral: live-attenuated Ty21a
• > 6 years old; Revaccinate every 5 years
• Should not be given to immunocompromised hosts/those on antibiotics
 IM: Vi capsular polysaccharide
• > 2 years old; Revaccinate every 2 years
 Protective efficacy (both) 70-80%
Case Presentation
 3wk-old term BB with 10d history cough and
poor feeding followed by breath-holding spells
and cyanosis requiring vigorous stimulation.
 Afebrile, not fussy, no GI symptoms, no rash,
normal amount of wet diapers
 ER in Modesto: sats 92%  85%  2.5L NC
 Wbc 57 (44% polys, 36% lymphs, 20% monos)
Case Presentation
 Rapidly worsening respiratory over 1st 24hrs 
intubated  HFOV  iNO
 Hypotensive  DA
 Wbc increased to 101 (18% polys, 21% bands, 9%
metas, 26% lymphs, 24% monos), CRP 6.8mg/dL
 Anemic, coagulopathic
 Lytes wnl; AST 72, ALT 31, alb 1.8
 CXR: patchy perihilar consolidations, small R pleural
effusion
 Ampicillin, cefotaxime started
 Transferred to LPCH PICU for higher level of care
Case Presentation
I.D. workup (in Modesto):
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Rapid flu A/B negative
Respiratory DFA panel negative
BCx NGTD
Ucx NGTD
CSF cx NGTD, gram stain neg, cells/chemistry wnl
Case Presentation
I.D. workup (in Modesto):
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Rapid fluA/B negative
Respiratory DFA panel negative
BCx NGTD
Ucx NGTD
CSF cx NGTD, gram stain neg, cells/chemistry wnl
ETT aspirate: 4+ gram-negative coccobacilli
Azithromycin 5mg/kg/day added
Case Presentation
 Positive for Bordetella pertussis by PCR
 Despite use of selective media, cultures were
negative
 Azithromycin changed to 10mg/kg q24h
 Developed pulmonary hypertension, worsening
hemodynamic instability
 Exchange transfusion performed
 Required ECMO, CVVH
 Support was withdrawn on hospital day 7
Pertussis Resurgence
10 BABIES DEAD as WHOOPING COUGH (pertussis) is
DECLARED an EPIDEMIC IN CALIFORNIA
Vaccination Is Steady, But Pertussis Is Surging
Whooping cough cases 'remain high'
38-Day-Old Baby Dies After Persisting Cough
Pertussis: Incidence
Pertussis: Incidence
Why the increase?
• Vaccine failures due to genetic change in
organism?
• Increased vaccine failures due to change from
DPT to DTaP?
• Greater awareness of pertussis?
• Better diagnostic tests?
• Less antibiotic use?1
• Macrolide resistance?
1. Finkelstein JA et al. Reduction in antibiotic use among US children. Pediatrics. 2003
Sep;112(3 Pt 1):620-7
.
Pertussis: Incidence
Pertussis: Incidence
Pertussis: Incidence
 Pertussis is the most poorly controlled vaccinepreventable disease
 Adults are susceptible to pertussis
• 27% of reported cases in 2004 were among adults
• Pertussis immunity is not lifelong and wanes 4-12 years after the DTaP
series and 4-20 years after natural infection
• ~20% of cough illness lasting >2 weeks is pertussis
Why here, why now?
 Pertussis epidemics occur every 3-5 years
• enough susceptible people accumulate in the
population to sustain widespread transmission of
pertussis
— Unvaccinated infants
— Waning population immunity from vaccines/disease
— Parental choice not to vaccinate
 It’s unclear why California has been the state most
affected so far in current epidemic
• one of 11 states that does not have a requirement that
all middle school students receive Tdap
California Pertussis Deaths
 Most of the fatal cases in 2010 had several contacts with health
care providers before pertussis was considered
 All CA pertussis deaths (~3/year) since 1996, except one, have
been in infants <3 months of age
 80% Hispanic (50% of birth cohort is Hispanic)
 The mean WBC of fatal cases in 1998-2009 was 75,000 (range
15,000-148,000);
 Of those with known status, all had pulmonary HTN
 A risk factor study is being conducted
Why are Hispanic infants over-represented
among infant cases?
 Increased incidence in Hispanic infants <6 months has been
noted in other states as well
 Higher mortality rates have been estimated nationwide for
Hispanic than for non-Hispanic infants since the 1990s
 In 2000, 30.6 percent of family households in which a Hispanic
person was the householder consisted of five or more people
vs. 11.8 percent of non-Hispanic white family households
Haberling D, et al. Pediatr Infect Dis J 2009;28:194–198
Pertussis: Morbidity and Mortality
 1926-1930: 36,013 deaths, most under 1yr of
age
 1900-1944: 5-fold decrease in infant mortality
 1945-1980: 85-fold decrease in mortality
 2010: 9,477, 10 infant deaths
 Highest rate in 65 years
Hypothetical Ex. 1
Adopted 18 month old who received BCG at
birth.
TST 14mm; IGRA is negative.
History unrevealing; PE normal; Chest x-ray
with no abnormalities.
Hypothetical Ex 2
5yo routine TST for school (SCC)
TST 13mm; IGRA negative
History denotes domestic (NYC) and
international (W&E. Europe) travel; PE
normal; Chest x-ray with no abnormalities.
Hypothetical Ex 3
2 yo with cervical lymph node (2cm)
PPD 10mm; IGRA negative.
History unrevealing (lives in SCC); PE normal
except LN; Chest x-ray with no abnormalities.
Dr. Julie Higashi – Deputy Health Officer SCCPHD
Hospital Employee Exposes Nearly 800
Patients and Staff to Tuberculosis
Four People Exposed To Tuberculosis Test
Positive
Tests for TB Infection
Tuberculin skin test (TST)
Interferon-gamma release assays (IGRA)
Andersen P. Lancet 2000, 356:1099
Interferon-γ Release Assays (IGRA)
Quantiferon®-TB Gold In-Tube
• (Cellestis, Victoria, Australia)
T-SPOT®.TB
• (Oxford Immunotec, Oxford, United Kingdom)
AAP allows use of IGRA for > 5 years old (plus
cautions)
Red Book – IGRA Excerpt
 Children with a positive result from an IGRA should be considered infected
with M. tuberculosis complex. A negative IGRA result cannot universally
be interpreted as absence of infection.
 Because of their higher specificity and lack of cross-reaction with BCG,
IGRAs may be useful in children who have received BCG vaccine. IGRAs
may be useful to determine whether a BCG-immunized child with a
reactive TST more likely has LTBI or has a false-positive TST reaction caused
by the BCG.
 IGRAs cannot be recommended routinely for use in children younger than
5 years of age or for immune-compromised children of any age because of
a lack of published data about their utility with these groups.
 Indeterminate IGRA results do not exclude tuberculosis infection and
should not be used to make clinical decisions.
Quantiferon® TB Gold In-Tube
Quantiferon® TB Gold In-Tube
T-SPOT®. TB
T-SPOT®. TB
M. tuberculosis Testing
Test
Measures T-cell
Response
Distinguishes
Infection vs.
Disease
Antigens
(quantity)
Incubation
Crossreactivity
*
TST
Yes
No
PPD-S
RT-23
(multiple)
48-72h
BCG
M. bovis
Multiple NTM
QIT
Yes
No
ESAT-6
CFP-10
TB 7.7
(3)
16-24h
M. bovis
M. kansasii
M. marinum
M. szulgai
T-SPOT
yes
No
ESAT-6
CFP-10
(2)
16-24h
M. bovis
M. kansasii
M. marinum
M. szulgai
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TST-tuberculin skin testing; BCG-Bacille Calmette-Guérin; NTM-non-TB mycobacteria; QITQuantiferon®-TB Gold In-Tube; T-Spot-T-SPOT®.TB; PPD-purified protein derivative; ESAT-6-early
secretory antigen target 6; CFP-10-culture filtrate protein 10.
IGRA Does not Identify TB Disease
Kampmann B. Eur Respir J 2009, 33:1374
0-5 years old: Lifetime Risk of TB Disease = 10-20%
Horsburgh. NEJM 2004, 350:2060
TB Infection
No gold standard for diagnosis of TB infection
• Thus, no formal sensitivity or specificity
Usefulness of TST for diagnosis of TB infection
is based on long-term follow-up.
Interpretation of Positive Quantiferon®?
Detected TB infection and increased risk of TB
disease
• Based on surrogate endpoint of TB disease.
• TST also positive (and few discordant results).
Interpretation of Negative Quantiferon®?
Did not detect TB infection and no risk of TB
disease.
Based on what?
• No long-term follow-up for future TB disease
• Large number of discordant results with TST
Quantiferon®≠ TST – Why?
TST + due to BCG vaccine?
Problem with IGRA test?
• Interferon-γ production low in young children
• Types of antigens used
• Appropriate “cut-off” points
BCG does not prevent primary TB Infection
Young Children and IFN-γ Response
(mitogen stimulation)
Pediatrics 2009, 123:e419
Indeterminate Quantiferon®
Cut-Off Points
Pai M. JAMA 2005, 293:2746
Quantiferon®≠ TST – Why?
TST + due to BCG vaccine? Not entirely.
Problem with IGRA test? Yes especially in
children
• Interferon-γ production low in young children
• Types of antigens used
• Appropriate “cut-off” points
TST
T-Spot
Mean age 7.5 y (1m – 16y)
Mean F/u duration 1.3 y
Hypothetical Ex. 1
Adopted 18 month old who received BCG at
birth.
TST 14mm; IGRA is negative.
History unrevealing; PE normal; Chest x-ray
with no abnormalities.
Hypothetical Ex 2
5yo routine TST for school (SCC)
TST 13mm; IGRA negative
History denotes domestic (NYC) and
international (W&E. Europe) travel; PE
normal; Chest x-ray with no abnormalities.
Hypothetical Ex 3
2 yo with cervical lymph node (2cm)
PPD 10mm; IGRA negative.
History unrevealing (lives in SCC); PE normal
except LN; Chest x-ray with no abnormalities.