Postexposure prophylaxis之適應症

衛生署 疾病管制局

中區傳染病防治醫療網指揮中心

王任賢 指揮官

Treatment Model

• Prophylaxis• Pre-emptive treatment• Empirical treatment• Target treatment

Post-Exposure Prophylaxis• Bacterial agents

– Meningococcus– Anthrax– Plaque– Tularemia

• Viral agents– HIV, Hep B, Hep C– Influenza, VZV, Vaccinia– Rabies

• Toxins– Few of options

• ClL. Botulinum-trivalent equine anti-toxin

PEP for Meningococcus

Prevention of meningococcal disease

• Antibiotics prophylaxis• Vaccination

Age-related nasopharyngeal meningocccal

carriage in 1238 asymptomatic Montreal children

0

0.5

1

1.5

2

2.5

3

< 2M 2M-2Y 3-5Y 6-10Y >11Y

asym

ptom

atic

car

rier (

%)

AgeAM J Epidemiol 1979;109:563-71

Meningococcal (group C) carrier rate in household contact

• < 1 year: 37.8% (14/37)• 1-14 years: 17.5% (43/246)• > 15 years: 6.9% (6/87)

J Pediatr 1981;98:485

Secondary attack rate of meningococcal meningitis

• Norton & Gordon (1929):4.4% (30/724)(data from outbreak in Detroit)

• Pizzi (1944):3.9% (< 15 y/o)1.5% (> 15 y/o)2.5% (all ages)(data from outbreak in Santiago, Chile)

• Jacobson, et al (1976):do not increase risk among classmate contact(data from Brazilian epidemic)

Eradication rates of meningococcusand HIB following treatment of carrier

Meningococcus HIBAgent tested % eradication Agent tested % eradicationOxytetracycline 5% Placebo 26%Erythromycin 0% Cefaclor 18%Pen G 25-33% EM/SMX 20%Procaine PC 49% TMP/SMX 58%Ampicillin 62% mpicillinA 70%Minocycline 83% Rifampin 71%Rifampin 93% (10 mg/kg/dose)Minocycline 100% Rifampin 96%/Rifampin (20 mg/kg/dose)

Ped Infect Dis 1982;1:140 & NEJM 1969;281:641

Prophylactic agents for bacterial meningitis

• for meningococcusrifampin: adult 600 mg bid for 2 days

< 12 y/o 10 mg/kg bid for 2 days< 1 m/o 5 mg/kg bid for 2 days

ciprofloxacin 500 mg PO single doseceftriaxone 250 mg, adult, IM single dose

125 mg, children, IM single dose• for HIB

rifampin: 20 mg/kg qd for 4 days

Prophylaxis of meningococcus• Indicated for chemoprophylaxis

all household contactsnursery school contactsmouth-to-mouth resuscitationindex case

• Not indicated for chemoprophylaxisschool-age contactsmedical personnel

Mass antibiotics prophylaxis to control a prolonged outbreak of meningococcal disease in an

Israeli villageEur J Clin Microbiol Infect Dis 1998;17:749-53

背景資料

• 以色列北部長期遭 meningococcus B的肆虐，疾病年平均發生率為 37.4/10萬，死亡率11%

• 其中有兩村落 Deir el-Asad與 B‘ine，總人口數11,600，環境衛生很差，死亡率23%

• 由於此兩村落的居民相當恐慌，當地衛生單位便對此二地於 Jan 15-18, 1994 實施全面抗生素預防性投藥 (ceftriaxone 125 mg IM stat or ciprofloxacin 500 mg PO stat)

Eur J Clin Microbiol Infect Dis 1998;17:749-53

N. meningitidis isolated from pharyngeal carriers* before vs after prophylaxis

Age (yrs) No. of Total isolate (%)subjects Before After

0 249 19 (7.6) 3 (1.2)1-9 118 18 (15.3) 1 (0.8)10-19 129 16 (12.4) 2 (1.5)20-29 141 3 (2.1) 3 (2.7)30-39 128 7 (5.5) 1 (0.8)>40 271 15 (5.5) 4 (1.4)Total 1036 86 (8.3) 14 (1.3)

*in control an prolonged outbreak in northern Israel

Eur J Clin Microb Infect Dis 1998;17:749-53

Incidence of meningococcal disease before & after mass antibiotic prophylaxis

Year Annual incidence/100,000 (no. of cases) RelativeVillages District Total risk*

1991 25.9 (3) 1.3 (4) 2.1 (7) 20.71992 8.7 (1) 1.6 (5) 1.8 (6) 5.41993 77.6 (9) 2.8 (9) 5.4 (18) 27.71991-93 37.4 (13) 1.9 (18) 3.1 (31) 19.61994 43.1 (5) 1.2 (4) 2.7 (9) 34.51995 43.1 (5) 0.9 (3) 2.4 (8) 45.81996 17.2 (2) 3.1 (10) 3.6 (12) 5.51994-96 34.5 (12) 1.8 (17) 2.9 (29) 19.2

*Reference group is the Akko district without villagesEur J Clin Microb Infect Dis 1998;17:749-53

PEP for Anthrax

Inhalational anthrax: post-exposure drug administration

• 6 groups/10 animals each– 30 days antimicrobial: 1) ciprofloxacin, 2)

doxycycline, 3) penicillin, 4) doxy + vaccine – 5) vaccine, 6) control

• Survival following aerosol challenge days 0-120

• Mortality rates– at 90 days (evaluable population)– up to 130 days (ITT population)

Friedlander et al 1993

Challenge (from Friedlander et al 1993)S

urvi

val

TOCEnd of treatment Days Post-Exposure0 20 40 60 80 100 120

0.0

0.2

0.4

0.6

0.8

1.0

ControlCipro

Challenge (from Friedlander et al 1993)S

urvi

val

TOCEnd of treatment Days Post-Exposure0 20 40 60 80 100 120

0.0

0.2

0.4

0.6

0.8

1.0

ControlVaccinePenCiproDoxyDoxy+Vacc

Intent-to-treat Analysis:Including all cause of death up to re-challenge

Treatment All

deaths P vs.

control 95% CI of

treatment - control

Control untreated

9/10

Vaccine alone 8/10 > 0.1 (-54, 37) Penicillin 3/10 0.0198 (-89, -12) Ciprofloxacin 3/10 0.0198 (-89, -12) Doxycycline 1/10 0.0011 (-98, -36) Doxy + vaccine 1/10 0.0011 (-98, -36)

P-value was calculated using a two-tailed Fisher’s exact test.95% confidence interval was calculated using an exact method.

Evaluable Population Analysis:Cause of death proven to be due to Anthax (TOC=90)

Treatment Anthrax

deaths P vs.

control 95% CI of treatment -

control Control untreated 9/10 Vaccine alone 8/10 > 0.1 (-54, 37) Penicillin 3/10 0.0198 (-89, -12) Ciprofloxacin 1/9 0.0011 (-98, -35) Doxycycline 1/10 0.0011 (-98, -36) Doxy + vaccine 0/9 0.0001 (-100, -52)

Prevention of inhalational anthrax: duration of drug administration

• 5, 10, 20 days too short• 30 days look better• Of the ciprofloxacin cohort, one anthrax death

at 36 days • Spore load decreases over time• Is there a minimum?

Prevention of inhalational anthrax:human epidemiology

• Sverdlovsk 1979 published account: longest incubation fatal case 43 days (Patient #42)

• Industrial exposure– nonimmunized mill workers inhale 150-700

anthrax-contaminated particles < 5µ/ shift– clinical disease rare– likelihood of development of anthrax independent

of duration of employment

Summary I: Inhalational anthrax

• Rare, rapidly progressive disease with very high mortality

• Little opportunity to improve outcome with treatment once clinical disease recognized

• Identified as a clinical manifestation of a biological agent of highest potential concern

Summary II: Inhalational anthrax

• Currently no drug approved for prophylaxis• Cannot be studied in humans• Non-human primate model demonstrates

similar pathology and mortality as humans

Summary III: Ciprofloxacin• Post-exposure administration in primate model

shown to significantly improve survival compared with placebo

• Comparable blood levels achieved with– dose used* for successful prophylaxis in primate model of

inhalational anthrax– 500 mg po q 12 hours in adults– 15 mg/kg po q 12 hours in children

• Blood levels achieved experimental animals and humans ~30-50x MIC90 B. anthracis

• *250 mg followed by 125 mg q 12 hr

Summary IV: Ciprofloxacin

• Broad array of indications with substantial clinical experience

• Well-characterized safety database

Summary V: Prophylaxis of inhalational anthrax

• Prophylaxis an effort to reduce risk• Ciprofloxacin survival better than placebo

following 30-day regimen• Epidemiologic data suggest duration of drug

administration at least 45 days• Duration of proposed regimen is 60 days

Anthrax: Post-Exposure Treatment

• Start oral antibiotics

Anthrax: Vaccine• Current U.S. vaccine (FDA Licensed)

– Culture supernatant (PA) of attenuated non-encapsulated strain

– Protective against cutaneous (human data) and possibly inhalational anthrax (animal data)

– Injections at 0, 2, and 4 weeks, then 6, 12, and 18 months, yearly boosters

– 3 dose schedule (0, 2, and 4 weeks ) may be effective

– 83% serologic response after 3 doses; 100% after 5 doses

– Limited availability

Anthrax: Vaccine• Up to 30% with mild discomfort (tenderness,

redness, swelling, or itching) at inoculation site for up to 72 hours

• < 2% with more severe local reactions, potentially limiting use of the arm for 1 to 2 days

• Systemic reactions uncommon

PEP for Plague, Tularemia

Plague: Prophylaxis• Bubonic contacts

– If common exposure to fleas or infected animals, consider oral Doxycycline, Tetracycline, or TMP/SMX for 7 days

– Other close contacts, fever watch for 7 days (treat if febrile)

• Pneumonic plague contacts (respiratory/droplet exposure)– Consider oral Doxycycline, Tetracycline, or TMP/SMX– Continue for 7 days after last exposure

• Vaccine no longer manufactured in U.S.

Tularemia: Treatment/Prophylaxis

• Treatment– Streptomycin or Gentamicin

• Prophylaxis– Observe for development of fever for 7 days

(preferable)– Doxycycline or Tetracycline for 14 days if febrile

• Vaccine investigational, not available

PEP for VZV

Options for Post-Exposure Prophylaxis in At-Risk Individuals

• IGIV• Vaccine• Antivirals• VZIG• (ISG or therapeutic antivirals)

IGIV•Advantages:

– Some data to support it’s use– Currently has good anti-varicella titers

•Will need 300 - 400mg/kg (3 - 8ml/ kg)– Usually in ample supply

•Disadvantages:– Cost and difficulty of administration:

• Intravenous line needed• 2 - 4 hours for administration• Volume of administration in Newborns?

– Not titered for VZV antibodies– Waning Anti-varicella titers in the post-vaccine era?

Comparison of VZV Antibody Titers in Patients Given IGIV or VZIG

– Pediatric oncology patients susceptible to varicella, but not exposed

• 4 patients - VZIG 1 vial/10 kg• 4 patients - IGIV 4 ml/kg at 4-week intervals • 5 patients – IGIV 6 ml/kg at 6-week intervals

– VZV IgG antibody titers for a period of 4 to 6 weeks after IGIV (4 ml/kg or 6 ml/kg) were equivalent to the titers measured 3 to 4 weeks after VZIG

– Maximum VZV IgG antibody titers similar in all three groups:

• achieved within 24 h after IGIV and 1 week after VZIG

Paryani, et al., J Pediatr, 1984

IGIV Prophylaxis in High Risk Children• Shu-Huey, et. al., Pediatr Hematol and Oncology, 1992:

– 5 VZV susceptible leukemic children– IGIV (200mg/kg) within 3 days of a household exposure– No varicella developed in any of the five (7 exposures)

• Kavaliotis et. al., Med and Pediatr Oncol, 1998:– 52 pediatric oncology patients (79 exposures)– Prophlylaxis within 6-24 hours after exposure

• 11 VZIG – 0 infected• 30 IGIV – 3 infected• 38 VZIG+IGIV – 3 infected

– Varicella was mild, recovered after ACV (IV 7 days + PO 7 days)– Only 11% of patients developed varicella

• Ferdman, et. al., PID, 2000:– 3 patients who developed varicella despite IGIV therapy (7, 11, 30 days

before exposure)– Varicella was mild (IGIV, CD4 count, acyclovir therapy)– IGIV-treated individuals with profound T cell deficiency or dysfunction may

not respond as well and VZIG prophylaxis should be considered

Vaccine for Post-exposure Prophylaxis

• Advantages:– Data in healthy individuals

• < 13 years of age at ≤ 36 hours post-exposure:– 0/42 vaccinated vs. 1/1 unvaccinated developed varicella

– Long-lasting protection– Easy to administer

• Disadvantages:– Not appropriate for immunocompromised hosts,

Pregnant women or Newborns– Efficacy of one dose for post-exposure prophylaxis in

Healthy Adults?

Antivirals for Prophylaxis• Advantages

– Some data in healthy children– Available (Acyclovir, Famciclovir, Valacyclovir)– Effective after the window for use of VZIG has passed

• Disadvantages:– Limited data in immunocompromised patients– Class C drugs in pregnancy– Use as P.O. prophylaxis in newborns?– Most of the data is with Acyclovir

• Poor adsorption of P.O. Acyclovir– No liquid formulations of Famciclovir or Valacyclovir

• Limits use in young children & infants–Multiple day regimen/ compliance will effect efficacy

Oral ACV During The Incubation Period (1)

ACV post-household exposure

0-3 days 6-10 days No ACVParticipants 13 14 19

Infection rate: 85% 79% 100%Clinical attack rate: 91% 27% 100%Severity: milder

Suga, et. al., Arch Dis Child, 1993

Postexposure Prophylaxis of Varicella in Household Contacts by Oral ACV (1)

• Asano et al (Pediatrics, 1993), Lin et al (PID, 1997), Huang et al (PID, 1997)– Oral ACV given to 69 healthy children, starting 7, 9, or 11 days

after HH exposure– Clinical features were compared with those among 51 controls

who did not receive ACV– The infection rate (seroconversion, ELISA) was similar in the

two groups – The clinical attack rate and severity of varicella were

significantly lower in the ACV group

Postexposure Prophylaxis with Oral ACV in High Risk Children (1)

• Hayakawa et al (J Hosp Infect, 2003)– Oral ACV administered to 6 preterm infants in cribs in the

NCU, starting 7 days post-exposure– None of them developed clinical varicella or had any adverse

effects associated with ACV – Seroconversion was not observed in any infant – VZV DNA was not detected in 6 preterm infants on the

expected day of onset of varicella (oral ACV completely inhibit replication or no transmission)

Postexposure Prophylaxis with Oral ACV in High Risk Children (2)

• Hernandez Martin (Pediatr Nephrol, 2000)– 2 children (3 and 5 yo) with nephrotic syndrome receiving

steroids– Oral ACV given on the 9th day post-exposure (used twice the

usual dose) – Both patients developed humoral immunity (ELISA 2, 6, 9

months postexposure) without evidence of clinical infection

Postexposure Prophylaxis with Oral ACV in High Risk Children (3)

• Ishida et al (Pediatrics, 1996)– 3 children (1-2 yo) with ALL– Oral ACV administered within 48 h post-exposure– Varicella was completely prevented in one child, 2 and 3

lesions were present in the other two (these 2 children also received gamma globulin )

– Seroconversion (ELISA) was observed in all children, but VZV antibodies disappeared 6 months later in the case who did not have symptoms

IGIV and ACV Prophylaxis in High Risk Children

• Huang et al (Eur J Pediatr, 2001)– High risk: 15 newborns whose mother’s rash was within 7

days before and 5 days after delivery• 4 received IGIV soon after birth – 2 developed varicella• 10 received IGIV and ACV (IV, 7 days after maternal rash

onset) – none developed varicella• 1 received ACV – no symptoms

– Not high risk: 9 newborns without prophylaxis• 7 born >7 days after mother’s rash onset, 2 IgG – developed

varicella• 2 whose mothers had rash >5 days after delivery developed

varicella

VZIG• Advantages:

– Benefits and Limitations are well understood– Long-standing experience– Utility in those who can not be vaccinated or when

antivirals are not appropriate– Small volume for newborns

• Disadvantages:– Cost of continuing production/ new source– Limited period of protection– May be more expensive to make in the vaccine era

What Are Our Options for Prophylaxis in VZV-Susceptible High Risk, Exposed

Patients?

• Immunocompromised Patients– Leukemia, Lymphoma, Transplants,

Immunosuppressive Therapy, HIV :• VZIG, or IGIV? or Antiviral ??

What Are Our Options in VZV-Susceptible High Risk, Exposed

patients?

• Neonates:– VZIG, or IGIV? or Antiviral ??

• Normal Adults:– Pregnant women:

• VZIG, or IGIV? or Antiviral ??– Other Adults:

• VZIG or IGIV? or Antiviral ?? or Vaccine ??

Summary• There probably is still a need for VZIG• IGIV is probably equivalent to VZIG in the

appropriate dose• Antivirals may be useful, especially if the

window for VZIG/ IGIV is missed, but should be tested in populations other than healthy children

• Vaccine will be of limited utility as a substitute for VZIG

PEP for Rabies

Postexposure Prophylaxis• Animal bite: Amoxacillin/clavulanate x 5 days, rabies

(if indicated)• Hepatitis A: ISG 0.02 mg/kg IM (within 2 weeks of

exposure)• Pertussis: Azithromycin Z-pack (5 days), TMP-SMX

1 DS tab PO 2x/day x 14 days• Meningococcus: Ciprofloxacin 500 mg PO x 1 or

ceftriaxone 250 mg IM x 1

Rabies Exposure

• Bite (common cause)• Non-bite (rarely causes

rabies)• Contacts with blood, urine,

feces, etc. are not considered exposure

• Many scenarios, such as merely seeing a rabid animal, being in the same room, petting, etc., are not considered grounds for prophylaxis

A small bat bite on a finger

PROPHYLAXIS

• Pre-exposure Vaccination

• PostexposureProphylaxis (PEP)

Pre-exposure Vaccination

• Provided to subjects at risk before occupational or vocational exposure to rabies

• Subjects include diagnosticians, laboratory & vaccine workers, veterinarians, cavers, etc.

• Simplifies postexposure management

Postexposure Prophylaxis

• Provided to subjects after rabies exposure• Consists of wound care, rabies immune

globulin, and vaccine• If prompt and proper, survival virtually

assured

Rabies Biologicals

• Rabies Vaccines (for pre- and PEP)• Rabies immune globulin (only in PEP)

Rabies Vaccines• Two Human Rabies Vaccines in USA:

Human Diploid Cell Vaccine Imovax® (HDCV)Purified Chick Embryo Cell RabAvert® (PCEC)

• RVA no longer available• Intradermal application no longer available in USA

Rabies IG• Two Human Rabies

Immune Globulins in the USA:HyperRabTM S/D Imogam® Rabies-HT

• Both supplied in vials at ~ 150 IU/ml

Pre-exposure Vaccination

• Vaccine given on days 0, 7, and 21 or 28• Serology occurs every 6 months to 2 years (if

remaining at risk)• If antibody titer not adequate, administer a single

booster dose• If ever exposed, give a vaccine dose on days 0

and 3, regardless of titer

Postexposure Prophylaxis

• Wash lesions well with soap and water (tetanus booster ad hoc)

• Infiltrate rabies immune globulin (20 IU/kg) into and around the margin of the bites

• Administer vaccine on days 0,3,7,14, and 28

Postexposure Prophylaxis

• Urgency rather than emergency, per se• Depends in part upon the animal species,

exposure details, rapidity of diagnostic testing, and epidemiology of rabies in the local area

• Consultation with knowledgeable public health officials should be routine

Adverse Reactions• PEP should not be interrupted because of

local or mild systemic adverse reactions • Use of anti-inflammatory, antihistaminic,

and antipyretic agents suggested• Serious systemic, anaphylactic, or

neuroparalytic reactions are rare (VAERS)

懇請賜教