Antivirals and Respiratory Outbreaks
Allison McGeer, MSc, MD, FRCPC
Mount Sinai Hospital
University of Toronto
www.microbiology.mtsinai.on.ca
Disclosures
My research group receives/has received funding for investigator
initiated research, and via sponsored clinical trials, participation on
data safety monitoring boards and honoraria for lectures and
advisory board participation, from the following companies with
products related to influenza diagnosis, management and
prevention:
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Adamas Pharmaceuticals
Astra-Zeneca
Biocryst
Copan Diagnostics
Gilead Biosciences
GlaxoSmithKline
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Hoffman LaRoche
Luminex Technologies
Medicago
Medonyx
Novartis
Sanofi-Pasteur
Solvay Biologics
Influenza in Ontario LTCFs 1990-1997
Season
90/91
91/92
92/93
93/94
94/95
95/96
96/97
97/98
No.
outbreaks
Attack rate
(mean, range)
% cases with
pneumonia
(mean, range)
Case fatality
rate
(mean, range)
Vaccine
efficacy
(mean)
8
21
20
32
39
13
94
155
15% (3-46)
34% (13-73)
26% (4-55)
33% (5-74)
27% (3-100)
38% (12-100)
27% (1-74)
11% (0-37)
12% (0-56)
7% (0-47)
2% (0-12)
5% (0-90)
14% (0-50)
11% (0-65)
3% (0-17)
5% (0-12)
5% (0-49)
38%
20%
23%
42%
Questions about antivirals
• What antiviral?
• Which residents need treatment/prophylaxis and
when?
 When should dose adjustment for reduced
creatinine clearance be considered?
 Which staff should receive prophylaxis?
 When can prophylaxis be discontinued?
 What response is appropriate if cases continue to
occur despite prophylaxis?
Neuraminidase inhibitors
(oseltamivir; zanamivir)
M2 inhibitors
(amantadine)
Antivirals:
Amantadine, oseltamivir, zanamivir
FOR SUSCEPTIBLE STRAINS
– Prophylaxis, all 65-80% effective
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No head-to-head comparisons, but no differences apparent
– Treatment
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No data to suggest that their effectiveness is different
More data for oseltamivir than zanamivir than amantadine
Amantadine - limitations
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Not effective against influenza B
Currently, both A(H3N2) and A(H1N1) are
resistant
Very limited data on effectiveness of
treatment
Rapid emergence of resistance on treatment
8-12% rate of CNS side effects (20% of
patients report some CNS side effect)
Relatively low toxic/therapeutic ratio
Zanamivir
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All influenza isolate strains susceptible
– Lower selection for resistance on therapy
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Not absorbed
– No systemic adverse events
– ?less effective in severe disease
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Difficult to deliver to demented,
frail elderly
Characteristics of residents associated
with difficulty performing inhalations
No (%) with difficulty P value
Activities of daily living:
<.001
Mostly independent
2/24 (8%)
Largely dependent
12/76 (16%)
Completely dependent 15/26 (58%)
Oriented
<.001
To person/place/time
1/33 (3%)
Two of three
2/19 (11%)
One of three
4/25 (16%)
Not oriented
22/49 (45%)
Amount of zanamivir delivered to residents
Oseltamivir
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Capsule or suspension
Very high toxic to therapeutic ratio
Day 1
Day 5
Dutkowski et al. International Journal of Antimicrobial Agents ; 2010:35: 461-467
Adverse effects associated with high dose
Adverse event
Placebo
Oseltamivir (bid)
75mg
225mg
450mg
Headache
20%
17%
24%
23%
Nausea
8%
8%
26%
31%
Vomiting
2%
3%
7%
16%
Dizziness
4%
2%
11%
10%
Dutkowski et al. International Journal of Antimicrobial Agents ; 2010:35: 461-467
Oseltamivir
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Capsule or suspension
Very high toxic to therapeutic ratio
Selection for resistance occurs
– Usually H275Y (but others described)
– Usually, virus is not fully virulent
Antiviral resistance
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Not driven by antiviral use
– Influenza viruses “balance” mutations
– Single viral clade becomes successful each year
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If the patient does not have influenza, NO selective
pressure
Prophylaxis is less selective than treatment
– BUT post-exposure prophylaxis MAY be pre-emptive
treatment
Residents
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Meet case definition
– Treatment doses x 5 days UNLESS case is lab-confirmed,
and clearly improving
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Ill (possibly related), but do not meet case definition
– Treatment doses x 5 days
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Ill, but have recovered
– Lab-confirmed influenza – NO prophylaxis
– Lab testing negative/not done: Prophylaxis
How long do you write prophylaxis scripts
for?
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Too short, and you need repeat orders and
repeat prescriptions for all residents
Too long, and you waste drug (and money)
Making a recommendation for initial
prescriptions
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14 day standard (IDSA recommendations)
How many cases in the outbreak so far?
What is the history of influenza outbreaks in
this home? In your public health unit?
How much activity is there due to other
viruses?
How big is the nursing home/unit?
Oseltamivir compassionate use program,
Ontario, 2000 (outbreak B8)
Number of new cases
12
Neg/not tested
Flu A positive
10
Oseltamivir start
8
6
4
2
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18
Outbreak Day Number
Number of new cases
Oseltamivir compassionate use program,
Ontario, 2000 (outbreak B4)
Oseltamivir start
8
7
6
5
4
3
2
1
0
1
2
3
Bowles, JAGS 2002
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18
Outbreak Day Number
Dose reduction in renal failure
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Penicillin: patients with impaired renal
function (<30ml/min) require modification of
dose and interval
Oseltamivir: for patients with a creatinine
clearance <30ml/min, it is recommended that
the dose is reduced to 75 mg od
Scatter plot of baseline creatinine clearance results
by age in LTCF residents (BCCDC)
Creatinine Clearance
140
120
100
80
60
40
20
0
20
40
60
Age (years)
80
100
120
Oseltamivir and renal failure
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For creatinine clearance above 10ml/min, 75
mg od is safe
Creatinine clearance of 10ml/min is
equivalent to serum creatinine of about 250
umol/L (85 year old, 40kg)
What about staff?
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Strongly recommend that staff who choose to be
unimmunized acquire a prescription that can be
filled later
– Consider providing letter to health care providers
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Consider offering a choice of active antivirals
Don’t worry about prophylaxis of immunized staff
unless:
(i) there is clearly defined lack of protection OR
(ii) there is lab-confirmed illness in multiple
vaccinated staff
Oseltamivir
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Capsule or suspension
Very high toxic to therapeutic ratio
Day 1
Day 5
Dutkowski et al. International Journal of Antimicrobial Agents ; 2010:35: 461-467
Staff categories
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Not exposed
– Minimum incubation period 12-18 hours – as long
as have started oseltamivir, will be protected
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Exposed and incubating infection
– Already shedding virus, or about to be shedding
virus – and at 4 hours, will still be shedding virus
– May develop symptoms at any time during next
24-48 hours
Effect of Oral Oseltamivir Treatment on Vital Titers in Nasal Lavages
Following Experimental Influenza A/Texas/36/91(H1N1) Infection
The viral titer area under the curve value was lower in the combined oseltamivir group (n=56)
compared with placebo (n=13); P=.02
Hayden, F. G. et al. JAMA 1999;282:1240-1246.
Questions?