Should we change the recommendations
related to antibiotic drug dosage/drug
duration?
Workshop on Economic Epidemiology
Makerere University
August, 2009
Patricia Geli Rolfhamre
Acknowledgements
Ramanan Laxminarayan, Resources for the Future
David L. Smith, Resources for the Future
Simon Levin, Princeton University
Michael Dunne, Advisory committee “Extending the Cure”
Agenda
• How are antibiotic guidelines developed?
• Are we basing all dosing regimens on TB experience?
• How can the guidelines be improved?
• Consequences v. benefit of different guidelines
• Conclusions and take home message
A drug to cure bacterial infections
Second most widespread drug after
analgesics:
Majority of the population will take antibiotics
at some time in their lives
Development of drug
dose/duration guidelines
Relationships between drug dose/duration and
therapeutic efficacy – only beginning to be
understood for many antibiotics
Introduction of first
antibiotic for clinical use
1930s
1940s
1950s
1960s
1970s
1980s
1990s
2000s
Development of drug
dose/duration guidelines
Relationships between drug dose/duration and
therapeutic efficacy – only beginning to be
understood for many antibiotics
Is leading to dramatic changes in drug
dose/duration recommendations
Then: Three smaller
doses per day
Ex: Aminoglycosides
1930s
1940s
1950s
1960s
1970s
1980s
Now: Single large
daily dose
1990s
2000s
Development of drug
dose/duration guidelines
Historically designed to achieve:
- maximal treatment efficacy
- minimal toxicity
Development of drug
dose/duration guidelines
Historically designed to achieve:
- maximal treatment efficacy
- minimal toxicity
BUT... Resistance not considered!
Resistance comes fast...
J. Davies, 1997
...is still growing
ICU Patients
Non-ICU Patients
Source: NNIS DATA, Clinics Chest Med. 20:303-315
The Paradox
“Selective pressure comes from a combination
of overuse in many parts of the world,
particularly for minor infections, misuse due
to lack of access to appropriate treatment and
underuse due to lack of financial support to
complete treatment courses”
Cited from: World Health Organization (2009), Community-Based Surveillance
of Antimicrobial Use and Resistance in Resource-Constrained Settings
From individuals to public health:
DOTS for TB
Treatment and prevention of resistance in individuals
=
key public health measure
This works for TB – but is it sound
for other infections?
When and why do we treat?
50% of all consumption for respiratory tract infections (RTI)
Most common symptoms:
otitis media
sore throats
sinusitis,...
Duration v. benefit of treatment
Many RTI symptoms are likely to be caused by viruses, i.e. no
benefit of antibiotic treatment
Even if bacterial, recent clinical evidence
suggests that shorter drug durations
can be equally effective as longer ones
For acute otitis media
(middle ear infection), the second
most common infection after
the common cold, 3 days has been
shown to be as effective as
10 days
S. aureus
“Normal” flora
1014 -1015 bacteria (or 1-2 kg) totally in
the human body
S. pneumoniae
H. influenzae
N. meningitidis
E. coli,
Klebsiella
Enterobacter
Enterococcus
faecium
Normal flora: Consequences
• Treatment exerts selection on “innocent bystanders”
• Most of the harm done by use of a drug may be on species
OTHER than the target of treatment
• Most of the exposure of a given
species to a given drug may be
due to treatment of OTHER
infections
Normal flora: Consequences
Resistance is contagious!
It will continue to spread even after
infection has been cleared
How can we investigate this further?
Traditional pharmacokinetic/
pharmacodynamic models
Pharmacokinetics: what the body does to the drug
Pharmacodynamics: what the drug does to the body
Our knowledge comes mostly from experimental trials
Immune responses NOT considered!
Pharmacokinetics/
Pharmacodynamics
Antibiotic concentration
# Bacteria
R
Growth R
Time
Emergence and selection
of resistance
Antibiotic concentration
# Bacteria
R Selection
S of R
Selective
Window
(SW)
Growth R
Growth S
Time in SW
Traditional pharmacokinetic/
pharmacodynamic models
Sensitive
population
Resistant
population
S
R
Incorporating the immune response
Sensitive
population
Resistant
population
S
R
I
Immune
response
Possible pathogen dynamics
Unregulated bacterial dynamics: Commensal bacteria
that uses body as a habitat
Regulated bacterial dynamics: Bacteria and the immune
response settles an equilibrium
Self-limiting dynamics: Bacterial populations are reduced
below a cut-off value (<1) and infection is successfully limited
Unregulated bacterial dynamics:
the TB example
Time symptoms
Selective Window (SW)
Resistance selection
Time
Time
Regulated bacterial dynamics:
the normal flora example
Time symptoms
Selective Window (SW)
Resistance selection
Time
Time
Regulated v. self-limiting dynamics
Time symptoms
Selective Window (SW)
Resistance selection
Resistance selection
self-limiting dynamics regulated dynamics
Time
Time
Time
Regulated v. self-limiting dynamics
Optimal dosing for treatment ≠ optimal to prevent resistance!
Time symptoms
Selective Window (SW)
Resistance selection
Resistance selection
self-limiting dynamics regulated dynamics
Time
Time
Time
Consequences v. benefit of treatment
for unregulated bacteria
For unregulated and regulated bacterial dynamics,
high concentrations for long durations are required to
clear bacteria
Time for clearance of TB does not exert selection in
normal flora, because the two key agents in the three
drug combination therapy for TB are not active
against any other micro-organisms
Consequences v. benefit of treatment
for self-limiting infections
Self-limiting infections are successfully cleared with
“shorter” duration of therapy
Shorter durations with therapy exert less selection of
resistance in normal flora, but give slightly longer
duration of symptoms
Consequences v. benefit of treatment
for self-limiting infections
Does the gain of treating the patient outweigh the
risk related to resistance development?
Some studies have reported a low, but increased
incidence in number of complications from countries
with lower prescribing for AOM
Conclusions
One size does NOT fit all!
We need to broaden the concept of selection of
resistance when devising optimal dosing strategies –
both for guidelines for future and existing antibiotics
Alternative strategies to save our antibiotics
for the next generation?
Webale! Thank you! Tack!