Transcript Slide 1

Antibiotic
Cycling
A solution to the evolutionary arms race?
Presented by Alexandra Roland
An “evolutionary arms race” is an
evolutionary struggle between
competing sets of co-evolving genes
that develop adaptations and counteradaptations against each other,
resembling an arms race. The term has
been used more and more for the
battle between bacteria and
antibiotics. An example of a coevolving gene set is a parasite and
its host. In recent years, many
bacteria and diseases have been
evolving faster than humans can
What are antibiotics?
• When someone’s immune system can’t fight off
a bacterial infection by itself, they may
need more aggressive medical treatment
• Antibiotics and other antibacterial drugs
are the major weapons against diseasecausing bacteria, and they can kill bacteria
or suppress their activity in various ways
• They can be natural, synthetic, or semisynthetic organic chemical compounds which
can kill or stop the growth of infections
• Penicillin is the most well-known antibiotic
and has been used to fight many infectious
diseases, including syphilis, gonorrhea,
tetanus, and scarlet fever
http://encarta.msn.com/encyclopedia_761577894/Antibiotics.html
Antimicrobial Resistance
History
• Louis Pasteur: first observed antibiotic effect
in 19th century, who discovered that certain
saprophytic bacteria can kill anthrax bacilli
• Paul Ehrlich: developed salvarsan in 1909, a
synthetic compound that remained the only
effective treatment for syphilis until
purification of penicillin in the 1940s
• Sir Alexander Fleming: 1928, accidentally
discovered Penicillin
• World War II: renewal of research, Sir Howard
Florey and Ernst Chain purified enough
penicillin to show that it would protect mice
from infection
• Soon after antibiotics were introduced into
clinical circulation, cases arose where their
ability to effectively stop infection was
decreased
• As the use of antibiotics became more
widespread, the prevalence of antibiotic
resistant bacteria increased
• Different time frames apply to different
bacteria because the number of mutations
necessary to develop resistance depend on the
strain
• ex. Staphylococcus aureus took 5 years to
become resistant to penicillin, while
Streptococcus pneumoniae took over 50 years
Relevant Definitions
• Gram-positive vs. gram-negative bacteria:
When gram-positive bacteria are stained with
a dye, the cell wall holds the dye inside
and the bacteria are stained dark purple.
Cell walls of gram-negative bacteria are
more permeable - they do not retain much of
the dye, and so their cell walls do not show
much stain
• Selective pressure: The influence exerted by
some factor (such as an antibiotic) on
natural selection to promote one group of
organisms over another. In the case of
antibiotic resistance, antibiotics cause a
selective pressure by killing susceptible
bacteria, allowing antibiotic-resistant
Increasing Trend of Penicillin
Resistance in US
•
Source:
http://www.uihealthcare.com/news/currents/vol5issue2/04antibioticresistencefig1.html
E. Coli have become
increasingly resistant to
antibiotic treatment
Diseases connected with
antimicrobial resistance
•
•
•
•
Tuberculosis
Head Lice
Malaria
MethicillinResistant
Staphylococcus
aureus (MRSA)
• Streptococcus
pneumoniae
• Gonorrhea
• Typhoid Fever
• Vancomycin/Glycopep
tide-Intermediate
Staphylococcus
aureus (VISA/GISA)
• VancomycinResistant
Enterococci (VRE)
How bad is it?
• Today, as many as 5 to 10 patients are
colonized with resistant bacteria for every
patient known to be infected
• The majority of antimicrobial resistance
occurs in intensive care unit (ICU) due to
patients who are more susceptible to
nosocomial (hospital-obtained) infections
because of underlying illnesses, suppressed
immune systems and frequent use of invasive
devices
• Recently in Atlanta, 25% of bacterial
pneumonia cases were shown to be resistant
to penicillin, while an additional 25% of
cases were resistant to more than one
• Perpetual research and development
has become necessary to find new
antibiotics to maintain a pool of
effective drugs
• While the development of resistant
strains is inevitable, the speed and
scale of development has been
aggravated by the practices we use to
distribute antibiotics
• Variations in resistance exist among
different countries, due at least in
part to individual antimicrobial use
Antibiotic Cycling: Basics
• Organisms resistant to antibiotics have genes that are
either carried on the bacterial chromosome or on the
small circular DNA plasmids, which direct the
synthesis of the traits that protect bacteria from
antibodies
• Certain resistance genes code for enzymes that degrade
antibiotics or chemically modify them to the point of
inactivation
• Other resistance genes may cause bacteria to modify or
replace molecules that are normally bound by an
antibiotic, removing the drug's target
• Others may possess genes that help eliminate entry
points to the cell, or that create pumps to move the
antibiotic from the cell before it reaches its target
http://www.paratekpharm.com/i_mechanism.html
Evolution of Bacteria
• Through mutations, some bacteria will
develop genes that help protect them
from antibiotic attack mechanisms
• A few bacteria will survive with
favorable traits and reproduce,
increasing the concentration of the
resistant trait in the population
• The selective advantage conferred by
the resistant trait will cause
natural selection and eventually the
population will be nearly entirely
Mutations are central to the
growth of antibiotic resistance
http://www.ideacenter.org/contentmgr/showdetails.php/id/1096
Methods of Antibiotic Resistance
a.) pumping out
of antibiotic
prior to
reaching target
b.) enzymatic
degradation of
antibiotics
c.) enzymatic
alteration of
antibiotics
http://www.paratekpharm.com/i_mechanism.html
Methods
• Robert G. Masterton looked at 4 papers on
antibiotic cycling, but results from many
studies are represented in table form
• 14 studies compared include: mainly ICU,
with two neonatal and one pediatric
• Comparison basis: unit cycling was done in,
length and number of cycles, change in
resistance of certain antibiotics, change
in number of resistant bacteria strains
• Cycles lasted 1-26 months, very high
variance in cycle period and number of
cycles
Results
• Most studies found reduced gentamicin
resistance and reduced incidence of Grampositive and Gram-negative infections
• General trend of success throughout various
studies in reducing development of
resistant microbes
• Masterton found that almost two-thirds of
the studies on antibiotic cycling look at
the potential it presents, rather than
actual results as ot it’s effectiveness
• It was found most successful to use cycles
that change class of antibiotic, such as
from β-lactams to fluoroquinolones or
aminoglycosides
Solutions to OverPrescription
• Improved adherence to prescribing protocol
• Programs to persuade patients that putting
pressure on doctors to prescribe antibiotics
inappropriately can have harmful effects
• Higher infection-control delivery and better
administration of antibiotics
• Education efforts to improve prescribing
• Restrict antimicrobial availability and the
use of antimicrobial request forms and
antibiotic cycling
• A study was done in the LDS Hospital in
Salt Lake City the first year they used
an automated antibiotic consultant, which
helps physicians quickly receive culture
results, antibiotics patients are
currently on, and antibiotics they have
been exposed to
• Huge improvements were made in limiting
over prescription, leading to excessive
dosing 87 times, versus 405 times in the
previous two years.
• Patients received an average of 4.7 fewer
doses and their antibiotic expenses
Other Reasons for Development of Antibiotic
Resistance Beyond Over-Prescribing
• Poorly cleaned wards: accumulation of
dirt can provide environment for
resistant bacteria
• Loss of survival for organisms in the
presence of a new antibiotic pressure
• Inducible resistance phenotypes exist,
that have protective mechanisms that
are only activated when an antibiotic
is there to induce it (can survive in
both antibiotic and non-antibiotic
environments)
Current Studies
• As of September 2005, mathematical modeling to
measure the effect of antibiotic cycling has
brought into question its effectiveness (Gibbs
2005)
• Masterton’s study of the overall success and
results of various troubles is the most thorough
representation of the success thus far with
cycling
• Studies lack consistency in parameters so it’s hard
to make judgments on how effective cycling is
because of no basis of comparison
• As of 2006, there are relatively few newly
published studies but
Future of Antibiotic Cycling
• What is the optimal cycle duration?
• Is a hospital-wide strategy better or
worse than a unit-specific strategy?
• When does it become necessary or is
it optimal to begin antibiotic
cycling?
• How can compliance be increased?
• How does antibiotic cost change when
beginning a cycling program?
References
Primary Article: Masterton, Robert G. "Antibiotic cycling: more than it might seem?" Journal
of Antimicrobial Chemotherapy 55 (2005): 1-5. Journal Access Center. 2006. British Society
for Antimicrobial Chemotherapy. 6 Dec. 2006
<http://jac.oxfordjournals.org/cgi/content/full/55/1/1>.
Gibbs, Winter J, and Richard H Drew. "More studies need to define potential role
of antibiotic cycling." Infectious Disease News (Sept. 2005). Medical
Matrix. 20 Nov. 2006. Infectious Disease News. 6 Dec. 2006
<http://www.infectiousdiseasenews.com/200509/frameset.asp?article=pharmconsult.asp>.
Van Loon, Harald J, et al. "Antibiotic Rotation and Development of Gram-Negative
Antibiotic Resistance." American Journal of Respiratory and Critical Care
Medicine 171 (2005): 480-487. AJRCCM.org. 2006. American Thoracic
Society. 6 Dec. 2006 <http://ajrccm.atsjournals.org/cgi/content/full/171/
5/480>.
"Glossary." Alliance for the Prudent Use of Antibiotics. 1999. Alliance for the
Prudent Use of Antibiotics. 6 Dec. 2006 <http://www.tufts.edu/med/apua/
Miscellaneous/Glossary.html>.
"'Antibiotics.'" Microsoft Encarta Online Encyclopedia. 2006. Microsoft
Corporation. 6 Dec. 2006 <http://encarta.msn.com/
encyclopedia_761577894_4/Antibiotics.html
Yim, Grace. "Attack of the Superbugs: Antibiotic Resistance." Science Creative
Quarterly Sept.-Oct. 2006, Issue Two ed. 6 Dec. 2006
<http://www.scq.ubc.ca/>.