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Antibiotic Resistant Pathogens
“Be afraid. Be very afraid.”
Patty W. Wright, M.D.
Division of Infectious Diseases
Vanderbilt University
September 2014
There are no financial disclosures for this lecture.
Objectives
• To discuss the mechanisms by which
bacteria become resistant to
antibiotics.
• To discuss the epidemiology of
antibiotic resistant pathogens.
• To review the clinical presentation
and treatment of antibiotic resistant
infections.
What Is an Antibiotic?

Antibiotics = chemical substances
produced by a microorganism that can kill
or inhibit the growth of other
microorganisms
 For example: penicillins

Newer, synthetic agents now exist which
are antibacterials, but not true antibiotics
 For example: quinolones
Antibiotic
Mechanisms of Action
• Inhibition of cell wall
synthesis
• Disruption of
bacterial membranes
• Inhibition of protein
synthesis
• Inhibition of nucleic
acid synthesis
• Antimetabolites
http://en.wikipedia.org/wiki/File:Prokaryote_cell_diagram.svg
Inhibition/Disruption of Cell Walls
and Membranes
• Inhibition of cell wall synthesis
– Beta-lactams
• Penicillins, Cephalosporins, Carbapenems
– Vancomycin
• Disruption of bacterial membranes
– Daptomycin
– Polymyxins
• Colistin
• Both mechanisms bactericidal
Inhibition of Protein Synthesis
• Includes
– Aminoglycosides
– Tetracyclines
– Clindamycin
– Macrolides
– Linezolid
• Result in production of defective proteins
• May be bactericidal or bacteriostatic
Inhibition of Nucleic Acid Synthesis
and Antimetabolites
• Inhibition of nucleic acid synthesis
• Quinolones
• Metronidazole
• Rifamycins
– Bacteriocidal
• Antimetabolites
• Sulfonamides, Trimethoprim
– Prevent bacterial synthesis of folic acid
– Bacteriostatic
5 Basic Mechanisms of Resistance
• Alteration of antibiotic binding sites
• Enzymatic destruction or modification of
the antibiotic
• Decreased uptake of the antibiotic
• Efflux of the antibiotic out of the cell
• Decreased affinity for the antibiotic in
specific pathways
Mechanisms of Resistance
• Alteration of antibiotic binding sites
– Changes in the Penicillin Binding Proteins
may lead to…
• MRSA
• Strep pneumo resistance to PCN
• Enzymatic destruction or modification of the
antibiotic
– Common cause of inactivation of the
aminoglycosides
Mechanisms of Resistance
• Decreased uptake of the antibiotic
– Vancomycin, rifampin, and clindamycin are
not able to enter Gram negatives
• Efflux of the antibiotic out of the cell
– Common resistance mechanism of
Pseudomonas and Acinetobacter
• Decreased affinity for the antibiotic in specific
pathways
– Provides resistance to the antimetabolites
(trim-sulfa)
Development of Resistance
MedicineNet.com
Development of Resistance
MedicineNet.com
Objectives
• To discuss the mechanisms by which
bacteria become resistant to
antibiotics.
• To discuss the epidemiology of
antibiotic resistant pathogens.
• To review the clinical presentation
and treatment of antibiotic resistant
infections.
Multidrug-Resistant Organisms (MDROs)
• Infectious agents that are resistant to key
antimicrobials. May include resistance to:
–
–
–
–
One or more antimicrobials
All but one antimicrobial or class
All antimicrobials and classes
Three or more antimicrobial classes*
• Limited treatment options
• Associated morbidity/mortality
*Management of MDRO in Healthcare Settings, 2006 HICPAC
MDR GN
Different
Antibiotic
Options
S = Sensitive (Antibiotic will treat)
R = Resistant (Antibiotic will NOT treat)
What options do we have to treat this patient?
Epidemiology of Antibiotic
Resistant Pathogens
•
•
Getting an antibiotic increases a patient’s
chance of becoming colonized or infected
with a resistant organism
Increasing use of antibiotics increases the
prevalence of resistant bacteria in
hospitals
www.cdc.gov
Antibiotic Exposure Increases
Risk of Resistance
Pathogen and Antibiotic Exposure
Increased Risk
Carbapenem Resistant Enterobactericeae
and Carbapenems
15 fold
ESBL producing organisms and Cephalosoprins
6- 29 fold
Patel G et al. Infect Control Hosp Epidemiol 2008;29:1099-1106
Zaoutis TE et al. Pediatrics 2005;114:942-9
Talon D et al. Clin Microbiol Infect 2000;6:376-84
Effect of Antibiotics on
Antimicrobial Resistance in Individual Patients
Costelloe C et al. BMJ.
2010;340:c2096.
systematic review and meta-analysis
Association of Vancomycin Use
with Resistance
250
85
200
80
150
75
100
70
50
65
0
60
1990
1991
1992
Patients with VRE
1993
1994
DDD vancomycin
1995
Defined daily doses of
vancomycin/1000 patient days
Number of patients with VRE
(JID 1999;179:163)
% Imipenem-resistant
P. aeruginosa
Annual Prevalence of Imipenem
Resistance in P. aeruginosa vs.
Carbapenem Use Rate
80
70
60
50
40
30
20
10
0
r = 0.41, p = .004
(Pearson correlation coefficient)
0
20
40
60
80
Carbapenem Use Rate
45 LTACHs, 2002-03 (59 LTACH years)
Gould et al. ICHE 2006;27:923-5
100
Infection with Resistant Pathogens
Is Associated with Higher Mortality
Mortality of resistant (MRSA) vs.
susceptible (MSSA) S. aureus
•
•
Mortality risk associated with MRSA
bacteremia, relative to MSSA bacteremia:
OR: 1.93; p < 0.001.1
Mortality of MRSA infections higher than
MSSA: relative risk [RR]: 1.7; 95%
confidence interval: 1.3–2.4).2
1. Clin. Infect. Dis.36(1),53–59 (2003).
2. Infect. Control Hosp. Epidemiol.28(3),273–279 (2007).
MRSA
MRSA and Mortality: Bacteremia
Cosgrove SE et al Clin Infect Dis 2003;36:53+
MRSA
MRSA and Mortality: Surgical Site Infections
Engemann JJ et al CID 2003;36:592+
Mortality Associated with Carbapenem
Resistant (CR) vs Susceptible (CS) Klebsiella
pneumoniae (KP)
60
p<0.001
Percent of subjects
50
p<0.001
40
30
20
10
0
Overall Mortality
OR 3.71 (1.97-7.01)
Attributable
Mortality
OR 4.5 (2.16-9.35)
Patel G et al. Infect Control Hosp Epidemiol 2008;29:1099-1106
CRKP
CSKP
Improving Antibiotic Use
Reduces Resistance
P. aeruginosa susceptibilities before and after
implementation of antibiotic restrictions
(CID 1997;25:230)
Before
After
Percent susceptible
100
80
60
40
20
0
Ticar/clav Imipenem Aztreonam
Ceftaz
P<0.01 for all increases
Cipro
Improving Antibiotic Use Is a
Public Health Imperative
•
•
•
Antibiotics are the only drug where use in
one patient can impact the effectiveness in
another
If everyone does not use antibiotics well, we
will all suffer the consequences
“Using antibiotics properly is analogous to
developing and maintaining good roads”
Antibiotic Prescribing



Doctors prescribe antibiotics to children 62% of
the time if they perceive parents expect & 7% of
the time if they feel parents do not expect them
Antibiotics were prescribed in 68% of acute
respiratory tract visits
 80% of those were unnecessary
$1.1 billion spent annually on unnecessary
antibiotics for adults upper respiratory tract
infections
PEDIATRICS 103:711-718, 1999
J FAM PRACT: 50(10): 853-8, 2001
ARCH INT MED: 163(4): 487-94, 2003
ALL MDROs
New Antibacterial Agents Approved
1983-2011: The Pipeline is Dry
• Only 15-16 antibiotics are in
development
• Only 8 of these have activity
against key Gram neg bacteria
• None have activity against bacteria
resistant to all current drugs
Adapted from Spellberg B et al. Clin Infect Dis. 2004;38:1279-86.
Objectives
• To discuss the mechanisms by which
bacteria become resistant to
antibiotics.
• To discuss the epidemiology of
antibiotic resistant pathogens.
• To review the clinical presentation
and treatment of antibiotic resistant
infections.
Selected Specific
Mechanisms of Resistance
Case
• A 57 yo male with diabetes and renal failure
is being treated for a foot ulcer with
associated bone infection. He has received
vancomycin after hemodialysis for almost 12
weeks. He continues to have poor wound
healing and undergoes repeat I&D. Cultures
grow S. aureus with intermediate sensitivity
to vancomycin.
Vancomycin Resistance in S. aureus
VISA
• MIC 4-8 mcg/ml
• Thickened cell walls
• Vancomycin cannot
penetrate
• Often associated with
decreased
susceptibility to
daptomycin
VRSA
• MIC ≥ 16 mcg/ml
• Acquired VanA gene
from VRE
• Causes alteration of
the binding site
VISA: vancomycin intermediate S. aureus
VRSA: vancomycin resistant S. aureus
NEJM. 2009; 360: 439
Case
• A 71 yo nursing home patient is admitted
with pneumonia. Sputum cultures grow
Klebsiella pneumoniae reported as
sensitive to ceftriaxone and ciprofloxacin,
but resistant to cefepime and ceftazidime.
He is treated with ceftriaxone, but
continues to have fever and respiratory
decline.
Enzymatic Destruction:
Beta-lactamases
• Breakdown beta-lactams faster than they can
bind the penicillin binding proteins
• Classes A, B, C, D
– A and C most common
– Point mutations in Class A may lead to extendedspectrum beta-lactamases (ESBLs), which inhibit
penicillins, cephalosporins and monobactams
– Class B contain zinc & hydrolyze all but
monobactams (aztreonam)
• Easily transmitted to other bacteria
How Does Clinical Practice
Contribute to the Development
of Resistance?
Case
• A 55 yo female presents with urinary
frequency and burning. She is placed on
cephalexin. Urine cultures grow
Enterococcus. The doctor notes that the
lab report does not mention sensitivity
results for cephalexin (as it does for
ampicillin), but decides not to change the
patient’s antibiotics. The patient returns
the next week with a kidney infection.
Repeat urine cultures again grow
Enterococcus.
Intrinsic Resistance
• Some bacteria are intrinsically resistant to the
certain antibiotics.
– A literal ton of cephalosporins will not treat
Enterococcus.
– One bug spray may work for fleas, but not
wasps.
Case
• A 67 yo female develops pneumonia and
dehydration following admission for a MI.
She is placed on renally-dosed
piperacillin-tazobactam. Sputum cultures
grow Enterobacter, sensitive to pip-tazo.
The patient’s renal function improves with
hydration; however, her pip-tazo dose is
not adjusted. A few days later the patient
becomes sicker and is found to have
Enterobacter, resistant to pip-tazo, in her
blood cultures.
Underdosing
• Bacteria may develop resistance to certain
antibiotics.
– The proper dosing of antibiotics is important
to prevent the development of resistance.
• Dosing decisions are often made on the
basis of drug levels (such as vancomycin
troughs). It is critical that they are drawn
correctly.
Underdosing
– You might kill the first few ants with the toxic
ant food, but the rest of them figure it out and
won’t eat anymore.
• This happens a lot faster if the ants only
take a little nibble of the poison instead of a
feast.
Case
• A 84 yo female develops abdominal pain
and fever. CT scan of the abdomen shows
diverticulitis and a left upper quadrant
abscess. She is placed on ciprofloxacin
and metronidazole. Surgery is consulted,
but declines to operate due to the patient’s
age and multiple medical problems. She is
treated with 4 wks of antibiotics; however,
a repeat CT shows persistence of the
abscess.
http://www.meddean.luc.ed
Poor Penetration
• Antibiotics may not be able to penetrate into
the site of the infection.
– Abscesses, infected joints, CNS infections, etc
• Infections of prosthetic devices, like central
lines and artificial heart valves, are very
difficult to treat without removal.
– It doesn’t matter how much bug spray is
outside, as long as the bees are safe
inside the hive.
Case
• A 4 yo female presents with a cough which
has been present for several months. Her
mother reports that the cough is worse at
night and after she exercises. She does not
have any associated fevers. The patient
has been treated with a variety of oral
antibiotics without improvement.
Incorrect Diagnosis
• The patient does not actually have a bacterial
infection.
– Cancer, rheumatologic disorders, and other
infections due to viruses, fungi, or mycobacteria
may masquerade as a bacterial infection.
– You can spray the “termites” with all the bug
spray you want, but if the damage to the wood
was actually due to water, then the poison is
not going to help.
Case
• A 43 yo patient with leukemia develops a
very low WBC count and fever following
chemotherapy. The patient is placed on
broad-spectrum antibiotics (meropenem
and vancomycin) without improvement in
her fevers. Blood and urine cultures are
negative. Unfortunately, the patient
becomes septic and dies. Repeat cultures
taken in the ICU prior to death are also
without growth.
Immunodeficiency
• A functioning immune system is often more
important than the antibiotics.
– Multiple levels and types of immunodeficiency
lead to various risks, i.e. BMT vs. AIDS vs.
DM vs. pregnancy, etc.
– If you are staked to the ant hill with your
hands tied behind your back, it really doesn’t
matter how much bug spray you own.
Case
• A 51 yo male develops MSSA endocarditis
involving a bicuspid aortic valve s/p a
localized skin infection. He is treated with
iv nafcillin with clearance of his blood
cultures. One of the medicine residents
reports reading an article that states you
can treat endocarditis with 2 weeks of
therapy. The patient completes 2 weeks of
nafcillin and returns a week later with
recurrent fever and chills.
Incorrect Duration
• The proper duration of treatment is
important.
• Some infections take longer to treat than
others:
– Endocarditis
– Osteomyelitis
– Prosthetic device infections
– Brain abscesses
• If you are supposed to treat the aphids daily for
2 weeks, but only do it for 2 days, some of them
will survive to breed and eat your roses.
Case
• A 44 yo male with a h/o iv drug abuse is
injured in a motor vehicle accident. He
develops an infection of his leg wound with
MRSA. He is treated with iv vancomycin
while hospitalized. Because of his history
of drug abuse, the physician wants to
avoid sending the patient home with an iv
line, so he writes the patient a script for
vancomycin 1000mg po Q12hrs. The
patient returns with recurrent infection.
Poor Bioavailability
 Some antibiotics have good oral bioavailability.
Some don’t…or in the case of vancomycin, none.
◦ Agents with good po bioavailability include:
 Quinolones, linezolid, TMP/sulfa,
metronidazole, doxycycline, clinda
◦ If you are supposed to feed
the roaches the poison,
but you shake it on them instead,
it’s probably not going to work.
Same Case…Different Drug
• A 44 yo male with a h/o iv drug abuse is
injured in a motor vehicle accident. He
develops an infection of his leg wound with
MRSA. He is treated with iv vancomycin
while hospitalized. Because of his history
of drug abuse, the physician wants to
avoid sending the patient home with an iv
line, so he writes the patient a script for
linezolid 600mg Q12hrs. The patient
returns with recurrent infection.
Non-adherence
• Patient non-adherence
– Multiple potential causes of non-adherence:
•
•
•
•
•
Inability to afford meds
Drug abuse
Mental illness
Side effects
Difficult dosing regimen
– The bug spray doesn’t work if the hornets are
in your backyard and the spray is at the
hardware store.
Summary:
Mechanisms of Action
• Mechanisms of action of common
antibiotics and antibacterial agents
– Inhibition of cell wall synthesis
– Disruption of bacterial membranes
– Inhibition of protein synthesis
– Inhibition of nucleic acid synthesis
– Antimetabolites
Summary:
Mechanisms of Resistance
• Bacterial resistance to antibiotics may occur by
– Decreased uptake of the antibiotic
– Efflux of the antibiotic out of the cell
– Alteration of antibiotic binding sites
– Enzymatic destruction or modification of the
antibiotic
– Decreased affinity for the antibiotic in specific
pathways
Summary:
Factors Leading to Clinical Failure
• Antibiotics fail for a variety of reasons.
• Different antibiotics provide coverage for different
bacteria.
• Proper antibiotic dose, duration, and route of
administration are all important to prevent the
development of resistance.
• Host factors, such as immunosuppression or
barriers to adherence, are also important to the
success of antibiotic therapy.