Antibiotic Resistant Pathogens “Be afraid. Be very afraid.”
-
Upload
mari-solis -
Category
Documents
-
view
48 -
download
0
description
Transcript of Antibiotic Resistant Pathogens “Be afraid. Be very afraid.”
Antibiotic Resistant Pathogens
“Be afraid. Be very afraid.”
Patty W. Wright, M.D.Division of Infectious Diseases
Vanderbilt UniversitySeptember 2014
There are no financial disclosures for this lecture.
• 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.
Objectives
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
• Inhibition of cell wall synthesis
• Disruption of bacterial membranes
• Inhibition of protein synthesis
• Inhibition of nucleic acid synthesis
• Antimetabolites
Antibiotic Mechanisms of Action
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
• 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
5 Basic 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)
Mechanisms of Resistance
Development of Resistance
MedicineNet.com
Development of Resistance
MedicineNet.com
• 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.
Objectives
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
S = Sensitive (Antibiotic will treat) R = Resistant (Antibiotic will NOT treat)
Different Antibioti
c Options
MDR GN
What options do we have to treat this patient?
• 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
Epidemiology of Antibiotic Resistant Pathogens
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;29:1099-1106Zaoutis TE et al. Pediatrics 2005;114:942-9Talon D et al. Clin Microbiol Infect 2000;6:376-84
Effect of Antibiotics onAntimicrobial Resistance in Individual
Patients
Costelloe C et al. BMJ. 2010;340:c2096.
systematic review and meta-analysis
Association of Vancomycin Use with Resistance
0
50
100
150
200
250
1990 1991 1992 1993 1994 1995
Nu
mb
er
of
pa
tie
nts
wit
h V
RE
60
65
70
75
80
85
De
fin
ed
da
ily d
os
es
of
va
nc
om
yc
in/1
00
0 p
ati
en
t d
ay
s
Patients with VRE DDD vancomycin
(JID 1999;179:163)
Annual Prevalence of Imipenem Resistance in P. aeruginosa vs.
Carbapenem Use Rate
0 10 20 30 40 50 60 70 80 900
10
20
30
40
50
60
70
80
Carbapenem Use Rate
% I
mip
en
em
-resis
tan
t P
. aeru
gin
osa
45 LTACHs, 2002-03 (59 LTACH years) Gould et al. ICHE 2006;27:923-5
r = 0.41, p = .004 (Pearson correlation coefficient)
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).
Cosgrove SE et al Clin Infect Dis 2003;36:53+
MRSA and Mortality: Bacteremia
MRSA
Engemann JJ et al CID 2003;36:592+
MRSA and Mortality: Surgical Site Infections
MRSA
Mortality Associated with Carbapenem Resistant (CR) vs Susceptible (CS)
Klebsiella pneumoniae (KP)
0
10
20
30
40
50
60
Overall Mortality Attributable Mortality
Pe
rce
nt o
f s
ub
jec
ts
CRKP
CSKP
Patel G et al. Infect Control Hosp Epidemiol 2008;29:1099-1106
OR 3.71 (1.97-7.01)
OR 4.5 (2.16-9.35)
p<0.001
p<0.001
Improving Antibiotic Use Reduces Resistance
P. aeruginosa susceptibilities before and after implementation of antibiotic
restrictions (CID 1997;25:230)
Ticar/clav
Imipenem
Aztreonam
Ceftaz Cipro0
20
40
60
80
100
Before After
Perc
en
t su
scep
tib
le
P<0.01 for all increases
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 infectionsPEDIATRICS 103:711-718, 1999
J FAM PRACT: 50(10): 853-8, 2001ARCH INT MED: 163(4): 487-94, 2003
Adapted from Spellberg B et al. Clin Infect Dis. 2004;38:1279-86.
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
ALL MDROs
• 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.
Objectives
Selected Specific
Mechanisms of Resistance
• 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.
Case
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
NEJM. 2009; 360: 439
VISA: vancomycin intermediate S. aureusVRSA: vancomycin resistant S. aureus
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
extended-spectrum 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?
• 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.
Case
• 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.
Intrinsic Resistance
• 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.
Case
• 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.
Underdosing
• 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.
Case
http://www.meddean.luc.ed
• 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.
Poor Penetration
• 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.
Case
• 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.
Incorrect Diagnosis
• 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.
Case
• 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.
Immunodeficiency
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.
• 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.
Case
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.
Poor Bioavailability
• 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.
Same Case…Different Drug
• 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.
Non-adherence
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
• 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: Mechanisms of Resistance
• 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.
Summary:Factors Leading to Clinical Failure