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10/9/2012
I have no conflicts of interest in relation to this program
Whitney Jones, PharmD
Antimicrobial Stewardship Pharmacist
Vanderbilt University Medical Center
October 25, 2012
Understand the epidemiology associated with gramnegative resistance
Discuss changing trends in resistance to
antimicrobials
Recognize current challenges in infectious diseases
pharmacotherapy
Understand the goals of antimicrobial stewardship
programs and the role pharmacists may play in
optimizing the use of antimicrobials
Unprecedented success of antibiotics in 1960s
“[It] is time to close the book on infectious
diseases and declare the war against pestilence
won”
- US Surgeon General William H. Stewart
Infectious diseases are #1 cause of mortality
worldwide
3rd most common reason for hospitalization in U.S.
Dellit TH. Clin Infect Dis 2007;44:159-77.
www.who.int. Accessed September 12, 2012.
Widespread use of antibiotics
inevitably leads to resistance
Definition
Acquired ability of a pathogen to
withstand an antibiotic that kills off
its sensitive counterparts
Multidrug-resistant (MDR)
bacteria
No consensus definition
> 3 antimicrobial classes
~ 70% of bacteria causing
hospital-acquired infections are
resistant to > 1 antibiotic
89% of A. baumannii isolates
www.cdc.gov. Accessed September 12, 2012.
Rice LB. J Infect Dis 2008;197:1079-81.
Pandrug
Resistant
Extensively
Drug
Resistant
Antipseudomonal
cephalosporins
Resistant
Resistant
Antipseudomonal
carbapenems
Susceptible
Resistant
Piperacillin/
tazobactam
Resistant
Resistant
Ciprofloxacin
Levofloxacin
Resistant
Resistant
Ticarcillin/
clavulanate
Resistant
Resistant
Aminoglycosides
Susceptible
Resistant
resistant to > 3 antibiotic classes
Gaynes R. Clin Infect Dis 2005;41:848-54.
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10/9/2012
E
cloacae
(n = 704)
K
pneumoniae
non-ESBL
(n = 931)
K
pneumoniae
ESBL
(n = 78)
P
aeruginosa
(n = 1,054)
A
baumannii
(n = 486)
P-T
81
93
41
90
50
TAZ
72
93
3
82
44
CFP
95
96
44
78
43
MER
99
98
69
84
64
AMK
99
98
73
96
72
LVX
90
94
23
65
42
MIN
80
85
53
5
81
TIG
96
96
90
NA*
NA†
Data are % susceptible. ESBL = extended-spectrum β-lactamase; P-T = piperacillin-tazobactam; TAZ = ceftazidime; CFP = cefepime;
MER = meropenem; AMK = amikacin; LVX = levofloxacin; MIN = minocycline; TIG = tigecycline.
P-T = piperacillin-tazobactam; TAZ = ceftazidime; IMP = imipenem; TOB = tobramycin; CIP = ciprofloxacin.
Rhomberg PR, et al. Diagn Microbiol Infect Dis. 2009;65:414-26.
Dowzicky MJ, et al. Clin Ther. 2008;30:2040-2050.
Financial impact in U.S.
$21 – 34 billion spent annually
> 8 million additional hospital days
Outcome
OR (95% CI)
P
Length of stay
1.56
0.001
Cost of
hospitalization
1.57
0.003
Clinical impact
P-T = piperacillin-tazobactam; TAZ = ceftazidime; IMP = imipenem; TOB = tobramycin; CIP = ciprofloxacin.
Rhomberg PR, et al. Diagn Microbiol Infect Dis. 2009;65:414-26.
Schwater MJ. Antimicrob Agents Chemother 2006;50:1287-62.
ESBL production associated with increased mortality
Organism
Resistant to
Mortality
LOS
Enterobacter
3rd-generation
cephalosporins
5.02
(1.10–22.9)
1.47
(1.25–1.72)
P aeruginosa
imipenem
1.94
(1.22–3.10)
15.5 vs 9 days*
(P = .02)
Acinetobacter
MDR
2.6
(0.3–26.1)
2.5
(1.2–5.2)
* Mean LOS post-culture
Schwaber MJ, et al. J Antimicrob Chemother. 2007;60:913-920.
Cosgrove SE, et al. Arch Intern Med. 2002;162:185-190.
Lautenbach E, et al. Infect Control Hosp Epidemiol. 2006;27:893-900.
Sunenshine RH, et al. Emerg Infect Dis. 2007;13:97-103.
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Ahead of the curve
3.5 billions years to adapt
Genetic plasticity
Rapid replication
▪ 20 – 30 minutes to replicate
Gram-negative pathogens
Possess features of particular concern
▪ Highly efficient up-regulation or acquisition of genes that code for
resistance mechanisms
▪ Plethora of resistance mechanisms
Multiple mechanisms at once
Single mechanism may affect multiple antibiotics
Inactivating
Enzyme
Altered
Target
Decreased
Permeability
Efflux
β-Lactams
++
+
+
+
Aminoglycosides
++
+
+
+
Fluoroquinolones
+
++
+
+
Sulfonamides
++
Trimethoprim
++
+
Tetracyclines
+
+
++
+
++
Tigecycline
Polymyxins
Changes in or protection of target
Binding site mutations in topoisomerase II and IV
▪ Most common for fluoroquinolones
Overproduction of the target
++
++: most common mechanism
+: other mechanism
Adapted from: Opal SM. Mandell, Douglas, and Bennett’s Principles and Practices of Infectious Diseases.
7th ed. Philadelphia, PA: Churchill Livingstone Elsevier;2010:279-95.
Drug- or class-specific efflux pumps
May recognize broad range of agents
▪ MexAB-OprM pump: meropenem, fluoroquinolones,
tetracyclines and tigecycline
▪ AcrAB-ToIC pump: fluoroquinolones, ampicillin,
tigecycline, macrolides and oxazolidinones
▪ MexXY-OprM pump: adaptive resistance to
aminoglycosides in P. aeruginosa
Loss of outer membrane proteins
Nicasio AM, et al. Pharmacotherapy. 2008;28:235-249.
One of most common mechanisms
Aminoglycoside-modifying enzymes
Acetyltransferases
Adenyltransferases
phosphoryltransferases
β-lactamase production
OprD: imipenem resistance
Nicasio AM, et al. Pharmacotherapy. 2008;28:235-249.
Poole K. J Antimicrob Chemother. 2005;56:20-51.
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10/9/2012
Amber classification
Class
A
β-Lactamases
penicillinases
Amino Acid
serine
B
zinc
C
metallo-βlactamases
cephalosporinases
Examples
TEM, SHV, KPC,
CTX-M
IMP, VIM
serine
AmpC
D
oxacillinases
serine
OXA
Commonly found in Enterobacteriaceae
Confer resistance to penicillins, cephalosporins and
aztreonam
Cephamycins, cefepime and piperacillin-tazobactam may appear
susceptible
Revised susceptibility breakpoints
Additional plasmid-mediated resistance
Aminoglycosides and fluoroquinolones
Carbapenems
Drugs of choice
Resistant to ESBL hydrolysis
Nicasio AM, et al. Pharmacotherapy. 2008;28:235-249.
Chromosomal production
Common bacteria
Broad terminology
Ambler Class
Enterobacter
Citrobacter
Serratia marcescens
A. baumannii
P. aeruginosa
Class
B
▪ Selection following β-lactam
exposure
▪ Primarily 3rd generation
cephalosporins
Nicasio AM, et al. Pharmacotherapy. 2008;28:235-249.
Jacoby GA, et al. N Engl J Med. 2005;352:380-391.
Paterson DL, et al. Clin Microbiol Rev. 2005;18:657-686.
Mushtaq S, et al. Antimicrob Agents Chemother. 2004;48:1313-1319.
A
D
Confer resistance to penicillins, cephalosporins and aztreonam
Generally including β-lactamase inhibitor combinations and cephamycins
Possible resistance to cefepime and carbapenems
β-Lactamases
metallo-βlactamases
Serine
carbapenemases
Examples
IMP, VIM, SPM
oxacillinases
OXA, PSE
KPC, IMI, SME
Carbapenem-resistant Enterobacteriaceae
Klebsiella pneumoniae carbapenemases (KPC)
Jacoby GA. Clin Microbiol Rev. 2009;22:161-182.
Livermore DM, et al. Trends Microbiol. 2006;14:413-420.
Chow JW. Ann Intern Med 1991;115:585-90.
Resistant to carbapenems, antipseudomonal
cephalosporins and antipseudomonal
penicillins
Increased MICs, usually requiring additional
First identified in 1996 in North Carolina
Widespread
mechanism (e.g. porin loss) to become fully
resistant
Aztreonam
May resist hydrolysis by carbapenemases
Poor clinical efficacy
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First reported in India (2006)
Plasmid mediated
Among the most significant multidrug-resistant
(MDR) pathogens in hospitals
Enterococcus faecium
Staphylococcus aureus
Klebsiella pneumoniae
Easily transferrable
Associated bacteria
K. pneumoniae
E. coli
E. cloacae
Acinetobacter baumanni
Pseudomonas aeruginosa
Enterobacter species
Susceptible to colistin and tigecycline
Colistin-resistant isolated detected
Rice LB. J Infect Dis. 2008;197:1079-1081.
Boucher HW, et al. Clin Infect Dis. 2009;48:1-12.
CB is a 56 year old WF who presents to ED
Chief complaint
Culture results
Many Enterobacter aerogenes
Dyspnea and cough with nonpurulent sputum
Afebrile
WBC 6K
PMH: COPD, DM, HTN, hypothyroidism
Admitted to pulmonary internal medicine floor for management of
COPD exacerbation
Physical exam
Cellulitis of LLE - erythematous, warm to touch and weeping
Medical resident plans to order ceftriaxone
Is this appropriate given the potential mechanisms of
resistance?
BB, an 78 yo AAM, presents to ED
CC: fever and chills x 24 hrs
SH: lives with son in Lexington, SC
PMH: type II diabetes, CKD, HTN, obesity,
recurrent UTIs
▪ Patient started on vancomycin and purulent fluid collected for culture….
Severity of illness
Prolonged hospital length of stay (LOS)
Prolonged intensive care unit (ICU) LOS
Transfer from another hospital or nursing
home
Invasive procedure or device
Immunocompromise
Prior antibiotic therapy
Safdar N, et al. Ann Intern Med. 2002;136:834-844.
Maragakis LL, et al. Clin Infect Dis. 2008;46:1254-1263.
Virk A, et al. Mayo Clin Proc. 2000;75:200-214.
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CXR – no infiltrates seen
UA – cloudy, positive nitrite/leukocytes, TNTC
bacteria
Blood, urine and sputum cultures obtained
Blood cultures
Lactose-fermenting gram-negative bacilli
(2 of 2)
$400 - $800 million per approved agent
Lower return on investment
Short course therapy
Need to limit use of new, broad-spectrum
antibiotics
▪ Decreased efficacy with increased use
Lack of available research guidance
DiMassa JA. J Health Econ 2003;22:151-85.
Projan SJ. Curr Opin Microbiol 2003;6:427-30.
Spellberg B. Clin Infect Dis 2008;46:155-64.
Boucher HW, et al. Clin Infect Dis 2009; 48: 1-12.
Patient and clinician
education
Infection control
Antimicrobial stewardship
Multifaceted approach
▪ Limit inappropriate use of
antimicrobials
▪ Optimize selection, dose, route,
and duration
▪ Limit emergence of resistance, adverse
drug reactions and minimize cost
McDonald LC, et al. Clin Infect Dis 2006; 42: S65-71.
Dellit TH, et al. Clin Infect Dis 2007; 44: 159-77.
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Education
Prospective audit and feedback
Medical/pharmacy staff education
Multidisciplinary approach
Antimicrobial Support Teams
▪
▪
▪
▪
Pharmacy
Infectious Diseases physicians
Microbiology
Hospital Epidemiology
Surveillance of resistance and
antibiotic use
Management of antibiotic use
Prospective audit and feedback
Institution of antibiotic restrictions
Therapeutic substitutions
Automatic stops
Antimicrobial order forms
Antibiotic dose optimization
Extended infusions
Pharmacokinetic services provided
“The struggle against antibiotic resistance is a war
we will never win. The strength of trillions upon
trillions of microorganisms, combined with the
ancient force of evolution by constant, unrelenting
variation, will inevitably overpower our drugs”
by pharmacists
Bug-drug mismatch
Sterile site list review
Review of antibiograms
-American Academy of Microbiology
▪ Institutional vs. location-specific
Whitney Jones, PharmD
Antimicrobial Stewardship Pharmacist
Vanderbilt University Medical Center
October 25, 2012
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