Presented by:
LCDR Jeffrey S. Gildow, Pharm.D., M.S., EMT-B
Infectious Diseases Pharmacist Provider
Indian Health Service: Winnebago Service Unit
Winnebago, Nebraska
“I have no financial relationship with pharmaceutical companies,
biomedical device manufacturers or distributors, or others
whose products or services may be considered related to the
subject matter of my presentation.”
1.
Classify key mechanisms of bacterial
antimicrobial resistance
2.
Distinguish current trends in
antimicrobial resistance
3.
Summarize the role of Antimicrobial
Stewardship Programs
 June
26, 1945 – “…the microbes are
educated to resist penicillin and a host of
penicillin-fast organisms is bread
out….In such cases the thoughtless
person playing with penicillin is morally
responsible for the death of the man who
finally succumbs to infection with the
penicillin-resistant organisms. I hope this
evil can be averted.”
• Sir Alexander Fleming
Ref.: New York Times, June 26, 1945: 21
b-lactams
Macrolides
Tetracyclines
Quinolones
Glycopeptide
Enzymatic
inactivation
+++
+ (gramnegative)
+
--
--
Decreased
perm.
+ (gramnegative)
++ (gramnegative)
+ (gramnegative)
+ (gramnegative)
++ (gramnegative)
+
++
+++
+
--
Alteration of
target site
++
+++
+ (H. pylori)
+++
+++
Protection of
target site
--
--
++
+
--
Efflux
+++, most common, ++ common, + less common, -- no used
* Over production of dihydropteroate synthase (DHPS) by felP – sulfonamide resistance
and by folA for trimethoprim resistance
** By pass ABX inhibition (thymine dependent): Thymidylate synthesis via salvage
pathways – resistant to SMX/TMP
Table modified from: Opal and Medeiros, 2005
 b-lactamases
• Bush-Jacoby-Medeiros Functional Classification
scheme of b-lactamases (Penicillinases,
Cephalosporinase, Extended-spectrum,
Carbapenemases)
 Erthromycin
esterases – isolated from E.
coli (hydrolyze the lactone ring, plasmid
mediated)
 Tetracycline-inactivating enzyme – tetX
(Described in Bacteroides spp.)
Ref: Opal and Medeiros, 2005
 Outer
Membrane Permeability
• Porin protein (ex. OmpF) suppression –
cephalosporin resistance
• P. aeruginosa resistance is partly attributed to the
loss of a specific entry protein – D2 porin
• Alterations of proteins – resistance to quinolones
in S. marcescens and P. aeruginosa
 Inner
Membrane Permeability
• Pseudomonas mutants have been found to be
deficient in certain cytochromes
Ref: Opal and Medeiros, 2005
 b-lactams
• P. aeruginosa has multidrug efflux pumps that
protect microbe from b-lactam agents
 Macrolides
• Some strains of S. pneumoniae (mef – macrolide
efflux), S. pyogenes, S. aureus (msr), and S.
epidermidis have active efflux mechanisms for
macrolide resistance
Ref: Opal and Medeiros, 2005
 Tetracyclines
• Some strains of E. coli, Shigella, and other Enteric
microbes (ex: tet A, and tet B)
 Fluoroquinolones
• Active efflux detected in enteric bacteria and
staph
• May be related to a multiple antibiotic resistance
transporter (norA) or specific quinolone efflux
pump (EmrAB, AcrAB)
Ref: Opal and Medeiros, 2005
 b-lactams
• Alteration of penicillin binding proteins (PBP)
• Either change in the amount or decrease in
affinity
 Macrolides/Licosamides/Streptogramins
• Primary mechanism of resistance for gram-
positives and gram-negatives
• MLSB – determinant methylase enzymes
methylate the ribosome
Ref: Opal and Medeiros, 2005
 Tetracyclines
• H. pylori possess a mutation in 16S ribosomal
RNA that limits binding
 Fluoroquinolones
• Alterations in DNA gyrase in P. aeruginosa and
Enterobacteriaceae
 Glycopeptides
• Alteration of D-ala-D-ala (termini of
peptiodoglycan precursors)
• Both inducible and constitutive in S. aureus and
Enterococcus -- class A-G ( vanA, vanB, etc)
Ref: Opal and Medeiros, 2005
 Tetracyclines
• Interferes with ability to bind to ribosome
• tetM gene generates protein that stabilizes
ribosome during transfer activities in presence
of tetracycline
 Fluoroquinolones
• Newly recognized mechanism that protects DNA
gyrase from binding to FQ
Ref: Opal and Medeiros, 2005
 ESKAPE
(E. faecium, S. aureus, K.
pneumoniae, Acinetobacter baumannii,
Pseudomonas aeruginosa, Enterobacter
sp.)
 MRSA/VISA aka GISA/VRSA
 VRE
 Multidrug-resistant S. pneumoniae
 XDR-TB – resistant to INH & RIF + FQ & at
least 1 of 3 second line drugs
(capreomycin, kanamycin, or amikacin)


MRSA
hVISA
• MIC 2-4 mcg/mL
• Questionable use of
Vancomycin in MIC ≥2
• Winnebago has increasing
numbers of hVISA (~35%)

VISA aka GISA
• MIC 8-16 mcg/mL (some
consider 4-8 mcg/mL)

VRSA
• >16 mcg/mL (some
suggest >32 mcg/mL)
Ref: http://cooper.imb.uq.edu.au/community_background.html
b-lactamaseproducing and carbapenemaseproducing Enterobacteriaceae
 NDM-1 Enterobacteriaceae
 Clostridum difficile NAP1 strain (resistant
to fluoroquinolones – noted to produce
several-fold more toxin in vitro)
 Extended-spectrum
Ref.: Warny et al., 2005.
 CDI
associated with
ABX use
 Can be spread via
fomites
• *to other patients not on
ABX
 Antimicrobials
are
the only medication
misuse affects
multiple people
Ref.: Internet site: http://www.fitsnews.com/2008/12/10/heres-our-surprised-face/, accessed 3/31/12
 Decreasing
development of new
antimicrobials
• Slow development due to difficult regulatory
environment compared w/ more profitable
markets
• Predicted in 2004 w/ est. of IDSA’s Antibiotic
Availability Task force & the “Bad Bugs, No
Drugs” document
• CDC & European Medicines Agency noted that
the last new class of drugs active against gramnegative bacilli was trimethoprim the1970’s
Ref.: Spellburg, et al, 2008.; Tabot, et al, 2006; ECDC/EMEA report
 Slow
development of microorganism
resistance
 Optimize medication selection, dose, and
duration
 Reduce adverse events
 Lower rates of morbidity/mortality
 Reduce hospital stay
 Drive down spending/cost
Septimus & Owens, 2001
 ID
pharmacist participation:
• Higher rates of appropriate use
• Higher cure rates
• Lower incidence of treatment failures
• Improved clinical and economic outcomes
• Decreased mortality and decreased adverse
events
Septimus & Owens, 2001
 Core
strategies:
• Prospective audit with direct intervention and
feedback
• Formulary restriction and preauthorization
requirements
Rapp et al, accessed 4/5/12
 Supplemental
Elements:
• Education
• Evidence-based guidelines and clinical
pathways
• Antimicrobial cycling (not routinely
recommended in IDSA/SHEA guidelines)
• Antimicrobial order forms
• Combination therapy (not routinely
recommended in IDSA/SHEA guidelines)
Rapp et al, accessed 4/5/12
 Supplemental
Elements cont.:
• Streamlining or de-escalation of therapy
• Dose optimization
• Parenteral to oral conversion
 Computer
programs are available to help
monitor
 Antimicrobial conservation
• Shortening treatment length (CAP, UTI)
Rapp et al, accessed 4/5/12; MacDougall & Polk, 2005
Ref: http://madmikesamerica.com/2011/04/world-health-organization-europe-losing-battle-with-superbugs/
 LT
Laura Botkins, Pharmacy Resident
 Dr. Susan Porter, Deputy COP
 Dr. Ahmed Mohammed, Physician
 Ms. Verna Spotted Wood, I.C. RN
 Ms. Patty Collisen, Lab Director
 LCDR
Gildow
• Email: jeffrey.gildow@ihs.gov
• Phone: 402-878-2231 ext. 2040
• Cellular: 402-719-4280
1.
2.
3.
4.
5.
6.
7.
8.
9.
European Centre for Disease prevention and Control, European Medicines Agency.
ECDC/EMEA Joint Technical Report: the bacterial challenge: time to react. Available at:
http://www.ecdc.europa.eu/en/publications/Publications/Forms/ECDC_DispForm.aspx?ID=4
44. Accessed 5 Apr 2012.
MacDougal C and Polk R. Antimicrobial Stewardship Programs in Health Care Systems.
Clinical Microbiology Review. 2005;18:638-656.
Opal S and Medeiros. Molecular mechanisms of antibiotic resistance in bacteria. Ch. 17 in
Principals and Practice of Infectious Diseases. Vol 1. 6th ed. Editors Mandel, Bennett, and Dolin.
Elsevier, Philadelphia, 2005.
Penicillin finder assays its future. New York Times. 26 June 1945:21.
Rapp R, Kaye J, Canon S, Hermsen E, DePestel D. A Hospital Pharmacist’s Guide to
Antimicrobial Stewardship Programs. Available at:
http://www.ashpadvantage.com/docs/stewardship-white-paper.pdf. Accessed: 5 April 2012.
Spellburg G, Guidos R, Gilbert D, et al. The epidemic of antibiotic-resistant infections: a call to
action for the medical community fro the IDSA. Clin Infect Dis 2008; 46:155-64.
Septimus E and Owens R. Need and potential of antimicrobial stewardship in community
hospitals. Clinical Infectious Diseases 2011;53(S1):S8-S14.
Talbot GH, Bradley J, Edwards JE Rj, Gilbert D, Scheld M, Barlett JG. Bad bugs need drugs: an
update on the development pipeline from the Antimicrobial Availability Task Force of the
IDSA. Clin Infect Dis 2006; 42:657-68.
Warny M, Pepin J, Fang A, et al. Toxin production by an emerging strain of Clostridium difficile
associated with outbreaks of severe disease in north America and Europe. Lancet 2005;
366:1079-84.