The clinical burden of Gram negative (-) Resistance

9/19/2012
Kimberly D. Boeser, PharmD.
Infectious Diseases Clinical Pharmacist
Antimicrobial Stewardship Coordinator
University of Minnesota Medical Center, Fairview
 None
to report
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 Review
the burden of hospital acquired
infections (HAIs)
 Understand the clinical burden of gram
negative resistant pathogens
 Identify some of the most common multidrug resistant gram negative pathogens
 Review the lack of research and development
target at these pathogens
 Cover the clinical treatment strategies for
these gram negative resistant pathogens
 Understand our role as health care providers
 What is the future efforts and outcomes
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9/19/2012
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June 18, 1988 – January 24, 2009: Mariana (Mari) Bridi da
Costa
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In 2006, 4th place in the Miss World Brazil 2006 beauty pageant
In 2007, she participated in the Miss Bikini International
contest & Face Of The Universe and won the title for the 4th
most beautiful face in the world
She was also a finalist for the Miss World 2008 beauty pageant
and won 4th place
In December 2008, became ill initially misdiagnosed as
having kidney stones
By early January, she was diagnosed with UTI that
worsened to become septic shock caused by a bacterial
infection
She had her hands and feet amputated, partial
gastrectomy and kidneys removed to prevent the
infection’s spread
She died of a multi-drug resistant Pseudomonas aeruginosa
infection
http://www.google.com/imgres?imgurl=http://www.abril.com.br/imagem/mariana-bridi-modelo-436.jpg&imgrefurl4
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CNN.com 2011 – A new crop of drug-resistant
superbugs is in our midst, and experts believe that
they could rival the deadly superbug MRSA.
A new report from the Infectious Diseases Society of
America says these superbugs are creeping onto the
radar in hospitals across the country, and our ability
to fight them is next to none.
Dr. Sanjay Gupta, CNN Chief Medical News
Correspondent:
First, let’s define what these superbugs are. They’re
called ―gram-negative‖ bacteria. They are extremely
drug-resistant; they have long, complicated names
like ―acinetobacter baumanii‖ and ―klebsiella
pneumoniae.‖ Two important issues related to these
bacteria: They are increasingly cropping up in
hospitals, and they are nearly impossible to treat.
http://www.google.com/imgres?imgurl/guptasanjay
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19th patient at the hospital to contract an
antibiotic resistant strain of KPC
 7th person at the National Institutes of Health
(NIH) Clinical Center in Maryland
 Boy arrived at the research hospital in Bethesda
in April and was being treated for complications
from a bone marrow transplant when he
contracted the bug
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First new infection of this superbug at NIH since
January
Outbreak stemmed from a single patient carrying
the superbug
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August 2011 with a New York woman who needed a
lung transplant was the index case
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…it gets worse
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 Centers
for Disease Control and Prevention
(CDC)estimates that roughly 1.7 million HAIs,
from all types of bacteria combined, cause
or contribute to 99,000 deaths each year
 1 out of every 20 hospitalized patients will
get a HAI
 Drug -Resistant infections prolong

Length of hospital stay by 24% and increase costs
by 29% vs. susceptible infections
 In
the U.S. antibiotic resistance adds 8
million additional hospital days per year
(Maudlin et al. Antimicrobial Agents and Chemotherapy
(2010) 54:109-115.)
Roberts et al. Clinical Infectious Diseases (2009) 49:117584; & PRN Newswire ―Antibiotic-Resistant Infections
Cost the U.S.)
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 National
Nosocomial Infection Surveillance
(NNIS) suggest from 1998-2002 (110 ICUs)
 6.1% of ~6000 K. pneumoniae isolates were
resistant to third generation cephs
 In 10% of the ICUs the resistance was noted
as high as 25%
 Non-ICUs: 5.7% of ~10,000 isolates were R:
ceftazidime
 Outpatient: 1.8% of ~12,000 isolates of K.
pneumoniae & 0.4% of ~71,000 E. coli were
resistant to ceftazidime
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Mortality = 2%
LOS = 4.7 days
 Average Cost =$37,943
Mortality = 12.2%
LOS = 19.7 days
 Average Cost = $191,872
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
Patients without (HAI)
Pennsylvania Health Care Cost Containment Council
January 2009
Patients with (HAI)
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9/19/2012
 Antibiotic-resistant
microbes infect
over 2 million
Americans annually
 Kill over 100,000/yr
 Antibiotic resistant
infections are
skyrocketing in
incidence
 Critical need for
new antibiotics
research and
development of
new antibiotics has
ground to a
screeching halt
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Research and Development programs takes ~10
years to bring a new agent to market
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An investment of $800 million to $1.7 billion
56% decrease in antimicrobial approval from the FDA
(1983-87 to 1998-2002)
Developing new drugs alone will not be sufficient
to address the growing resistance problem
 It is essential to preserve the efficacy of existing
drugs
 It will take ALL levels of health care providers to
understand and commit to these efforts
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Extending the Cure: http://www.rff.org/RFF/Documents/ETC-06.pdf
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 Can
encompass all gram negative bacteria
Pseudomonas aeruginosa
 Acentiobacter baumanii
 Enterobacteriaceae species
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 Reported
rates continue to increase: globally
and locally
 Severity of illness is wide-morbidity and
mortality are high
 NOT just a nosocomial problem

Community-acquired infections are being widely
described
 Global
public health crisis
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MDR-PSA
www.google.com/image/tulip.ccny.cuny.edu
 One
of the most common nosocomial gram
negative pathogens
 Several mechanisms of resistance (MOR)
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Active efflux pumps
Porin loss leading to impermeability
Plasmid encoded with beta lactamases or
carbapenemases
Enzymatic or mutation associated changes in
targeted abx
 One
strain can demonstrate multiple MOR
selective pressure is the leading
cause of MDR-PSA
 Antibiotic
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What to do?
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Another highly resistant aerobic gram negative
bacteria
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Identification can be tricky as it can resemble H.
influenzae on gram stain
baumanii is the most relevant species in the
human host
 Associated with wounded war vets and has been
termed ―Iraqibacter‖
 Problematic in immunocompromised hosts but
also associated:

VAP
CA-BSI
Chronic foley catheter placement
 Sepsis
 SSTI-wounds or burn patients
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 Simply
do the best we can
dosing schemes
 Optimize
Push the doses (within safe limits)
Double coverage
 Prolonged/continuous infusions
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 Request
additional sensitivities
Colistin
 Tigecycline (only A. baumanii)
 All carbapenems
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 Isolation
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to prevent spread
Tracking for future admissions
 Education
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 Pay
attention to your antibiogram
carbapenems + aminoglycoside
 DOC:
Amikacin for A. baumanii
Tobramycin or amikacin for PSA
 Can possibly consider extended spectrum betalactam abx such as piperacillin/tazobactam
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 Tigecycline
100 mg x1 then 50 mg IV Q12hr
Bacteriostatic
 FDA approved for CAP, SSTI, and intra-abdominal
infections
 Affected clearance in severe hepatic impairment
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Meropenem, Imipenem/cilastatin, or Doripenem
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Ertapenem lacks pseudomonal coverage
Broadest spectrum of the beta-lactam class
 Considered our nuclear weapon
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Know when to use
 AE:
seizures in elderly or h/o seizures (0.2%
vs. 33%), higher doses and not renally
adjusted, bone marrow suppression, infusion
related hypotension
 Major DDI (drug-drug interactions): CYP p450
(VA-decreases levels, increasing risk for
seizures)
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
Spectrum of activity: should be reserved for
documented resistant pathogens
Gram positive included Strep and enterococcus
Gram negative w/ exception of Pseudomonas
 Anaerobic, Proteus and Providencia species
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Indications for use: MDR organism (primarily
gram negative) including carbapenemase
producing gram negatives, complicated SSSI, or
complicated intra-abdominal infections
 Treatment of bacteremia is problematic and note
recommended d/t low achievable serum
concentrations
 AE: highly associated with N/V (20-30%)
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 Spectrum:
Most MDR Gram- organisms
including Pseudomonas aeruginosa,
Acinetobacter spp., ESBL and KPC producers
 Indication: Last resort  reserved for MDR
infections
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Inhalation – CF patients or nosocomial pneumonia
 Rapidly
bactericidal – development of
resistance is slow
 AE: Nephrotoxicity – up to 20% (usually
reversible), neurotoxicity
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Inhaled – bronchospasm, ARDS
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Extended spectrum beta-lactamases (ESBL) & Metallo betalactams
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Includes the New Delhi metallo beta-lactamase (NDM-1)
Verona integron-encoded metallo BL (VIM)
AmpC beta-lactamase
Carbapenemase producing
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Klebsiella producing carbapenemase (KPC)
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Extended spectrum β-lactamases are enzymes that mediate
resistance to extended spectrum cephalosporins (ceftriaxone,
cefotaxime, ceftazidime) and monobactams (aztreonam) but do
not affect cephamycins (cefoxitin and cefotetan) or carbapenems
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Plasmid containing genes that are encoded w/ ESBLs
Multiple mechanisms of resistance are now being described in
single strains (e.g. ESBL and AmpC)
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1940: 1st β-lactamase identified in E. coli
1965: 1st plasmid-mediated β-lactamase
discovered in a gram- negative bacteria in
Greece (TEM-1) Another plasmid-mediated βlactamase found in K. pneumoniae and E. coli
(SHV-1)
 1980s: development of oxyimino-cephalosporins
(cefotaxime, ceftazidime, ceftriaxone)
 1983: 1st ESBL found in K. pneumoniae in
Germany (SHV-2)
 1984: TEM-related ESBLs discovered in France
 1988: TEM-related ESBLs discovered in USA
 1980s-90s: development of carbapenems
 1993: 1st carbapenemase discovered
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TEM-1, TEM-2 or SHV-1 or SHV-2 describe the genetic differences
 ESBL
 DOC:
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E. coli or Klebsiella sp.
carbapenems
Meropenem, Imipenem/cilastatin, Ertapenem or
Doripenem
 Can
consider fosfomycin
FDA approved for UTIs
 Easy to give 3 gm PO (dissolved in water) X1
dose/day for up to 3 days
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http://www.google.com/imgres?imgurl=http://medicinepanel.com/wpcontent/uploads/2009/10/monurol.jpg
http://www.google.com/imgres?imgurl=http://www.uic.edu/pharmacy/_ima
ges/druginfogroup/carbapenem.jpg
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 Most
common of the carbapenem-R
Enterobacteriaceae in the U.S.
 RESISTANT to almost all available antibiotics
on the market
 Identified in 41 states of the US
 MN is one of them!!!
 Associated increased mortality, LOS and
increased costs
 High risk for dissemination
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Centers for Disease Control and Prevention 1600 Clifton Rd. Atlanta, GA 30333, USA
800-CDC-INFO (800-232-4636) TTY: (888) 232-6348 - cdcinfo@cdc.gov
Volume 17, Number 10—October 2011
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
February 2009: KPC+ K. pneumoniae confirmed at MDH
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2010: 14 KPC+ isolates
 K. pneumoniae (6)
 E. cloacae (6)
 K. oxytocae (2)
2011: 21 KPC+ isolates
 K. pneumoniae (10)
 E. cloacae (10)
 C. freundii (1)
October 2011: E. coli and K. ozaenae isolates (urine) NDM1+ and KPC–
 History of recent hospitalization in India
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Permission and release-MN Department of Health 9/17/2012; Dr. Ruth Lynfield, MN State Epidemiologist and Medical Director
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 Its
simple…
Colistin
 Tigecycline
 Or nothing
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 Keep
fighting!
our patients
 Surveillance
 Quick identification and treatment
 Support local and national legislation
 Work with industry
 Protect
 Be
stewards…
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The WHO for Global Containment of Antimicrobial Resistance addresses the
challenge of resistance:
• reducing the disease burden and spread of disease
•Improving access to appropriate antimicrobials and use of antimicrobials
•Strengthening health systems and their surveillance capabilities
•Enforcing regulations and legislation
•Encouraging the development of appropriate new antimicrobials and
vaccines
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•Develop integrated approaches to
improving the use of antimicrobials,
reducing the incidence and spread of
hospital-acquired(nosocomial)
infections
•Training of key individuals and the
allocation of resources to effective
surveillance, infection control and
therapeutic support
•Recommend local surveillance data
should guide clinical management and
update clinical guidelines
•Prompt identification, reporting and
treatment are key
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http://www.health.state.mn.us/divs/idepc/dtopics/antibioticresistance/index.html
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 The
speed with which bacteria develop
resistance to antibiotics, in contrast with
the slow development of new drugs, has
led some experts to warn of a ―postantibiotic era‖
 Can we prevent this? NO!
 BUT….Judicious use of the antibiotics
currently available—particularly through
better infection control in hospitals and
more rational prescribing, may help
conserve their effectiveness
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It takes a change in culture to understand the
riskiness of antimicrobial prescribing and overutilization of antibiotics both inpatient and
outpatient
It takes the efforts of everyone from top
(medical/hospital executive leadership) to front line
workers and everyone in between
Your future practice will likely be impacted by MDR
gram negative infections and stewardship efforts
We ultimately will not win this battle of
resistance as the bugs have been here a lot
longer than we have…they will continue to
outsmart us and ultimately outlive us!
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―Sometimes by losing a battle you find a way
to win the war‖-Donald Trump
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National Institute of Allergy and Infectious Diseases. The problem of antibiotic
resistance. www.niaid.nih.gov/factsheets/antimicro.htm (accessed 2006 Nov).
Centers for Disease Control and Prevention. National Nosocomial Infections
Surveillance (NNIS) System report, data summary from January 1992 through
June 2004, issued October 2004.
www.cdc.gov/ncidod/dhap/pdf/nnis/2004NNISreport.pdf (accessed 2006 Nov).
Infectious Diseases Society of America. Bad bugs, no drugs. As antibiotic
discovery stagnates…a public health crisis brews.
www.idsociety.org/pa/IDSA_Paper4_final_web.pdf (accessed 2006 Nov).
Centers for Disease Control and Prevention. Management of Multidrug-Resistant
Organisms In Healthcare Settings, 2006.
www.cdc.gov/ncidod/dhqp/pdf/ar/mdroGuideline2006.pdf (accessed 2006
Nov).
Wenzel RP. The Antibiotic Pipeline-Challenges, Costs and Values. N Engl J Med.
2004; 351(6):523-26.
Nelson R.. Antibiotic development pipeline runs dry. The Lancet. 2003; 362:
1726-27.
Kollef MH, Sherman G, Ward S, et al. Inadequate antimicrobial treatment of
infections: a risk factor for hospital mortality among critically ill patients.
Chest. 1999; 115:462-74.
Scheetz MH, Hurt KM, Noskin GA, Oliphant CM. Applying antimicrobial
pharmacodynamics to resistant gram-negative pathogens. Am J Health-Syst
Pharm. 2006; 63: 1346-1360.
Finch, R. Current challenges in antimicrobial resistance and healthcare
associated infections:
role and organization of ARHAI. J Antimicrob
Chemother 2012:67(1);i3-i10.
Wilson APR and Kiernan W. Recommendations for surveillance priorities for
healthcare associated and criteria for their conduct. J Antimicrob Chemother
2012:67(1);i23-i27.
WHO Global strategy for containment of antimicrobial resistance.
http://www.who.int/csr/resources/publications/drugresist/WHO_CDS_CSR_DRS
_2001_2_EN/en/. Last accessed 9/17/12
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