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Multi-drug resistant pathogens. Helmut Albrecht, MD Division of Infectious Diseases. Disclosures. Grant/Research Support–MSD, J&J, VIIF, Gilead (no payment to me) Consultant–France Foundation (non profit project with Duke), VIIF, Gilead (no honoraria) Speaker’s Bureau–(no honoraria). Agenda.

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multi drug resistant pathogens

Multi-drug resistant pathogens

Helmut Albrecht, MD

Division of Infectious Diseases

disclosures
Disclosures
  • Grant/Research Support–MSD, J&J, VIIF, Gilead (no payment to me)
  • Consultant–France Foundation (non profit project with Duke), VIIF, Gilead (no honoraria)
  • Speaker’s Bureau–(no honoraria)
agenda
Agenda
  • State of the union
  • The players (Resistant pathogens)
  • What to do about them
antibiotics
Antibiotics
  • “Deaths in the US declined by 220 per 100,000 with the introduction of sulfonamides and penicillin. This far outweighs any other medical advance in the past century.”
  • Armstrong et al. JAMA 1999;6:61ff
  • From 1983 to 2010, FDA approval of new antibiotics has continuously declined, from 4 per year in the early 1980s to less than 1 antibiotic per year now
  • The last class of drugs with a novel mechanism of action against GN bacteria goes back 40 years. A review of drugs currently in trials revealed no such new drugs.
  • For the US, antibiotic resistance is responsible for nearly 100,000 deaths caused by hospital-acquired infections per year at an estimated annual cost of $23 billion.
  • Roberts et al CID 2009;49:1175ff
why do we see more resistance
Why do we see more resistance?
  • Sicker inpatient population
  • Patients chronically ill
  • Larger immunocompromised population
  • More instrumentation/new procedures
  • Presence of devices
  • Increasing resistance in community
  • Emerging pathogens
  • Complacency regarding antibiotics
  • Increased use of (empiric) broad-spectrum antibiotics
  • Ineffective infection control and compliance
  • Crowding of patients in confined areas
  • Decreasing nurse/patient ratio
why do we see more resistance6
Why do we see more resistance?
  • Sicker inpatient population
  • Patients chronically ill
  • Larger immunocompromised population
  • More instrumentation/new procedures
  • Presence of devices
  • Increasing resistance in community
  • Emerging pathogens (Superbugs!)
  • Complacency regarding antibiotics
  • Increased use of (empiric) broad-spectrum antibiotics
  • Ineffective infection control and compliance
  • Crowding of patients in confined areas
  • Decreasing nurse/patient ratio
my patient is really ill
My patient is really ill…
  • What is the price of prescribing a little more than needed if I do not want to think that hard?
  • Healthcare dollars (irrelevant, if title true)
  • C. difficile (potentially deadly)
  • Side effects (potentially deadly)
  • Resistance (relevant?)
getting it right ventilator associated pneumonia
Getting It RightVentilator-associated Pneumonia

% Mortality

It is a lot more difficult to get it right if the bacteria are multi-drug resistant

scope of the problem
Scope of the problem
  • Nosocomial infections > 8 million excess hospital days
  • Approximately 80,000 deaths
  • >75% resistant to at least one drug class
  • > 50% of inpatients receive antibiotics
  • 30-50% of these receive them inappropriately
  • Cost of res. pathogens 100 million - 30 billion US$/year
  • Phelps Med Care 1989
the gram negative cell wall
The Gram Negative Cell Wall

Efflux system

Porin channels

B-lactamases

PBPs

Adapted from Livermore and Woodford, Trends in Microbiol, 2006.

slide14

Substrate Profile

  • Penicillinase
  • Cephalosporinase
  • Broad spectrum
  • Extended broad spectrum
  • Carbapenemase
slide15

Substrate Profile

  • Penicillinase
  • Cephalosporinase
  • Broad spectrum
  • Extended broad spectrum
  • Carbapenemase
slide16

19 Months ESBL Klebsiella pneumoniae Outbreak New York Hospital Medical Center of Queens

  • 432 ceftazidime-resistant Klebsiella pneumoniae
  • 155 patients colonized (61%) or infected (39%)
  • 53% crude mortality rate
  • Not detected for 12 months!

Meyer et al. Ann. Int. Med. 119: 353-358 1993

slide17

Substrate Profile

  • Penicillinase
  • Cephalosporinase
  • Broad spectrum
  • Extended broad spectrum
  • Carbapenemase
is klebsiella bad
Is Klebsiella bad?

It depends!

Most Klebsiella infections are easy to deal with, but some are worse than others

Because the host is bad?!

Because the bug is bad?!

Because the drugs are bad?!

slide20

Drugs with Most Reliable Activity Against

ESBL-producing Enterobacteriaceae

  • Carbapenems
  • (Cephamycins)
  • (Fluoroquinolones)
k lebsiella p neumoniae c arbapenemase
Klebsiella Pneumoniae Carbapenemase
  • KPC is a class A b-lactamase
    • Confers resistance to all b-lactams including extended-spectrum cephalosporins and carbapenems
  • Occurs in Enterobacteriaceae
    • Most commonly in Klebsiella pneumoniae
    • Also reported in: K. oxytoca, Citrobacter freundii, Enterobacter spp., Escherichia coli, Salmonella spp., Serratia spp.,
  • Also reported in Pseudomonas aeruginosa (Columbia, thankfully we are talking the country, not us!)
kpc enzymes
KPC Enzymes
  • Located on plasmids; conjugative and nonconjugative
  • blaKPC is usually flanked by transposon sequences
  • blaKPC reported on plasmids with:
    • Normal spectrum b-lactamases
    • Extended spectrum b-lactamases
    • Aminoglycoside resistance
slide27

Geographical Distribution of KPC-Producers

Frequent Occurrence

Sporadic Isolate(s)

kpc outside of united states
KPC Outside of United States
  • France (Nass et al. 2005. AAC 49:4423-4424)
  • Singapore (report from survey)
  • Puerto Rico (ICAAC 2007)
  • Columbia (Villegas et al. 2006. AAC 50:2880-2882 & ICAAC 07)
  • Brazil (ICAAC 2007)
  • Israel (Navon-Venezia et al. 2006. AAC 50:3098-3101)
  • China (Wei Z, et al. 2007. AAC 51: 763-765)
carbapenemase producing enteric gnr u k
Carbapenemase – Producing Enteric GNR; U.K.

< 10% susceptible to usual Rx

>40% resistant to tigecycline, >90% susceptible to colistin

ndm1 carbapenemase
NDM1 Carbapenemase
  • First described from India 2008
  • Novel resistance mechanism
  • Gene compatible with multiple types of plasmids- greatly enhances global spread
  • Already in California, Illinois and Mass.
  • Some strains sensitive to only polymyxins (highly neuro and nephro-toxic) or Tigecycline
  • No new drugs close to release
phenotypic tests for carbapenemase activity
Phenotypic Tests for Carbapenemase Activity
  • Modified Hodge Test
    • 100% sensitivity in detecting KPC; also positive when other carbapenemases are present
    • 100% specificity

Procedure described by Lee et al. CMI, 7, 88-102. 2001.

new transmission mechanisms
New transmission mechanisms
  • NDM-1: 77 cases in 13 European countries
    • 60% from England
    • Travel to India (including medical tourism)
  • ESBLs
    • Travellers diarrhea
    • Foodborne outbreak
    • Adoption
slide34

25% of E. coli ESBL (3% Europe, 79 % India, 50% Egypt, 22% Thailand)

  • Antibiotic use not predictive except for ciprofloxacin
  • 5/21 persistently colonized
slide35

156 pts affected

  • 35% of kitchen surfaces colonized
  • 6 of 44 (14%) of food workers fecal carriers
  • 2 y.o. from China
  • Adopted
  • Secondary transmission in family
modified hodge test
Modified Hodge Test

Lawn of E. coli ATCC 25922

1:10 dilution of a

0.5 McFarland suspension

Test isolates

Imipenem disk

Described by Lee et al. CMI, 7, 88-102. 2001.

resistance in gram positive organisms
Resistance in gram-positive organisms
  • 1990 1997 2000
  • PRSP 4% 30-50% 48%
  • VTSP < 0.2% 3.6-5.1%
  • MRSA 20-25% 25-50%
  • GISA 0 <0.1 <0.1
  • VRE <0.1 15 21
evolution of e faecium resistance

Community acquired (ca-) MRSA strains generally CANNOT be distinguished from hospital acquired strains by the presence of:

    • MEC-A gene
    • SCC pattern
    • Panton-Valentine leukocidin
Evolution of E. faecium resistance
  • MIC90 of E. faecium
  • 1968 1969-88 1989-90
  • Penicillin 8 64 512
  • Ampicillin 2 32 128
  • % VRE 0 0 61%

Grayson et al, AAC

why is this different
Why is this different?
  • Outbreaks in new populations
  • Different disease spectrum (boils, CAP)
  • Spider bite history
  • Specific clones
  • SCCmec type IV
  • Panton-Valentine Leukocidin (PVL)
  • Susceptible to many antibiotics
populations with ca mrsa
Children

Inmates

Military recruits

Native populations

MSM

HIV+ patients

Religious communities

Football teams

Wrestlers

Gymnasts

Fencing teams

IDU

Homeless

Populations with ca-MRSA
mrsa skin infection differential diagnosis
MRSA skin infection: differential diagnosis
  • Common misdiagnosis: “spider bite”, complete with history of having been bitten!
slide47

déjà vu II

  • Phage type 80/81: PCN-R clone of SA
  • Neonatal outbreaks in Australia in 50’s
  • Became pandemic in adults/children
  • in hospitals/communities
  • Highly transmissible and virulent
  • Carried leukocidin
  • Robinson et al
  • Phage type 80/81 carried PVL
  • MLST 30
  • Current SWP clone of CA-MRSA
  • descendant – acquired SCC IV
distribution of virulence and resistance determinants ca mrsa france switzerland usa oceania
Distribution of Virulence and Resistance DeterminantsCA-MRSA (France, Switzerland, USA, Oceania)

Vandenesch et al. EID Aug 2003

pvl associated with severe disease
PVL associated with severe disease
  • Necrotizing pneumonias
  • Septic syndrome
  • Empyema
  • Most CA-MRSA strains PVL +
    • Causal role in severe disease presentations is not proven
centers for disease control campaign 12 steps to prevent antimicrobial resistance
Centers for Disease Control Campaign12 steps to prevent antimicrobial resistance
  • Prevent Infection
  • Vaccinate
  • Remove catheters
  • Diagnose and Treat Effectively
  • Target the pathogen
  • Access the experts
  • Use Antimicrobials Wisely
  • Practice antimicrobial control
  • Use local data
  • Treat infection, not colonization
  • Know when to say no to vancomycin
  • Stop treatment when infection is cured or unlikely
  • Prevent transmission
  • Isolate the pathogen
  • Brake the chain of contagion
how to prevent resistance
How To Prevent Resistance
  • Adequate infection control
  • Appropriate use of antibiotics
strategies for managing outbreaks of resistance

Lack of association

of resistance with a

plasmid mechanism

Plasmid-mediated

mechanism

Polyclonal

epidemiology

Favors clonal or

oligoclonal epidemiology

Amenable to strict

infection control procedures

Necessitates antibiotic

restriction before

significant reduction in

resistance occurs

Strategies for Managing Outbreaks of Resistance

Ahmad M et al. Clin Infect Dis 1999;29:352-355

optimal use of antimicrobial it s role in preventing resistance
Optimal Use of Antimicrobial: It’s Role in Preventing Resistance
  • Will optimal use, including control of antibiotic use, prevent or slow the emergence of resistance?
    • “It is unlikely that the resistance problem will rapidly wane, simply by being more prudent in our use of antimicrobial agents; on the other hand, it is certain that if we do not cut back on the use of these agents, the resistance problem will worsen.”
    • Williams Science 1998;279:1153
what to do to slow antibiotic resistance
What to do to slow antibiotic resistance
  • Aggressively attack misuse
  • Animal feeds and “treatment” of inanimate objects
  • Upper respiratory tract infection
  • • Colds
  • • Sinusitis
  • • Pharyngitis
  • • Bronchitis - acute
  • Fever without evidence of bacterial infections
  • • ICUs
  • • Children
  • • Chronic care facilities
appropriate use of antibiotics
Appropriate Use of Antibiotics
  • The appropriate empiric treatment for the patient with
  • Sneezococcus congestii
  • Coughobacillus snifficile
  • is Tylenol, decongestants and antitussives not antibiotics
  • If the patient is really sick and may have pneumonia with
  • Tyrannococcus rex or other superbugs
  • you may want to consider Bumfacillin or Gorillamycin
shea and idsa recommendation for hospitals
SHEA and IDSA Recommendation for Hospitals
  • Implementation of a system for periodic monitoring of antimicrobial resistance in community and nosocomial isolates
  • Implementation of a system for periodic monitoring of antibiotic use according to hospital location and/or prescribing service
  • Monitoring of relationship between antibiotic use and resistance, assignment of responsibility through practice guidelines or other institutional policies
  • Application of contact isolation precautions in patients known or suspected to be colonized or infected with epidemiologically important microorganisms
can we win the global battle
Can we win the global battle?
  • Keep on developing new antibiotics
  • Surprise your opponent (combination, rotation)
  • Use the optimal dose of the right antibiotic
  • for the appropriate duration of therapy
  • Know as much about antibiotics as your ID folks
  • alternatively call them to help you
double coverage
Double coverage?
  • Reasonable data for some gram-positives
  • No good data for gram-negatives
  • May still be reasonableto cover 2 organisms and in specific situations
  • Double coverage across the board will result in increased financial burden, resistance, drug-associated morbidity, and potentially antagonism
slide62

Synergy vs. antagonism

1 + 1 = 3 vs. 1 + 1 = 0

=

=

can we win the global battle63
Can we win the global battle?
  • Keep on developing new antibiotics
  • Surprise your opponent (combination, rotation)
  • Use the optimal dose of the right antibiotic for the appropriate duration of therapy
  • Know as much about antibiotics as your ID folks, alternatively call them to help you
know antibiotic principles
Know Antibiotic Principles!
  • Drug levels and activity
  • Volume of distribution (Obesity, third spacing)
  • Compartments
  • Protein binding
  • Time vs. concentration-dependant killing
  • >MIC > 50% DI vs. Cmax/MIC >8-10
  • Aminoglycosides and quinolones
  • Combining drugs
  • Synergy vs. antagonism
empiric therapy
Empiric Therapy
  • Empiric therapy is not an educated guess but a
  • sophisticated decision based on intimate knowledge of
  • The bug
  • The host
  • The local environment
  • All available options
  • • Antimicrobials
  • • Principles of antimicrobial therapy
  • • Supportive and critical care
take home
Take home
  • Empiric therapy is overrated
  • Diagnostic effort is underrated
  • Consider going narrow (may be diagnostic)
  • Your empiric therapy will save some, not save some (if you do not get it right), or in some cases kill someone
ad