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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

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Multi drug resistant pathogens l.jpg

Multi-drug resistant pathogens

Helmut Albrecht, MD

Division of Infectious Diseases


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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)


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Agenda

  • State of the union

  • The players (Resistant pathogens)

  • What to do about them


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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


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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


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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


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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?)


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Getting It RightBloodstream Infections

% Mortality


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Getting It RightVentilator-associated Pneumonia

% Mortality

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


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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


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NEW SUPERBUGS


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The Gram Negative Cell Wall

Efflux system

Porin channels

B-lactamases

PBPs

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


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Bush classification of β-lactamases in GN bacteria


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Substrate Profile

  • Penicillinase

  • Cephalosporinase

  • Broad spectrum

  • Extended broad spectrum

  • Carbapenemase


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Substrate Profile

  • Penicillinase

  • Cephalosporinase

  • Broad spectrum

  • Extended broad spectrum

  • Carbapenemase


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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


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Substrate Profile

  • Penicillinase

  • Cephalosporinase

  • Broad spectrum

  • Extended broad spectrum

  • Carbapenemase


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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?!


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Susceptibility Profile of KPC-Producing K. pneumoniae


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Drugs with Most Reliable Activity Against

ESBL-producing Enterobacteriaceae

  • Carbapenems

  • (Cephamycins)

  • (Fluoroquinolones)


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Carbapenem Resistance: Mechanisms


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Carbapenemases


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Carbapenemases in the U.S.


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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!)


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Susceptibility Profile of KPC-Producing K. pneumoniae


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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


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Geographical Distribution of KPC-Producers

Frequent Occurrence

Sporadic Isolate(s)


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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)


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Inter-Institutional & Inter-State Spread of KPC-Producing K. pneumoniae


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Carbapenemase – Producing Enteric GNR; U.K.

< 10% susceptible to usual Rx

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


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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


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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.


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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


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

  • Antibiotic use not predictive except for ciprofloxacin

  • 5/21 persistently colonized


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  • 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


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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.


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Which is more dangerous?


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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


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  • 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

  • 19681969-88 1989-90

  • Penicillin 8 64 512

  • Ampicillin 2 32 128

  • % VRE 0 0 61%

Grayson et al, AAC


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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


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Children

Inmates

Military recruits

Native populations

MSM

HIV+ patients

Religious communities

Football teams

Wrestlers

Gymnasts

Fencing teams

IDU

Homeless

Populations with ca-MRSA


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Clinically Relevant CA-MRSA Disease(GA/MD/MN n=1,674, 78%)

Fridkin et al. NEJM, 2005


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MRSA skin infection: differential diagnosis

  • Common misdiagnosis: “spider bite”, complete with history of having been bitten!


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Range of the brown recluse


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déjà vu


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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


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Okuma et al. J Clin Micro 2002


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Distribution of Virulence and Resistance DeterminantsCA-MRSA (France, Switzerland, USA, Oceania)

Vandenesch et al. EID Aug 2003


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PVL associated with severe disease

  • Necrotizing pneumonias

  • Septic syndrome

  • Empyema

  • Most CA-MRSA strains PVL +

    • Causal role in severe disease presentations is not proven


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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


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How To Prevent Resistance

  • Adequate infection control

  • Appropriate use of antibiotics


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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


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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


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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


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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


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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


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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


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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


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Synergy vs. antagonism

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

=

=


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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


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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


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You have homefield advantage – use it


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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


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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


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