Multi-drug resistant pathogensMulti-drug resistant pathogens

Helmut Albrecht, MD

Division of Infectious Diseases

DisclosuresDisclosures

• 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)

AgendaAgenda

• State of the union

• The players (Resistant pathogens)

• What to do about them

AntibioticsAntibiotics• “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 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 (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?)

27.4

38.4

17.8

30.7

20.2

34.4

0

5

10

15

20

25

30

35

40

45

Kang et al Micek et al Leibovici et al

Appropriate Therapy

Inappropriate Therapy

Getting It RightGetting It RightBloodstream InfectionsBloodstream Infections

% Mortality

14.8

44.237.5

91.2

15.6

37.1

0

10

20

30

40

50

60

70

80

90

100

Clec'h et al Luna et al Rello et al

Appropriate Therapy

Inappropriate Therapy

Getting It RightGetting It RightVentilator-associated PneumoniaVentilator-associated Pneumonia

% Mortality

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

Scope of the problemScope 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

NEW SUPERBUGSNEW SUPERBUGS

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

The Gram Negative Cell Wall

Porin channels

Efflux system

PBPs

B-lactamases

Bush classification of Bush classification of ββ-lactamases in GN bacteria-lactamases in GN bacteria

Functional Group

Major Subgroups

Attributes Known types in 2000

1 AllChromosal >>> plasmid, SPICE-A bacteria, all β-lactams except carbapenem, not inhibited by beta-lactamase inhibitors

51

2 2-bPlasmid >>> chromosomal, broad-spectrum β-lactamases (TEM, SHV), usually inhibited by β-lactamase inhibitors

16

2 2-bePlasmid >>> chromosomal, ESBLs, variably inhibited by β-lactamase inhibitors 119

3 3-a,b,cMetallo β-lactamases, ESBLs including carbapenems (not monobactams)

not inhibited by β-lactamase inhibitors24

4 AllMixed group (incl. B. fragilis)

Inhibited by β-lactamase inhibitors 9

Substrate ProfileSubstrate Profile

• Penicillinase

• Cephalosporinase

• Broad spectrum

• Extended broad spectrum

• Carbapenemase

Substrate ProfileSubstrate Profile

• Penicillinase

• Cephalosporinase

• Broad spectrum

• Extended broad spectrum

• Carbapenemase

19 Months ESBL Klebsiella pneumoniae Outbreak 19 Months ESBL Klebsiella pneumoniae Outbreak

New York Hospital Medical Center of QueensNew 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

Substrate ProfileSubstrate 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?!

Susceptibility Profile of KPC-Producing K. pneumoniaeAntimicrobial Interpretation Antimicrobial Interpretation

Amikacin I Chloramphenicol R

Amox/clav R Ciprofloxacin R

Ampicillin R Ertapenem R

Aztreonam R Gentamicin R

Cefazolin R Imipenem R

Cefpodoxime R Meropenem R

Cefotaxime R Pipercillin/Tazo R

Cetotetan R Tobramycin R

Cefoxitin R Trimeth/Sulfa R

Ceftazidime R Polymyxin B MIC >4g/ml

Ceftriaxone R Colistin MIC >4g/ml

Cefepime R Tigecycline S

Drugs with Most Reliable Activity Against Drugs with Most Reliable Activity Against

ESBL-producing Enterobacteriaceae ESBL-producing Enterobacteriaceae

Drugs with Most Reliable Activity Against Drugs with Most Reliable Activity Against

ESBL-producing Enterobacteriaceae ESBL-producing Enterobacteriaceae

• CarbapenemsCarbapenems

• (Cephamycins)(Cephamycins)

• (Fluoroquinolones)(Fluoroquinolones)

Carbapenem Resistance: Mechanisms

Enterobacteriaceae Cephalosporinase + porin loss

Carbapenemase

P. aeruginosa Porin loss

Up-regulated efflux

Carbapenemase

Acinetobacter spp. Cephalosporinase + porin loss

Carbapenemase

Carbapenemases

Classification Enzyme Most Common Bacteria

Class A KPC, SME, IMI, NMC, GES

Enterobacteriaceae(rare reports in P. aeruginosa)

Class B

(metallo--lactamse)

IMP, VIM, GIM, SPM

NDM

P. aeruginosa

Enterobacteriacea

Acinetobacter spp.

Class D OXA Acinetobacter spp.

Carbapenemases in the U.S.Enzyme Bacteria

KPC, NDM Enterobacteriaceae

Metallo--lactamase P. aeruginosa

OXA Acinetobacter spp.

SME Serratia marcesens

Klebsiella Pneumoniae Carbapenemase KPC is a class A -lactamase

Confers resistance to all -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!)

Susceptibility Profile of KPC-Producing K. pneumoniaeAntimicrobial Interpretation Antimicrobial Interpretation

Amikacin I Chloramphenicol R

Amox/clav R Ciprofloxacin R

Ampicillin R Ertapenem R

Aztreonam R Gentamicin R

Cefazolin R Imipenem R

Cefpodoxime R Meropenem R

Cefotaxime R Pipercillin/Tazo R

Cetotetan R Tobramycin R

Cefoxitin R Trimeth/Sulfa R

Ceftazidime R Polymyxin B MIC >4g/ml

Ceftriaxone R Colistin MIC >4g/ml

Cefepime R Tigecycline S

KPC Enzymes Located on plasmids; conjugative and

nonconjugative

blaKPC is usually flanked by transposon sequences

blaKPC reported on plasmids with: Normal spectrum -lactamases Extended spectrum -lactamases Aminoglycoside resistance

Geographical Distribution of KPC-Producers

Frequent Occurrence

Sporadic Isolate(s)

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)

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

Carbapenemase – Producing Enteric GNR; U.K.

< 10% susceptible to usual Rx>40% resistant to tigecycline, >90% susceptible to colistin

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

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

NDM-1: 77 cases in 13 European countries 60% from England Travel to India (including medical tourism)

ESBLs Travellers diarrhea Foodborne outbreak Adoption

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

Antibiotic use not predictive except for ciprofloxacin

5/21 persistently colonized

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

Lawn of E. coli ATCC 25922 1:10 dilution of a 0.5 McFarland suspension

Imipenem disk

Test isolates

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

Which is more dangerous?Which is more dangerous?

Resistance in gram-positive organismsResistance 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 Evolution of E. faecium resistanceresistance

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

1.Community acquired (ca-) MRSA strains generally CANNOT be distinguished from hospital acquired strains by the presence of:1.MEC-A gene 2.SCC pattern 3.Panton-Valentine leukocidin

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-MRSAPopulations with ca-MRSA

• Children

• Inmates

• Military recruits

• Native populations

• MSM

• HIV+ patients

• Religious communities

• Football teams

• Wrestlers

• Gymnasts

• Fencing teams

• IDU

• Homeless

Disease Syndrome

Skin/soft tissue (non-Trauma)

Abscess

Cellulitis

Folliculitis

Other/Unknown

Wound (Traumatic)

Urinary Tract Infection

Sinusitis

Bacteremia

Pneumonia

Osteomyelitis

Septic arthritis

Bursitis

No. (%)

1, 266 (77%)

751 (59%)

528 (42%)

88 ( 7%)

212 (17%)

157 (10%)

64 ( 4%)

61 ( 4%)

43 ( 3%)

31 ( 2%)

21 ( 2%)

15 ( 1%)

19 ( 1%)

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

Fridkin et al. NEJM, 2005

MRSA skin infection: differential MRSA skin infection: differential diagnosisdiagnosis

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

Range of the brown recluseRange of the brown recluse

déjà vudéjà vu

Prevalence of PCN resistant Staph aureus

0

20

40

60

80

100

1940 1950 1960 1970 1980

HospitalCommunity

Phage type 80/81: PCN-R clone of SANeonatal outbreaks in Australia in 50’sBecame pandemic in adults/children

in hospitals/communitiesHighly transmissible and virulentCarried leukocidin

Robinson et alPhage type 80/81 carried PVLMLST 30Current SWP clone of CA-MRSA

descendant – acquired SCC IV

déjà vu IIdéjà vu II

Okuma et al. J Clin Micro 2002

Distribution of Virulence and Resistance DeterminantsDistribution of Virulence and Resistance DeterminantsCA-MRSA CA-MRSA

(France, Switzerland, USA, Oceania)(France, Switzerland, USA, Oceania)

Gene/Gene Product Total n=117 (%)

SCCmec IV

PVL

lukE-lukD (leukocidin)

γ-hemolysin

γ -hemolysin variant

enterotoxin a

enterotoxin b

enterotoxin c

enterotoxin h

enterotoxin k

117 (100%)

117 (100%)

116 (99%)

13 (11%)

100 (85%)

23 (20)

9 (8%)

20 (17%)

29 (25%)

24 (21%)Vandenesch et al. EID Aug 2003

PVL associated with severe PVL associated with severe diseasedisease

Necrotizing pneumonias

Septic syndrome

Empyema

Most CA-MRSA strains PVL +

Causal role in severe disease presentations is not

proven

Centers for Disease Control CampaignCenters for Disease Control Campaign

12 steps to prevent antimicrobial resistance 12 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 ResistanceHow To Prevent Resistance

Adequate infection control

Appropriate use of antibiotics

Strategies for Managing Outbreaks of ResistanceStrategies for Managing Outbreaks of Resistance

Lack of associationof resistance with aplasmid mechanism

Plasmid-mediatedmechanism

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

Amenable to strictinfection control procedures

Necessitates antibioticrestriction before

significant reduction in resistance occurs

Favors clonal oroligoclonal epidemiology

Polyclonalepidemiology

Optimal Use of Antimicrobial: Optimal Use of Antimicrobial: It’s Role in Preventing ResistanceIt’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 resistanceWhat to do to slow antibiotic resistance

Aggressively attack misuseAggressively 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 AntibioticsAppropriate 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 SHEA and IDSA Recommendation for HospitalsRecommendation 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 folksalternatively call them to help you

Double coverage?Double coverage?

• Reasonable data for some gram-positives

• No good data for gram-negatives

• May still be reasonable to 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

=

=

Synergy vs. antagonism

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

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

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

You have homefield advantage – use itYou have homefield advantage – use it

Empiric TherapyEmpiric Therapy

Empiric therapy is not an educated guess but asophisticated 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 homeTake 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