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Infectious Disease: Drug Resistance Pattern in New Mexico

Obi C. Okoli, MD.,MPH.

Clinic for Infectious Diseases

Las Cruces, NM.

Are these the world's sexiest accents?

Are these the world's sexiest accents?

• 13. Argentine • 12. Thai • 11. Trinidadian • 10. Brazilian Portuguese • 9. U.S. Southern • 8. Scottish • 7. Irish • 5. Queen's English • 4. Czech • 3. Spanish • 2. French • 1. Italian

• 6. Nigerian - Dignified, with just a hint of willful naivete, the deep, rich "oh's" and "eh's" of Naija bend the English language without breaking it, arousing tremors in places other languages can't reach.

Penicillin became commercially available in 1941, when was the first case of penicillin resistant Staphylococcus species reported?

• A. 1941

• B. 1942

• C. 1947

• D. 1952

• E. 1957

Methicillin was introduced in 1961, when was the first case of methicillin resistant Staphylococcus aureus (MRSA) in the U.S reported?

• A. 1962

• B. 1964

• C. 1968

• D. 1968

• E. 1970

Vancomycin became commerically available in 1954, when was the first case of vancomycin resistant Staphylococcus aureus (VRSA) reported?

• A. 1972

• B. 1982

• C. 1992

• D. 2002

• E. 2012

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Reasons for Increasing Antibiotic Resistance • Total antibiotic consumption growing worldwide.

• 2000 – 2010 about 30% increase

• USA consumes 10% of world output

• Increased use of antibiotics in livestock

• Inappropriate use • We know everything about antibiotics except how much to give –

Maxwell Finland.

Largest five consumers of antimicrobials in livestock in 2010

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Estimates of antimicrobial consumption in cattle, chickens, and pigs in OECD countries

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Antibiotics and Obesity

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Jess T. N Engl J Med 2014;371:2526-2528.

Timing of Low-Dose Penicillin Treatment and Risk of Obesity. Principles of Anti-infective Therapy • Identification of the infecting organism and

source of infection • Determination of antimicrobial susceptibility of

infecting organism • Host factors • Previous adverse reactions • Age • Genetic or metabolic abnormalities • Pregnancy • Renal and hepatic function • Site of infection

Antibacterial Drug Classes

• β-lactams

• Aminoglycosides

• Tetracyclines and chloramphenicol

• Macrolides, clindamycin and ketolides

• Glycopeptides

• Polymyxins

• Oxazolidiones

• Quinolones

• Metronidazole

• Sulfonamides and Trimethoprim

• Rifamycins

Which of the following antibiotic class has the most drug-drug interactions?

• A. Penicillins

• B. Fluoroquinolones

• C. Macrolides

• D. Aminoglycosides

• E. Rifampin

β-lactams

β-lactams

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How bacteria acquire genes that control resistance mechanisms • Transduction via bacteriophages (bacterial viruses) – specie

specific

• Transformation: scavenge and incorporate DNA from dead bacteria

• Conjugation: cytoplasmic bridges between species with transfer of plasmids

• Spontaneous mutations

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What is a plasmid?

• Extra chromosomal circular DNA

• Can replicate independent of chromosomal DNA

• Exchanged between species by conjugation

• Can carry multiple antibacterial resistance determinants

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What is a transposon?

• Mobile short stretch of DNA

• Can move between different point within a genome by a process termed transposition

• Not capable of self-replication

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What is an integron?

• Collects genes from transposons and forms chunks of DNA called cassettes

• Integrons allow transposons/cassettes to move from chromosome to plasmid DNA

• Then the plasmid DNA can spread via conjugation from one genus to another

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Challenges Determining Resistance Mechanisms • Bacterial have complex genetics including chromosomal and

plasmid methods

• Phenotypic determination requires interpretation and can be subjective

• Molecular detection works well if the target of interest is known.

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Major Mechanisms of Antibiotic Resistance • Enzymatic inactivation – β-lactams

• Target site absent – intrinsic resistance

• Target site modification – MRSA PBP2 to PBP2a

• Excessive binding sites – hVISA and VISA

• Altered cell wall permeability - porin channel shrink up

• Drug efflux - tetracyclines

Common Resistant Organisms in New Mexico • Methicillin-resistant Staphylococcus aureus (MRSA)

• Escherichia coli (ESBL)

• Pseudomonas aeruginosa

• Vancomycin resistant Enterococcus faecium (VRE)

• Klebsiella pneumonia (ESBL and KPC)

• Acinetobater sp

• Stenotrophomonas maltophilia

• Clostridium difficile

β-lactams Resistance • β-lactams inhibit bacterial cell wall synthesis

• Peptidoglycan in cell wall protects bacterial against osmotic rupture

• β-lactams inactivate penicillin-binding proteins (PBPs)

β-lactams Resistance

• Destruction of antibiotic by β-lactamase

• Failure of of antibiotic to penetrate the outer membrane of gram-negative bacteria to reach PBP targets

• Efflux of drug across outer membrane of gram-negative bacteria

• Low-affinity binding of antibiotic to target PBPs

• NDM-1

Staphylococcal Resistance

• Penicillin became commercially available in 1941

• Staphylococcal resistance reported soon after

• Staphylococcal cassette chromosome (SCCmec) carries mecA gene that encodes an altered PBP2 -- MRSA

• mecC is a novel gene that confers resistance, often cefoxitin resistant and oxacillin susceptible

Arias CA, Murray BE. N Engl J Med 2009;360:439-443.

Common Mechanisms of Resistance in Methicillin-Resistant Staphylococccus aureus.

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Lowy FD. N Engl J Med 1998;339:520-532.

S. aureus Infections in Intensive Care Units in the National Nosocomial Infections Surveillance System, 1987 through 1997.

Vancomycin Resistance

• hVISA: Heteroresistant VISA

• Presence of subpopulations of VISA at a rate of 1 organism per 105 to 106 organisms

• VISA: Vancomycin intermediate S. aureus

• MIC for vancomycin is 4-8µg/ml

• VRSA: Vancomycin resistant S. aureus

• VRSA if the vancomycin MIC is ≥16µg/ml.

Mechanisms of S. aureus resistance to vancomycin

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Carbapenem Resistant Organisms – CRE & KPC • Production of β-lactamase that hydrolyzes carbapenems

• Diminished permeability

• Efflux of drug across outer membrane of gram-negative bacteria

• Production of altered PBP target

• Intrinsic resistance – Proteus, Providencia, Morganella

Treatment of Resistant Organims • Consult local antibiogram

• Consult Infectious Disease

• Appropriate antibiotic therapy

• Antibiotic stewardship

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MRSA and VRE Prevalence and Incidence Rates from 2012 to 2014

42

38

40

30

24 23

10

8 7

4 5

6

0

5

10

15

20

25

30

35

40

45

2012 2013 2014

Per

cen

t MRSA Prevalence

MRSA Incidence

VRE Prevalence

VRE Incidence

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ESBL Rates from 2012 to 2014

2.7

2.5

3.5

0.3 0.5

2.2

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

2012 2013 2014

Per

cen

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ESBL E.coli

ESBL Kleb. Pneumoniae

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MRSA, VRE and E.coli Resistant to ciprofloxacin from 2002 to 2013

40

43

48

43

46 47

50

48 46

48

42

38

8 15

18

20

17 17

22 23

24 24 25 26

5 3 3

4 3 3

6

11 11 10 10 8

0

10

20

30

40

50

60

Per

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MRSA

E.coli Resist to Ciprofloxacin

VRE

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Treatment of Resistant Bacteria – Staphylococcus sp • TMP-SMX

• Doxycyline/Minocycline

• Clindamycin

• Linezolid

• Vancomycin

• Daptomycin

• Telavancin

• Tigecycline

• Quinupristin-Dalfopristin

• Oritavancin

• Dalbavancin

• Ceftaroline

Which of this drugs should not be used to treat MRSA that is resistance to erythromycin?

• A. TMP-SMX

• B. Doxycyline

• C. Clindamycin

• D. Linezolid

• E. Vancomycin

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D-test for Macrolide-Inducible Resistance to Clindamycin

Treatment of Resistant Bacteria – Enterococcus sp • Ampicillin

• Vancomycin

• Linezolid

• Daptomycin

• Quinupristin-Dalfopristin

• Combination treatment

• Penicillin G + gentamicin

• Ampicillin + ceftriaxone

• Ampicillin + gentamicin

• Daptomycin + Ampicillin or ceftaroline

What is the drug of choice for treatment of pan-sensitive Enterococcus faecalis?

• A. Ampicillin

• B. Vancomycin

• C. Linezolid

• D. Gentamicin

• E. Streptomycin

Treatment of MDR Gram-negative bacteria • Carbapenems

• Colistin

• Polymyxin

• Tigecycline

• Sulbactam

• Doxycycline/Minocycline

• Ceftazidime/Avibactam

• Ceftolazone/tazobactam

Treatment of Resistant Bacteria – ESBL • Carbapenems

• Cephalosporin-β-lactamase agents

• Ceftazidime-avibactam

• Ceftolazone-tazobactam

• Aminoglycosides

Treatment of Resistant Bacteria – ESBL

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Treatment of Resistant Bacteria – MDR Pseudomonas • Carbapenems

• Cephalosporin-β-lactamase agents

• Ceftazidime-avibactam

• Ceftolazone-tazobactam

• Polymyxins

• Aminoglycosides

What is the preferred dose of Piperacillin/tazobactam for treatment of Pseudomonas aeruginosa infections?

• A. 3.375 g IV q6h

• B. 3.375 g IV over 4 hours three times daily

• C. 4.5 g IV over 4 hours three times daily

• D. Continuous infusion of 13.5 g over 24 hours

• E. Continuous infusion of 16 g over 24 hours

Carbpenems

• Imipenem, meropenem and doripenem (but not Ertapenem) are active against P.aeruginosa and Acinetobacter

• Used for ESBL producers and all are susceptible to Acinetobacter carbapenemases

• Acinetobacter activity of Doripenem ≥ Imipenem > Meropenem, but differences are small

• Doripenem may be more effective for P. aeruginosa than other carbapenems.

• Use in combination therapy for MDR bacteria.

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Polymyxins

• Active against most Gram-negative pathogens

• >90% of Acinetobacter, P.aeruginosa, E.coli, Klebsiella and Citrobacter

• >80% of Enterobacter are susceptible

• Resistance increasing, particularly in P.aeruginosa, Acinetobacter, and KPC producers

• Susceptibility issues/Formulation issues.

• Clinical indications

• Bacteremia

• VAP

• Meningitis

• Now mainstay treatment for MDR

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Tigecycline

• Broad spectrum

• Aerobes and anaerobes

• Lacks activity for P. aeruginosa

• Activity against MDR isolates

• Clinical indications

• VAP

• Clinical resolution reported

• Non-bacteremia

• Low serum concentrations

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Sulbactam

• Place in therapy

• VAP

• Aerosolized administration is experimental

• Bacteremia

• Meningitis

• Limited data, non conclusive

• Not available in the US

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Doxycycline/Minocycline

• Clinical indications

• Minocycline has essentially the same spectrum of activity against mico-organisms as doxycycline

• Stenotrophomonas maltophilia

• MDR Acinetobacter baumannii

• Clinical indications

• VAP?

• Bactermia?

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Combination Therapy

• Targets multiple mechanisms of action thereby preventing resistance

• Synergy among antibiotics resulting in broad spectrum

• To reduce severity or incidence of adverse effects

• No combination exhibits synergy consistently

• Combination therapy remains controversial

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Potential Combinations

• Polymyxin B + carbapenems

• Polymyxin B + rifampin

• Polymyxin B + carbapenems + rifampin

• Polymyxin B + Doxycycline

• Polymyxin B + ceftriaxone

• Carbapenems + rifampin

• Tigecycline + aminoglycosides

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Treatment of Resistant Bacteria – Clostridium difficile • Metronidazole

• Oral vancomycin

• Fidaxomicin

• FMT

• Questions?