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Associated Antibiotic Resistance Among Common Hospital- and Community-Acquired Bacterial Pathogens. James H. Jorgensen, Ph.D. The Environment of the Early 2000’s. The era of emerging resistance, e.g., VRE, VISA, VRSA, MRSA, DRSP, ESBL, other MDR gram-negatives

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Associated Antibiotic Resistance Among Common Hospital- and Community-Acquired Bacterial Pathogens

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Associated antibiotic resistance among common hospital and community acquired bacterial pathogens

Associated Antibiotic Resistance Among Common Hospital- and Community-Acquired Bacterial Pathogens

James H. Jorgensen, Ph.D.

The environment of the early 2000 s

The Environment of the Early 2000’s

  • The era of emerging resistance, e.g., VRE, VISA, VRSA, MRSA, DRSP, ESBL, other MDR gram-negatives

  • Increasing resistance to some drug classes, e.g., cephalosporins, macrolides, quinolones,

  • A need for new antimicrobial agents with activity against resistant pathogens

Associated resistance

Associated Resistance

  • Resistance mechanisms that affect multiple members of a class or subclass

  • Resistance traits that may be genetically-linked or frequently associated

Cdc nnis incidence of vre

CDC NNIS - Incidence of VRE

(www.cdcgov/ncidod/hip/NNIS/AR Surv1198.htm.)

Other resistance problems among vre

Other Resistance Problems Among VRE

  • Vancomycin-resistant E. faecium

    • Ampicillin-resistant (90%)

  • High-level aminoglycoside resistance

  • Emerging resistance among VREF

    • Linezolid and quinupristin-dalfopristin resistance

Mechanisms of resistance that affect multiple drugs

Mechanisms of Resistance that Affect Multiple Drugs

  • Low affinity PBP 5 by E. faecium

    • Resistance to pen/amp/carbapenems

  • Production of PBP 2a by staphylococci

    • Resistance to all penicillins, inhibitor combos, cephalosporins, carbapenems

  • Production of ESBLs by gram-negs

    • Hydrolysis of all pens, cephalosporins, aztreonam

  • Mutations in parC and gyrA in pneumococci

    • Diminished susceptibility to all fluoroquinolones

Evolution of mrsa

Evolution of MRSA

  • Methicillin introduced into clinical practice in 1959-60 to combat penicillin resistance in S. aureus

  • First MRSA reported in the U.K. in 1961

  • MRSA has spread among healthcare facilities throughout the world since the 1970s - usually MDR

Community acquired mrsa

Community-Acquired MRSA

  • First noted among IVDU in Detroit in 1980-81

  • Australia, New Zealand in early 1990’s

    • MRSA that was not MDR

  • Children without identified risks (‘90s)

  • Native American populations in late 1990s (AK, MN, WA)

  • Prisons and jail populations (‘90s)

  • Urban homeless population (‘99-’00)

Some definitions

Some Definitions

  • Healthcare-associated MRSA (HA-MRSA)

    • from hospitalization, rehab, dialysis, communicated from a healthcare worker

  • Community-acquired (CA-MRSA) or Community-onset (CO-MRSA)

    • patients with conventional risk factors

    • patients without risk factors

Differences between ha and ca mrsa


Multi-drug-resistant (clinda, gent, FQ)

Contain SCCmec I, II, or III

Usually PVL-negative


Usually only resistant to pen, ox + eryth + FQs

Contain SCCmec IV

Usually produce PVL

Quite virulent (esp. skin)

Differences between HA- and CA-MRSA

Scc mec types

SCCmec Types

  • SCCmec - staphylococcal cassette chromosome mec type

    • Type I - second smallest mec element

    • Type II - second largest SCCmec, contains Tn554

    • Type III - largest SCCmec, contains 2 Tn554

    • Type IV - smallest (20-24 kb), no other R genes

Failure of cephalosprins in treatment of mrsa

Failure of Cephalosprins* in Treatment of MRSA

No. PatientsPersistent



Ceph alone87 (87%)

Ceph + aminoglyc147 (50%)


Ceph alone22 (100%)

Ceph + aminoglyc44 (100%)

*Cephalothin or cephaloridine

Acar, AAC 280-285, 1971

Other resistance mechanisms in ha mrsa

Other Resistance Mechanisms in HA-MRSA

  • Macrolide and lincosamide - MLSB (ermA or ermC)

  • Aminoglycosides - inactivating enzymes, including aac(6’)-aph(2”)

  • Fluoroquinolones - gyrA or efflux

  • Tetracyclines - tetM or efflux

Another problem with mrsa

Another Problem with MRSA

  • VISA - vancomycin-intermediate S. aureus (vanc MIC=8 µg/ml) has occurred in MRSA strains in the U.S., Japan, U.K., France, etc.

  • VRSA - Two cases of true VRSA (due to vanA gene from Enterococcus) have occurred in the U.S.

Extended spectrum lactamases

Extended Spectrum ß-lactamases

  • Most ESBL - mutations of TEM or SHV enzymes normally found in E. coli and Klebsiella

  • Now TEM-1 to 121, SHV-1 to 47 (2-28-03)

  • Now also CTX-M and OXA enzymes

  • Differences in substrate specificity - inconsistent or illogical susceptibility patterns - S vs. I vs. R

  • Hydrolyze 3rd gen cephs and aztreonam at high inoculum

Associated antibiotic resistance among common hospital and community acquired bacterial pathogens

Molecular Basis of ESBLs

Enzyme pI Ceftaz Amino Acid Position


TEM-15.4 0.12GluArgGlu

TEM-105.6 > 256GluSerLys

TEM-125.25 16GluSerGlu

TEM-265.6 256LysSerGlu

from: Jacoby, IDCNA 11:875, 1997

Different substrate affinities of esbl

Different Substrate Affinities of ESBL

Enzyme MICs

Ceftaz Cefotax Aztreo


TEM-10> 256 1128

TEM-12 160.12 1

TEM-26 2560.5 64

from: Jacoby, IDCNA 11:875, 1997

Inoculum effect with esbl

Inoculum Effect with ESBL

MICs (µg/ml)



K. pneum.4>1280.12 1

E. coli8>1280.12 1

from Jett, et al, AAC 39:1187, 1995

Clinical significance of esbls

Clinical Significance of ESBLs

  • 455 K. pneumoniae bacteremias in ‘96 and ‘97

    • 18.7% (85) produced ESBLs

    • 9 treated with a cephalosporin that was S/I

    • 3 died, 5 required Rx change

  • Overall, 32 pts. RX with a ceph (S/I)

    • 4/4 I’s failed; 15/28 S’s failed

    • 4/5 treated with cefepime failed

      Paterson, JCM 39:2206-2212, 2001

Mechanisms of resistance that may be genetically linked or frequently associated

Mechanisms of Resistance that May Be Genetically Linked or Frequently Associated

  • ESBL-producing E. coli or Klebsiella

    • Trim-sulfa, gent on same plasmid

    • Fluroquinolone-resistance common

  • HA-MRSA - MLSB, gent, fluoroquinololone resistance

  • VR E. faecium - also pen/amp, HLGR

Other mdr gram negatives pseudomonas aeruginosa

Other MDR Gram-Negatives:Pseudomonas aeruginosa

  • Beta-Lactam resistance

    • AmpC chromosomal beta-lactamase

    • PSE-1, -3, -4, occasionally ESBL (e.g., OXA-enzymes), Grp. 3 metallo-enzymes

    • OMP modifications - OmpD

  • Aminogycoside resistance - inact. enzs., OMP modifications

  • Fluroquinolone resistance - gyrA

  • MDR - Mex B, D, F efflux - cephs, FQ

Beta lactam resistance in pneumococci

Beta-Lactam Resistance in Pneumococci

  • Structural alterations in penicillin binding proteins (PBPs) that result in lower binding affinities

    • 1A, 1B, 2A, 2B, 2X, 3 (ceph R)

  • Often directed by “mosaic” genes

  • Penicillins, cephalosporins, and carbapenems use the same targets

Association of penicillin resistance with resistance to other classes

Association of Penicillin Resistance with Resistance to Other Classes

Pen SPen IPen R

Cefotaxime 02.8%42.4%




Levofloxacin0.1% 0.3% 0.7%

R > 3 drugs 14%

Whitney, et al. NEJM 343:1917, 2000

Associated resistance mechanisms in pneumococci

Associated Resistance Mechanisms in Pneumococci

  • Macrolide resistance

    • mefA efflux pump in 75% US strains

    • ermB ribosomal methylation in 25%

  • Tetracycline resistance

    • Ribosomal target protection - tetM

    • Active efflux

  • Trimethoprim and sulfa resistance

    • Trimeth - hyperproduction of DHFR

    • Sulfa - altered affinity DHPS

Quinolone resistance in pneumococci

Quinolone Resistance in Pneumococci

  • “first step” mutants - parC (4.5%)

    • low level resistance to cipro, oflox

  • “second step” or “double” mutants - parC + gyrA (0.2 - 0.5%)

    • high level cipro,oflox,levoflox resistance;

    • gatiflox, moxiflox, gemiflox increased MICs

      Davies, AAC 46:119, 2002; Whitney, et al, NEJM 2000

Resistant pneumococci and the newer quinolones

Resistant Pneumococci and the “Newer” Quinolones

Levo Gati Moxi Gemi

ATCC 49619 1 0.25 0.25 0.03

TN4201 (parC) 4 1 0.5 0.12

MD3904 (parC + gyrA) 16 8 4 0.5

J3810 (parC(2)+gyrA) 32 8 4 0.5

F30084 (parE + gyrA) 8 4 - 0.06

Jorgensen, AAC 44: 2962-2968, 2000.

Evolution of fq resistance among pneumococci in hong kong

Evolution of FQ Resistance Among PneumococciinHong Kong

  • Levofloxacin resistance (MIC >4 µg/ml)

    1995< 0.5%

    1998 5.5%

    2000 13.3%

  • Resistance in pen R strains - 27.3%

  • All FQ-R isols - R to pen, cefotax, eryth

  • Clonal spread of 23F (Spain) deriv.

    Ho, et al, JAC 48:659, 2001

Vancomycin tolerance associated resistance

Vancomycin Tolerance - Associated Resistance?

  • Meningitis treatment failure due to “tolerance” to vancomycin

    • 10 month old treated with cefotaxime (9d) and vancomycin (7d)

    • recurrent meningitis 8 days after discharge

  • Strain not killed in vitro by vancomycin or cefotaxime (failure in autolysis)

    McCullers, et al, JID 181:369, 2000

Reasons for associated resistance

Reasons for Associated Resistance

  • Mechanisms that directly affect closely-related members of a drug class

  • Mechanisms that may be linked or co-transferred on the same plasmid or transposon

  • Clonal spread of organisms that harbor MDR mechanisms

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