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. 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

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 Community-Acquired Bacterial Pathogens

  • 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 Community-Acquired Bacterial Pathogens

  • 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 Community-Acquired Bacterial Pathogens

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


Other resistance problems among vre
Other Resistance Problems Among VRE Community-Acquired Bacterial Pathogens

  • 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 Community-Acquired Bacterial Pathogens

  • 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 Community-Acquired Bacterial Pathogens

  • 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 Community-Acquired Bacterial Pathogens

  • 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 Community-Acquired Bacterial Pathogens

  • 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

HA-MRSA Community-Acquired Bacterial Pathogens

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

Contain SCCmec I, II, or III

Usually PVL-negative

CA-MRSA

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
SCC Community-Acquired Bacterial Pathogensmec 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 Community-Acquired Bacterial Pathogens

No. Patients Persistent

Bacteremia

Bacteremia

Ceph alone 8 7 (87%)

Ceph + aminoglyc 14 7 (50%)

Endocarditis

Ceph alone 2 2 (100%)

Ceph + aminoglyc 4 4 (100%)

*Cephalothin or cephaloridine

Acar, AAC 280-285, 1971


Other resistance mechanisms in ha mrsa
Other Resistance Mechanisms in HA-MRSA Community-Acquired Bacterial Pathogens

  • 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 Community-Acquired Bacterial Pathogens

  • 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 Community-Acquired Bacterial Pathogens

  • 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


Molecular Basis of ESBLs Community-Acquired Bacterial Pathogens

Enzyme pI Ceftaz Amino Acid Position

MIC 104 164 240

TEM-1 5.4 0.12 Glu Arg Glu

TEM-10 5.6 > 256 Glu Ser Lys

TEM-12 5.25 16 Glu Ser Glu

TEM-26 5.6 256 Lys Ser Glu

from: Jacoby, IDCNA 11:875, 1997


Different substrate affinities of esbl
Different Substrate Affinities of ESBL Community-Acquired Bacterial Pathogens

Enzyme MICs

Ceftaz Cefotax Aztreo

TEM-1 0.12 0.06 0.12

TEM-10 > 256 1 128

TEM-12 16 0.12 1

TEM-26 256 0.5 64

from: Jacoby, IDCNA 11:875, 1997


Inoculum effect with esbl
Inoculum Effect with ESBL Community-Acquired Bacterial Pathogens

MICs (µg/ml)

Cefepime Imipenem

105 107 105 107

K. pneum. 4 >128 0.12 1

E. coli 8 >128 0.12 1

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


Clinical significance of esbls
Clinical Significance of ESBLs Community-Acquired Bacterial Pathogens

  • 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: Frequently AssociatedPseudomonas 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 Frequently Associated

  • 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 S Pen I Pen R

Cefotaxime 0 2.8% 42.4%

Erythromycin 3.2% 35.1% 61.3%

TMP/SMX 6.6% 49.4% 92.3%

Tetracycline 1.3% 19.1% 25.5%

Levofloxacin 0.1% 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 Other Classes

  • 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 Other Classes

  • “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 Other Classes

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 Pneumococci Other ClassesinHong 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? Other Classes

  • 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 Other Classes

  • 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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