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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 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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  1. Associated Antibiotic Resistance Among Common Hospital- and Community-Acquired Bacterial Pathogens James H. Jorgensen, Ph.D.

  2. 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

  3. Associated Resistance • Resistance mechanisms that affect multiple members of a class or subclass • Resistance traits that may be genetically-linked or frequently associated

  4. CDC NNIS - Incidence of VRE (www.cdcgov/ncidod/hip/NNIS/AR Surv1198.htm.)

  5. 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

  6. 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

  7. 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

  8. 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)

  9. 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

  10. HA-MRSA 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

  11. 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

  12. Failure of Cephalosprins* in Treatment of MRSA 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

  13. 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

  14. 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.

  15. 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

  16. Molecular Basis of ESBLs 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

  17. Different Substrate Affinities of ESBL 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

  18. Inoculum Effect with ESBL 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

  19. 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

  20. 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

  21. 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

  22. 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

  23. 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

  24. 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

  25. 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

  26. 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.

  27. 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

  28. 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

  29. 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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