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Volume 4, Number 2—June 1998
Synopsis

Multiple-Drug Resistant Enterococci: The Nature of the Problem and an Agenda for the Future

Mark M. Huycke*†, Daniel F. Sahm‡, and Michael S. Gilmore†Comments to Author 
Author affiliations: *University of Oklahoma Health Sciences Center, Oklahoma, USA; †Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma, USA; ‡MLR Pharmaceutical Services, Inc., Reston, Virginia, USA

Main Article

Figure 4

Cytolysin is expressed and processed through a complex maturation pathway (64). The cytolysin precursors, CylLL and CylLS, are ribosomally synthesized. The putative modification protein, CylM, is required for the expression of CylLL and CylLS in an activatable form, and the secreted forms, CylLL and CylLS were recently shown to possess the amino acid lanthionine as the result of posttranslational modification (64). CylLL and CylLS both are secreted by CylB (65), which is accompanied by an initia

Figure 4. Cytolysin is expressed and processed through a complex maturation pathway (64). The cytolysin precursors, CylLL and CylLS, are ribosomally synthesized. The putative modification protein, CylM, is required for the expression of CylLL and CylLS in an activatable form, and the secreted forms, CylLL and CylLS were recently shown to possess the amino acid lanthionine as the result of posttranslational modification (64). CylLL and CylLS both are secreted by CylB (65), which is accompanied by an initial proteolytic trimming event (64) converting each to CylLL' and CylLS', respectively. Once secreted, CylLL' and CylLS' are both functionally inactive until six amino acids are removed from each amino terminus. This final step in maturation is catalyzed by CylA (64), a subtilisin-type serine protease. Since this final catalytic event is essential, occurs extracellularly, and is catalyzed by a class of enzyme for which a substantial body of structural information exists, it represents an ideal therapeutic target. As shown in Figure 3, inhibition of cytolysin by mutation (or potentially by therapeutic intervention) results in a reduction by several orders of magnitude in the number of circulating organisms.

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References
  1. Kaye  D. Enterococci: biologic and epidemiologic characteristics and in vitro susceptibility. Arch Intern Med. 1982;142:20069. DOIPubMedGoogle Scholar
  2. Emori  TG, Gaynes  RP. An overview of nosocomial infections, including the role of the microbiology laboratory. Clin Microbiol Rev. 1993;6:42842.PubMedGoogle Scholar
  3. Jarvis  WR, Gaynes  RP, Horan  TC, Emori  TG, Stroud  LA, Archibald  LK, Semiannual report: aggregated data from the National Nosocomial Infections Surveillance (NNIS) system. CDC, 1996:1-27.
  4. Cohen  ML. Epidemiology of drug resistance: implications for a post-antimicrobial era. Science. 1992;257:10505. DOIPubMedGoogle Scholar
  5. Jett  BD, Huycke  MM, Gilmore  MS. Virulence of enterococci. Clin Microbiol Rev. 1994;7:46278.PubMedGoogle Scholar
  6. Rice  EW, Messer  JW, Johnson  CH, Reasoner  DJ. Occurrence of high-level aminoglycoside resistance in environmental isolates of enterococci. Appl Environ Microbiol. 1995;61:3746.PubMedGoogle Scholar
  7. Devriese  LA, Pot  B, Collins  MD. Phenotypic identification of the genus Enterococcus and differentiation of phylogenetically distinct enterococcal species and species groups. J Appl Bacteriol. 1993;75:399408.PubMedGoogle Scholar
  8. Willett  HP. Energy metabolism. In: Joklik WK, Willett HP, Amos DB, Wilfert CM, editors. Zinsser microbiology. 20th ed. East Norwalk (CT): Appleton & Lange; 1992. p. 53-75.
  9. Ritchey  TW, Seeley  HW. Cytochromes in Streptococcus faecalis var. zymogenes grown in a haematin-containing medium. J Gen Microbiol. 1974;85:2208.PubMedGoogle Scholar
  10. Pritchard  GG, Wimpenny  JWT. Cytochrome formation, oxygen-induced proton extrusion and respiratory activity in Streptococcus faecalis var. zymogenes grown in the presence of haematin. J Gen Microbiol. 1978;104:1522.PubMedGoogle Scholar
  11. Ritchey  TW, Seeley  HW Jr. Distribution of cytochrome-like respiration in streptococci. J Gen Microbiol. 1976;93:195203.PubMedGoogle Scholar
  12. Bryan-Jones  DG, Whittenbury  R. Haematin-dependent oxidative phosphorylation in Streptococcus faecalis. J Gen Microbiol. 1969;58:24760.PubMedGoogle Scholar
  13. Williamson  R. Le Bougu,nec C, Gutmann L, Horaud T. One or two low affinity penicillin-binding proteins may be responsible for the range of susceptibility of Enterococcus faecium to benzylpenicillin. J Gen Microbiol. 1985;131:193340.PubMedGoogle Scholar
  14. Bush  LM, Calmon  J, Cherney  CL, Wendeler  M, Pitsakis  P, Poupard  J, High-level penicillin resistance among isolates of enterococci: implications for treatment of enterococcal infections. Ann Intern Med. 1989;110:51520.PubMedGoogle Scholar
  15. Sapico  FL, Canawati  HN, Ginunas  VJ, Gilmore  DS, Montgomerie  JZ, Tuddenham  WJ, Enterococci highly resistant to penicillin and ampicillin: an emerging clinical problem? J Clin Microbiol. 1989;27:20915.PubMedGoogle Scholar
  16. Horodniceanu  T, Bougueleret  L, El-Solh  N, Bieth  G, Delbos  F. High-level, plasmid-borne resistance to gentamicin in Streptococcus faecalis subsp zymogenes. Antimicrob Agents Chemother. 1979;16:6869.PubMedGoogle Scholar
  17. Zervos  MJ, Kauffman  CA, Therasse  PM, Bergman  AG, Mikesell  TS, Schaberg  DR. Nosocomial infection by gentamicin-resistant Streptococcus faecalis: an epidemiologic study. Ann Intern Med. 1987;106:68791.PubMedGoogle Scholar
  18. Murray  BE, Singh  KV, Markowitz  SM, Lopardo  HA, Patterson  JE, Zervos  MJ, Evidence for clonal spread of a single strain of ß-lactamase-producing Enterococcus (Streptococcus) faecalis to six hospitals in five states. J Infect Dis. 1991;163:7805.PubMedGoogle Scholar
  19. Uttley  AHC, Collins  CH, Naidoo  J, George  RC. Vancomycin-resistant enterococci. Lancet. 1988;1:578. DOIPubMedGoogle Scholar
  20. Leclercq  R, Derlot  E, Duval  J, Courvalin  P. Plasmid-mediated resistance to vancomycin and teicoplanin in Enterococcus faecium. N Engl J Med. 1988;319:15761.PubMedGoogle Scholar
  21. Sahm  DF, Kissinger  J, Gilmore  MS, Murray  PR, Mulder  R, Solliday  J, In vitro susceptibility studies of vancomycin-resistant Enterococcus faecalis. Antimicrob Agents Chemother. 1989;33:158891.PubMedGoogle Scholar
  22. Arthur  M, Courvalin  P. Genetics and mechanisms of glycopeptide resistance in enterococci. Antimicrob Agents Chemother. 1993;37:156371.PubMedGoogle Scholar
  23. Clark  NC, Cooksey  RC, Hill  BC, Swenson  JM, Tenover  FC. Characterization of glycopeptide-resistant enterococci from U.S. hospitals. Antimicrob Agents Chemother. 1993;37:23117.PubMedGoogle Scholar
  24. Klare  I, Heier  H, Claus  H, Reissbrodt  R, Van Witte  W. A-mediated high-level glycopeptide resistance in Enterococcus faecium from animal husbandry. FEMS Microbiol Lett. 1995;125:16572. DOIPubMedGoogle Scholar
  25. Noble  WC, Virani  Z, Cree  RGA. Co-transfer of vancomycin and other resistance genes from Enterococcus faecalis NCTC 12201 to Staphylococcus aureus. FEMS Microbiol Lett. 1992;93:1958. DOIGoogle Scholar
  26. Hiramatsu  K, Hanaki  H, Ino  T, Yabuta  K, Oguri  T, Tenover  FC. Methicillin-resistant Staphylococcus aureus clinical strain with reduced vancomycin susceptibility. J Antimicrob Chemother. 1997;40:13546. DOIPubMedGoogle Scholar
  27. Haley  RW, Culver  DH, White  JW, Meade  WM, Emori  TG, Munn  VP, The efficacy of infection surveillance and control programs in preventing nosocomial infections in US hospitals. Am J Epidemiol. 1985;121:182205.PubMedGoogle Scholar
  28. Harris  SL. Definitions and demographic characteristics. In: Kaye D, editor. Infective endocarditis. New York: Raven Press, Ltd.; 1992. p. 1-18.
  29. Hughes  JM, Culver  DH. W, Morgan WM, Munn VP, Mosser JL, Emori TG. Nosocomial infection surveillance, 1980-1982. MMWR Morb Mortal Wkly Rep 1983;32:1SS-16SS.
  30. Edmond  MB, Ober  JF, Dawson  JD, Weinbaum  DL, Wenzel  RP. Vancomycin-resistant enterococcal bacteremia: natural history and attributable mortality. Clin Infect Dis. 1996;23:12349.PubMedGoogle Scholar
  31. Rhinehart  E, Smith  NE, Wennersten  C, Gorss  E, Freeman  J, Eliopoulos  GM, Rapid dissemination of ß-lactamase-producing, aminoglycoside-resistant Enterococcus faecalis among patients and staff on an infant-toddler surgical ward. N Engl J Med. 1990;26:18148.
  32. Chow  JW, Kuritza  A, Shlaes  DM, Green  M, Sahm  DF, Zervos  MJ. Clonal spread of vancomycin-resistant Enterococcus faecium between patients in three hospitals in two states. J Clin Microbiol. 1993;31:160911.PubMedGoogle Scholar
  33. Montecalvo  MA, Horowitz  H, Gedris  C, Carbonaro  C, Tenover  FC, Issah  A, Outbreak of vancomycin-, ampicillin-, and aminoglycoside-resistant Enterococcus faecium bacteremia in an adult oncology unit. Antimicrob Agents Chemother. 1994;38:13637.PubMedGoogle Scholar
  34. Livornese  LL, Dias  S, Samel  C, Romanowski  B, Taylor  S, May  P, Hospital-acquired infection with vancomycin-resistant Enterococcus faecium transmitted by electronic thermometers. Ann Intern Med. 1992;117:1126.PubMedGoogle Scholar
  35. Handwerger  S, Raucher  B, Altarac  D, Monka  J, Marchione  S, Singh  KV, Nosocomial outbreak due to Enterococcus faecium highly resistant to vancomycin, penicillin, and gentamicin. Clin Infect Dis. 1993;16:7505.PubMedGoogle Scholar
  36. Centers for Disease Control and Prevention. Recommendations for preventing the spread of vancomycin resistance: recommendations of the Hospital Infection Control Practices Advisory Committee (HICPAC). MMWR Morb Mortal Wkly Rep. 1995;44(No. RR-12):113.PubMedGoogle Scholar
  37. Morris  JG Jr, Shay  DK, Hebden  JN, McCarter  RJ Jr, Perdue  BE, Jarvis  W, Enterococci resistant to multiple antimicrobial agents, including vancomycin. Ann Intern Med. 1995;123:2509.PubMedGoogle Scholar
  38. Edmond  MB, Ober  JF, Weinbaum  DL, Pfaller  MA, Hwang  T, Sanford  MD, Vancomycin-resistant Enterococcus faecium bacteremia: risk factors for infection. Clin Infect Dis. 1995;20:112633.PubMedGoogle Scholar
  39. Goldmann  D, Larson  E. Hand-washing and nosocomial infections. N Engl J Med. 1992;327:1202.PubMedGoogle Scholar
  40. Noskin  GA, Stosor  V, Cooper  I, Peterson  LR. Recovery of vancomycin-resistant enterococci on fingertips and environmental surfaces. Infect Control Hosp Epidemiol. 1995;16:57781. DOIPubMedGoogle Scholar
  41. Vollaard  EJ, Clasener  HAL. Colonization resistance. Antimicrob Agents Chemother. 1994;38:40914.PubMedGoogle Scholar
  42. Quale  J, Landman  D, Saurina  G, Atwood  E, DiTore  V, Patel  K. Manipulation of a hospital antimicrobial formulary to control an outbreak of vancomycin-resistant enterococci. Clin Infect Dis. 1996;23:10205.PubMedGoogle Scholar
  43. Caron  F, Pestel  M, Kitzis  M-D, Lemeland  JF, Humbert  G, Gutmann  L. Comparison of different ß-lactam-glycopeptide-gentamicin combinations for an experimental endocarditis caused by a highly ß-lactam-resistant and highly glycopeptide-resistant isolate of Enterococcus faecium. J Infect Dis. 1995;171:10612.PubMedGoogle Scholar
  44. Norris  AH, Reilly  JP, Edelstein  PH, Brennan  PJ, Schuster  MG. Chloramphenicol for the treatment of vancomycin-resistant enterococcal infections. Clin Infect Dis. 1995;20:113744.PubMedGoogle Scholar
  45. Cohen  MA, Yoder  SL, Huband  MD, Roland  GE, Courtney  CL. In vitro and in vivo activities of clinafloxacin, CI-990 (PD 131112), and PD 138312 versus enterococci. Antimicrob Agents Chemother. 1995;39:21237.PubMedGoogle Scholar
  46. Aumercier  M, Bouhallab  S, Capmau  M-L, LeGoffic  F. RP 59500: A proposed mechanism for its bactericidal activity. J Antimicrob Chemother. 1992;30(Suppl A):914.PubMedGoogle Scholar
  47. Collins  LA, Malanoski  GJ, Eliopoulos  GM, Wennersten  CB, Ferraro  MJ, Moellering  RC Jr. In vitro activity of RP59500, an injectable streptogramin antibiotic, against vancomycin-resistant gram-positive organisms. Antimicrob Agents Chemother. 1993;37:598601.PubMedGoogle Scholar
  48. Chow  JW, Davidson  A, Sanford  E III, Zervos  MJ. Superinfection with Enterococcus faecalis during quinupristin/dalfopristin therapy. Clin Infect Dis. 1997;24:912.PubMedGoogle Scholar
  49. Chow  JW, Donahedian  SM, Zervos  MJ. Emergence of increased resistance to quinupristin/dalfopristin during therapy for Enterococcus faecium bacteremia. Clin Infect Dis. 1997;24:901.PubMedGoogle Scholar
  50. Eliopoulos  GM, Wennersten  CB, Cole  G, Moellering  RC. In vitro activities of two glycylcyclines against gram-positive bacteria. Antimicrob Agents Chemother. 1994;38:53441.PubMedGoogle Scholar
  51. Jones  RN, Johnson  DM, Erwin  ME. In vitro antimicrobial activities and spectra of U-100592 and U-100766, two novel fluorinated oxazolidinones. Antimicrob Agents Chemother. 1996;40:7206.PubMedGoogle Scholar
  52. Hillyard  DR. The molecular approach to microbial diagnosis. Am J Clin Pathol. 1994;101:S1821.PubMedGoogle Scholar
  53. Strohl  WR. Biotechnology of Antibiotics. 2nd ed: Drugs and the Pharmaceutical Sciences 82, 1997.
  54. Jett  BD, Jensen  HG, Nordquist  RE, Gilmore  MS. Contribution of the pAD1-encoded cytolysin to the severity of experimental Enterococcus faecalis endophthalmitis. Infect Immun. 1992;60:244552.PubMedGoogle Scholar
  55. Ike  Y, Hashimoto  H, Clewell  DB. High incidence of hemolysin production by Enterococcus (Streptococcus) faecalis strains associated with human parenteral infections. J Clin Microbiol. 1987;25:15248.PubMedGoogle Scholar
  56. Huycke  MM, Spiegel  CA, Gilmore  MS. Bacteremia caused by hemolytic, high-level gentamicin-resistant Enterococcus faecalis. Antimicrob Agents Chemother. 1991;35:162634.PubMedGoogle Scholar
  57. Jett  BD, Jensen  HG, Atkuri  R, Gilmore  MS. Evaluation of therapeutic measures for treating endophthalmitis cause by isogenic toxin producing and toxin non-producing Enterococcus faecalis strains. Invest Ophthalmol Vis Sci. 1995;36:915.PubMedGoogle Scholar
  58. Ike  Y, Hashimoto  H, Clewell  DB. Hemolysin of Streptococcus faecalis subspecies zymogenes contributes to virulence in mice. Infect Immun. 1984;45:52830.PubMedGoogle Scholar
  59. Chow  JW, Thal  LA, Perri  MB, Vazquez  JA, Donabedian  SM, Clewell  DB, Plasmid-associated hemolysin and aggregation substance production contributes to virulence in experimental enterococcal endocarditis. Antimicrob Agents Chemother. 1993;37:24747.PubMedGoogle Scholar
  60. Ike  Y, Clewell  DB. Genetic analysis of pAD1 pheromone response in Streptococcus faecalis using transposon Tn917 as an insertional mutagen. J Bacteriol. 1984;158:77783.PubMedGoogle Scholar
  61. Ike  Y, Clewell  DB, Segarra  RA, Gilmore  MS. Genetic analysis of the pAD1 hemolysin/bacteriocin determinant in Enterococcus faecalis: Tn917 insertional mutagenesis and cloning. J Bacteriol. 1990;172:15563.PubMedGoogle Scholar
  62. Huycke  MM, Gilmore  MS. Frequency of aggregation substance and cytolysin genes among enterococcal endocarditis isolates. Plasmid. 1995;34:1526. DOIPubMedGoogle Scholar
  63. Todd  EW. A comparative serological study of streptolysins derived from human and from animal infections, with notes on pneumococcal haemolysin, tetanolysin and staphylococcus toxin. J Pathol Bacteriol. 1934;39:299321. DOIGoogle Scholar
  64. Booth  MC, Bogie  CP, Sahl  H-G, Siezen  RJ, Hatter  KL, Gilmore  MS. Structural analysis and proteolytic activation of Enterococcus faecalis cytolysin, a novel lantibiotic. Mol Microbiol. 1996;21:117584. DOIPubMedGoogle Scholar
  65. Gilmore  MS, Segarra  RA, Booth  MC. An hlyB-type function is required for expression of the Enterococcus faecalis hemolysin/bacteriocin. Infect Immun. 1990;58:391423.PubMedGoogle Scholar
  66. Katz  L, Chu  DT, Reich  K. Bacterial genomics and the search for novel antibiotics. In: Plattner JJ, editor. Annual Reports in Medicinal Chemistry. Vol. 32. New York: Academic Press, Inc., 1997. p. 121-30.
  67. Shankar  V, Gilmore  MS. Structure and expression of a novel surface protein of Enterococcus faecalis. In: Abstracts of the 97th General Meeting of the American Society for Microbioloty; 4-8 May 1997;Miami Beach, Florida. Washington: The Society; 1997.
  68. Hancock  LE, Gilmore  MS. The contribution of a cell wall associated carbohydrate to the in vivo survival of Enterococcus faecalis in a murine model of infection. In: Abstracts of the 97th General Meeting of the American Society for Microbioloty. 4-8 May 1997;Miami Beach, Florida. Washington: The Society; 1997.
  69. Arduino  RC, Murray  BE, Rakita  RM. Roles of antibodies and complement in phagocytic killing of enterococci. Infect Immun. 1994;62:98793.PubMedGoogle Scholar
  70. Arduino  RC, Palaz-Jacques  K, Murray  BE, Rakita  RM. Resistance of Enterococcus faecium to neutrophil-mediated phagocytosis. Infect Immun. 1994;62:558794.PubMedGoogle Scholar
  71. Huycke  MM, Joyce  W, Wack  MF. Augmented production of extracellular superoxide production by blood isolates of Enterococcus faecalis. J Infect Dis. 1996;173:7436.PubMedGoogle Scholar
  72. Swartz  MN. Hospital-acquired infections: diseases with increasingly limited therapies. Proc Natl Acad Sci U S A. 1994;91:24207. DOIPubMedGoogle Scholar

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