• Information
  1. Species
  2. Nosocomial Infections
  3. Enterococcal Infections
  4. Mechanisms of Antibiotic Resistance
  5. Vancomycin Resistant Enterococci
  6. Active Antibiotics
  7. Risk factors for development of Vancomycin Resistance

A. Species

1. Classification
   1. Originally considered a type of streptococcus
   2. Clearly related to streptococcus (Group D)
   3. However, now considered a distinct genus
2. Most are part of normal enteric flora
3. Species
   1. E. faecalis 80-85%
   2. E. faecium 10-15%
   3. E. durans ~1-2%
   4. E. gallinarum
   5. Others (rare)

B. Nosocomial Infections (in order of prevalence)

1. E. coli
2. Enterococcus ssp. - increasing number of E. faecium
3. Pseudomonas ssp.
4. S. aureus

C. Enterococcal Infections

1. Urinary Tract Infections (UTI)
2. Bacteremia
3. Endocarditis
4. Small risk in pathogenesis of abdominal infections, though commonly present
5. Frequent carriage in stool of hospitalized patients [1,3]

D. Mechanisms of Antibiotic Resistance [6]

1. High tolerance to antibiotics
   1. Ratio of lytic to static dose of most antibiotics is >32 for entercoccus
   2. This is definition of antibiotic tolerance
   3. No single antibiotic has been found to kill enterococcus
   4. Combination anti-cell wall agent and aminoglycoside required for lysis
2. ß-Lactamase production is rare and only in E. faecalis [10]
   1. In addition, production of any ß-lactamase, when it occurs, is at low levels
   2. Combination extended range penicillin and penicillinase inhibitor are often effective
3. Alteration in penicillin binding proteins is common in E. faecium
   1. Nearly all strains of E. faecalis are moderately susceptible to ampicillins
   2. Most strains of E. faecium are inherently more resistant to penicillins
4. High level aminoglycoside resistance - prevalence increasing [10]
5. Vancomycin Resistance
   1. Prevalence increasing
   2. Aminoglycoside resistance often accompanies vancomycin resisitance
   3. Probably began in wild with animals fed avoparcin [11]
6. Clarithromycin-metronidazole therapy for H. pylori can lead to long term persistence of clarithromycin resistant Eterococci [19]

E. Vancomycin Resistant Enterococci [2,3,6,8,9,11]

1. Five phenotypes: A, B, C, D, and E
   1. All are plasmid/transposon mediated except VanC, which is chromosomal
   2. VanC is not found in E. faecium and E. faecalis
   3. VanA is most common
   4. VanD is found only in E. faecium
   5. VanE is found only in E. faecalis
2. VanA [2]
   1. High level resistance to vancomycin and to teicoplanin
   2. Also resistant to teicoplanin
   3. Often accompanied by high level aminoglycoside resistance
   4. VanA complex consists of 7 genes which produce cell wall C-Ala-D-Lac molecules
   5. Vancomycin binds D-ALA-D-ALA on bacterial cell walls with high affinity
   6. May be sensitive to doxycycline, chloramphenicol, streptogramins, combinations
3. VanB
   1. Moderate level resistance
   2. Majority of VanB strains are sensitive to teicoplanin
   3. Some strains have become vancomycin "dependent", require drug for growth
4. VanC
   1. Low level, chromosome mediated, resistance
   2. Found in E. gallinarum and E. casseliflavus (not E. faecium or E. faecalis)
5. VanD
   1. Acquired moderate level resistance
   2. Low level resistance to teicoplanin
   3. E. faecium
6. VanE
   1. Acquired low to moderate resistance
   2. Sensitive to teicoplainin
   3. E. faecalis
7. Infection Containment
   1. Restriction of iv and po vancomycin use [3]
   2. Isolation of carriers
   3. Treatment with antianaerobic antibiotics leads to increases in VREF levels in stool [15]
   4. Reduced use of vancomycin and 3rd generation cephalosporins associated with reduced incidence of vancomycin-resistant enterococci (VREF) [16]
8. Aminoglycoside resistance coexists in about 50% of isolates [8]
9. Treatment depends on sensitivities and site of infection (see also below)
10. Endocarditis
    1. High dose ampicillin-sulbactam + aminoglycoside (gentamicin or streptomycin)
    2. For aminoglycoside resistance use quinupristin-dalfopristin
    3. Valve replacement may be required
11. Meningitis
    1. Consider quinupristin-dalfopristin IV ± intrathecal
    2. Other agents as susceptibility dictates
    3. Consider penetration to cerebrospinal fluid

F. Active Antibiotics [2,17]

1. Most strains still sensitive to ampicillin
2. Combination ampicillin or vancomycin + aminoglycoside
   1. Bacteremia - treat with one or two drugs; optimal combination not defined
   2. Endocarditis requires full course of combination (two drug) therapy
   3. UTI generally requires only single agent
   4. Very ill patients are at high risk for developing rapid drug resistance [10]
3. Other Agents
   1. Ciprofloxacin or Norfloxacin or Ofloxacin - for UTI only; often resistant
   2. Chloramphenicol [5]
   3. Doxycycline - bacteriostatic
   4. Nitrofurantoin (Macrodantin®) - for UTI only
   5. Imipenem - many strains resistant but may be synergistic with ampicillin
   6. TMP/SMX (Bactrim®, Septra®) - ineffective in vivo
4. Vancomycin Resistant Strains [6,8,11]
   1. Van A - Chloramphenicol, Doxycycline, Pistinamycin, Glycylglycines
   2. Van B - vancomycin or ampicillin (or teicoplanin) + aminoglycoside
   3. Van C - high dose vancomycin or ampicillin (or teicoplanin) + aminoglycoside
   4. Doxycycline may be active in many infections and synergistic with other agents
   5. Quinupristin-dalfopristin (Synercid®) - not active against E. faecalis
   6. Linezolid (Zyvox®)
   7. Chloramphenicol is occasionally active against these strains [5,8]
   8. Nitrofurantoin is occasionally used for UTI only
   9. Rifampin - always in combination
   10. Fosfomycin (Monurol®), often with cefotaxime - mainly for UTI
   11. Daptomycin (Cubicin®)
   12. Evernimycin - experimental
5. Pristinamycin (Quinupristin/Dalfopristin, Synercid®) [12,13]
   1. Bactericidal against streptococci and staphylococci
   2. Bacteriostatic against E. faecium only
   3. Nearly 70% of vancomycin resistant E. faecium (VREF) had clinical responses
   4. No activity against E. faecalis
   5. Active against methicillin (and vancomycin) resistant Staph aureus (MRSA, VRSA)
   6. Dose is typically 5mg/kg iv q12 hours
6. Linezolid (Zyvox®) [14,18]
   1. Oxazolidinone which inhibits protein synthesis by bacterial ribosome
   2. Activity against all gram positive organisms and many anaerobes
   3. Cytostatic activity against both E. faceium AND E. faecalis
   4. Oral and IV available, usual dose is 600mg twice daily
   5. Clinical cure rates in VRE infections 67% (range 50-85%)
7. Suggested Combinations [9]
   1. Pristinamycin or linezolid alone may be sufficient
   2. Rifampin-ciprofloxacin-gentamicin
   3. Teicoplanin-gentamicin
   4. Novobiocin + fluoroquinolone
   5. Vancomycin or Teicoplanin + ß-lactam + aminoglycoside
   6. Ampicillin-imipenem-aminoglycoside
   7. Doxycycline and/or chloramphenicol + other drugs
8. Cephalosporins have no activity

G. Risk factors for development of Vancomycin Resistance

1. Use of oral vancomycin (for C. difficle diarrhea)
2. Use of broad spectrum antibiotics
3. Debilitated condition with prolonged hospitalization [4]
   1. Hematologic Maliganancy
   2. Organ Failure: Respiratory or Renal Failure
   3. Prolonged antibiotic use during hospitalization
4. Majority of patients are are or have been in intensive care units, often surgical [7]

References

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2. Murray BE. 2000. NEJM. 342(10):710
3. Morris JG Jr, Shay DK, Hebden JN, et al. 1995. Ann Intern Med. 123:250
4. Montecalvo MA, Shay DK, Patel P, et al. 1996. Arch Intern Med. 156(13):1458
5. Norris AH, Reilly JP, Edelstein PH, et al. 1995. Clin Infect Dis. 20:1137
6. Gold HS and Moellering RC Jr. 1996. NEJM. 335(19):1445
7. Lai KK. 1996. Arch Intern Med. 156(22):2579
8. Jacoby GA. 1996. Annu Rev Med. 47:169
9. Murray BE. 1997. Am J Med. 102(3):284
10. Wells VD, Wong ES, Murray BE, et al. 1992. Ann Intern Med. 116(4):285
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12. Vo HK and Zervos MJ. 1998. Infect Dis Clin Pract. 7(8):416
13. Quinupristin / Dalfopristin. Med Let. 1999. 41(1066):109
14. Linezolid. 2000. Med Let. 42(1079):45
15. Donskey CJ, Chowdhry TK, Hecker MT, et al. 2000. NEJM. 343(26):1925
16. Fridkin SK, Edwards JR, Courval JM, et al. 2001. Ann Intern Med. 135(3):175
17. Choice of Antibacterial Drugs. 2001. Med Let. 43(1111):69
18. Diekema DJ and Jones RN. 2001. Lancet. 358(9297):1975
19. Sjolund M, Wreiber K, Andersson DI, et al. 2003. Ann Intern Med. 139(6):483