Vancomycin

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Vancomycin
300px
Systematic (IUPAC) name
(1S,2R,18R,19R,22S,25R,28R,40S)- 48- {[(2S,3R,4S,5S,6R)- 3- {[(2S,4S,5S,6S)- 4- amino- 5- hydroxy- 4,6- dimethyloxan- 2- yl]oxy}- 4,5- dihydroxy- 6- (hydroxymethyl)oxan- 2- yl]oxy}- 22- (carbamoylmethyl)- 5,15- dichloro- 2,18,32,35,37- pentahydroxy- 19- [(2R)- 4- methyl- 2- (methylamino)pentanamido]- 20,23,26,42,44- pentaoxo- 7,13- dioxa- 21,24,27,41,43- pentaazaoctacyclo[26.14.2.23,6.214,17.18,12.129,33.010,25.034,39]pentaconta- 3,5,8(48),9,11,14,16,29(45),30,32,34,36,38,46,49- pentadecaene- 40- carboxylic acid
Clinical data
Pregnancy
category
Routes of
administration		 IV, oral
Legal status
Legal status
  • S4 (Au), POM (UK), ℞-only (U.S.)
Pharmacokinetic data
Bioavailability Negligible (oral)
Metabolism Excreted unchanged
Biological half-life 4–11 hours (adults)
6-10 days (adults, impaired renal function)
Excretion Renal
Identifiers
CAS Number 1404-90-6
ATC code A07AA09 (WHO) J01XA01
PubChem CID 14969
DrugBank DB00512
ChemSpider 14253
Chemical data
Formula C66H75Cl2N9O24
Molar mass 1449.3 g.mol-1[[Script error: No such module "String".]]
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File:Vancomysin AntimicrobAgentsChemother 1990 1342 commons.jpg
Crystal structure of a short peptide L-Lys-D-Ala-D-Ala (bacterial cell wall precursor, in green) bound to vancomycin (blue) through hydrogen bonds. Reported by Knox and Pratt in Antimicrob. Agents. Chemother., 1990 1342-1347

Vancomycin (INN) (pronounced /væŋkɵˈmaɪsɨn/) is a glycopeptide antibiotic used in the prophylaxis and treatment of infections caused by Gram-positive bacteria. It has traditionally been reserved as a drug of "last resort", used only after treatment with other antibiotics had failed, although the emergence of vancomycin-resistant organisms means that it is increasingly being displaced from this role by linezolid and daptomycin.

History

Vancomycin was first isolated in 1953 by Edmund Kornfeld (working at Eli Lilly) from a soil sample collected from the interior jungles of Borneo by a missionary.[1] The organism that produced it was eventually named Amycolatopsis orientalis.[2] The original indication for vancomycin was for the treatment of penicillin-resistant Staphylococcus aureus.[2][3]

The compound was initially labeled compound 05865, but was eventually given the generic name, vancomycin (derived from the Latin, "vanquished").[2] One advantage that was quickly apparent is that staphylococci did not develop significant resistance despite serial passage in culture media containing vancomycin. The rapid development of penicillin resistance by staphylococci led to the compound's being fast-tracked for approval by the FDA in 1958. Eli Lilly first marketed vancomycin hydrochloride under the trade name Vancocin.[3]

Vancomycin never became first-line treatment for Staphylococcus aureus for several reasons:

  1. The drug must be given intravenously, because it is not absorbed orally.[citation needed]
  2. β-lactamase-resistant semi-synthetic penicillins such as methicillin (and its successors, nafcillin and cloxacillin) were subsequently developed.
  3. Early trials used early impure forms of vancomycin ("Mississippi mud"), which were found to be toxic to the ears and to the kidneys;[4] these findings led to vancomycin's being relegated to the position of a drug of last resort.

In 2004, Eli Lilly licensed Vancocin to ViroPharma in the U.S., Flynn Pharma in the UK, and Aspen Pharmacare in Australia. The patent expired in the early 1980s, but the FDA has not authorized the sale of any generic versions in the USA.

Biosynthesis

File:Vancomycin Modules.png
Figure 1: Modules and Domains of Vancomycin assembly.

Vancomycin biosynthesis occurs via different nonribosomal protein synthases (NRPSs).[5] The enzymes determine the amino acid sequence during its assembly through its 7 modules. Before Vancomycin is assembled through NRPS, the amino acids are first modified. L-tyrosine is modified to become the β-hydroxychlorotyrosine (β-hTyr) and 4-hydroxyphenylglycine (HPG) residues. On the other hand, acetate is used to derive the 3,5 dihydroxyphenylglycine ring (3,5-DPG).[6]

File:Linear heptapeptide of Vancomycin.png
Figure 2: Linear heptapeptide, which consists of modified aromatic rings

Nonribosomal peptide synthesis occurs through distinct modules that can load and extend the protein by one amino acid through the amide bond formation at the contact sites of the activating domains.[7] Each module typically consists of an adenylation (A) domain, a peptidyl carrier protein (PCP) domain, and a condensation (C) or elongation domain. In the A domain, the specific amino acid is activated by converting into an aminoacyl adenylate enzyme complex attached to a 4’phosphopantetheine cofactor by thioesterification[8][9] The complex is then transferred to the PCP domain with the expulsion of AMP. The PCP domain uses the attached 4’-phosphopantethein prosthetic group to load the growing peptide chain and their precursors.[10] The organization of the modules necessary to biosynthesize Vancomycin is shown in Figure 1. In the biosynthesis of Vancomycin, additional modification domains are present, such as the epimerization (E) domain, which is used isomerizes the amino acid from one stereochemistry to another, and a thioesterase domain (TE) is used as a catalyst for cyclization and releases of the molecule via a thioesterase scission.

File:Biosynthesis of Vancomycin.png
Figure 3: Modifications that are necessary for Vancomycin to become biologically active.

A set of multienzymes (peptide synthase CepA, CepB, and CepC) are responsible for assembling the heptapeptide. (Figure 2). The organization of CepA, CepB, and Cep C closely resembles other peptide synthases such as those for surfactin (SrfA1, SrfA2 and SrfA3) and gramicidin (GrsA and GrsB).[7] Each peptide synthase activates codes for various amino acids in order to activate each domain. CepA codes for modules 1, 2 and 3, CepB codes for modules 4,5,and 6, and CepC codes for module 7 codes. The three peptide synthases are located at the start of the region of the bacterial genome linked with antibiotic biosynthesis and spans 27kb.[7]

After the linear heptapeptide molecule is synthesized, Vancomycin has to further undergo post-translational modifications, such as oxidative cross-linking and glycosylation, in trans by distinct enzymes, referred to as tailoring enzymes, in order to become biologically active (Figure 3). To convert the linear heptapeptide, eight enzymes, Open Reading Frames (ORF) 7, 8, 9, 10, 11, 14, 18, 20, and 21 are used. The enzymes ORF 7, 8,9 and 20 are P450 enzymes, ORF 10 and 18 show to nonheme haloperoxidases and ORF 9 and 14 are identified as putative hydroxylation enzymes.[11] With the help of these enzymes, β-hydroxyl groups are introduced onto tyrosine residues 2 and 6 and coupling occurs for rings 5 and 7, rings 4 and 6, and rings 4 and 2. In addition, a haloperoxidase is used to attach the chlorine atoms onto rings 2 and 6 via an oxidative process.[7]

Pharmacology and chemistry

It is a branched tricyclic glycosylated nonribosomal peptide produced by the fermentation of the Actinobacteria species Amycolatopsis orientalis (formerly designated Nocardia orientalis).

Vancomycin acts by inhibiting proper cell wall synthesis in Gram-positive bacteria. Due to the different mechanism by which Gram-negative bacteria produce their cell walls and the various factors related to entering the outer membrane of Gram-negative organisms, vancomycin is not active against Gram-negative bacteria (except some non-gonococcal species of Neisseria).

To be specific, vancomycin prevents incorporation of N-acetylmuramic acid (NAM) and N-acetylglucosamine (NAG) peptide subunits into the peptidoglycan matrix; which forms the major structural component of Gram-positive cell walls.

The large hydrophilic molecule is able to form hydrogen bond interactions with the terminal D-alanyl-D-alanine moieties of the NAM/NAG-peptides. Under normal circumstances, this is a five-point interaction. This binding of vancomycin to the D-Ala-D-Ala prevents the incorporation of the NAM/NAG-peptide subunits into the peptidoglycan matrix.

Vancomycin exhibits atropisomerism — it has two chemically distinct rotamers owing to the rotational restriction of the chlorotyrosine residue (on the righthand side of the figure). The form present in the drug is the thermodynamically more stable conformer and, therefore, has more potent activity.

Clinical use

Indications

Vancomycin is indicated for the treatment of serious, life-threatening infections by Gram-positive bacteria that are unresponsive to other less-toxic antibiotics. In particular, vancomycin should not be used to treat methicillin-sensitive Staphylococcus aureus because it is inferior to penicillins such as nafcillin.[12][13]

The increasing emergence of vancomycin-resistant enterococci has resulted in the development of guidelines for use by the Centers for Disease Control (CDC) Hospital Infection Control Practices Advisory Committee. These guidelines restrict use of vancomycin to the following indications:[14]

Adverse effects

Although vancomycin levels are usually monitored, in an effort to reduce adverse events, the value of this is not beyond debate.[15] Peak and trough levels are usually monitored, and, for research purposes, the area under the curve is also sometimes used. Toxicity is best monitored by looking at trough values.[16]

Common adverse drug reactions (≥1% of patients) associated with IV vancomycin include: local pain, which may be severe and/or thrombophlebitis.

Damage to the kidneys and to the hearing were a side-effect of the early impure versions of vancomycin, and these were prominent in the clinical trials conducted in the mid-1950s.[2][3] Later trials using purer forms of vancomycin found that nephrotoxicity is an infrequent adverse effect (0.1–1% of patients), but that this is accentuated in the presence of aminoglycosides.[17]

Rare adverse effects (<0.1% of patients) include: anaphylaxis, toxic epidermal necrolysis, erythema multiforme, red man syndrome (see below), superinfection, thrombocytopenia, neutropenia, leucopenia, tinnitus, dizziness and/or ototoxicity (see below).[14]

Lately, it has been emphasized that vancomycin can induce platelet-reactive antibodies in the patient, leading to severe thrombocytopenia and bleeding with florid petechial hemorrhages, ecchymoses, and wet purpura.[18]

Dosing considerations

Intravenous vs oral administration

Vancomycin must be given intravenously (IV) for systemic therapy, since it does not cross through the intestinal lining. It is a large hydrophilic molecule that partitions poorly across the gastrointestinal mucosa. The only indication for oral vancomycin therapy is in the treatment of pseudomembranous colitis, where it must be given orally to reach the site of infection in the colon. Following oral administration, the fecal concentration of vancomycin is around 500 µg/ml[19] (sensitive strains of C. difficile have a mean inhibitory concentration of ≤2 µg/ml[20])

Inhaled vancomycin has also been used (off-label), via nebulizer, for treatment of various infections of the upper and lower respiratory tract. The caustic nature of Vancomycin makes IV therapy using midline PICC lines a risk for thrombophlebitis.[21]

Red man syndrome

See also: Erythroderma

Vancomycin must be administered in a dilute solution slowly, over at least 60 minutes (maximum rate of 10 mg/minute for doses >500 mg).[14] This is due to the high incidence of pain and thrombophlebitis and to avoid an infusion reaction known as the red man syndrome or red neck syndrome. This syndrome, usually appearing within 4–10 minutes after the commencement or soon after the completion of an infusion, is characterized by flushing and/or an erythematous rash that affects the face, neck, and upper torso. These findings are due to non-specific mast cell degranulation and are not an IgE-mediated allergic reaction. Less frequently, hypotension and angioedema may also occur. Symptoms may be treated or prevented with antihistamines, including diphenhydramine, and are less likely to occur with slow infusion.[22][23]:120-1

Therapeutic drug monitoring

Vancomycin activity is considered to be time-dependent; that is, antimicrobial activity depends on the duration that the drug level exceeds the minimum inhibitory concentration (MIC) of the target organism. Thus, peak levels have not been shown to correlate with efficacy or toxicity – indeed concentration monitoring is unnecessary in most cases. Circumstances where therapeutic drug monitoring (TDM) is warranted include: patients receiving concomitant aminoglycoside therapy, patients with (potentially) altered pharmacokinetic parameters, patients on haemodialysis, during high-dose or prolonged treatment, and patients with impaired renal function. In such cases, trough concentrations are measured.[14][24][25][26]

The levels aimed for have changed over the years. Early authors suggested peak levels of 30 to 40 mg/L and trough levels of 5 to 10 mg/L,[27] but current recommentations are that peak levels need not be measured and that, for serious infections, trough levels of 15 to 20 mg/L should be aimed for.[28]

Toxicity

Vancomycin has traditionally been considered a nephrotoxic and ototoxic drug, based on observations by early investigators of elevated serum levels in renally impaired patients that had experienced ototoxicity, and subsequently through case reports in the medical literature. However, as the use of vancomycin increased with the spread of MRSA beginning in the 1970s, it was recognised that the previously reported rates of toxicity were not being observed. This was attributed to the removal of the impurities present in the earlier formulation of the drug, although those impurities were not specifically tested for toxicity.[2]

Nephrotoxicity

Subsequent reviews of accumulated case reports of vancomycin-related nephrotoxicity found that many of the patients had also received other known nephrotoxins, in particular, aminoglycosides. Most of the rest had other confounding factors, or insufficient data regarding the possibility of such, that prohibited the clear association of vancomycin with the observed renal dysfunction.

In 1994, Cantu and colleagues found that the use of vancomycin monotherapy was clearly documented in only three of 82 available cases in the literature.[24] Prospective and retrospective studies attempting to evaluate the incidence of vancomycin-related nephrotoxicity have largely been methodologically flawed and have produced variable results. The most methodologically sound investigations indicate that the actual incidence of vancomycin-induced nephrotoxicity is around 5–7%. To put this into context, similar rates of renal dysfunction have been reported for cefamandole and benzylpenicillin, two reputedly non-nephrotoxic antibiotics.

In addition, evidence to relate nephrotoxicity to vancomycin serum levels is inconsistent. Some studies have indicated an increased rate of nephrotoxicity when trough levels exceed 10 µg/mL, but others have not reproduced these results. Nephrotoxicity has also been observed with concentrations within the "therapeutic" range as well. In essence, the reputation of vancomycin as a nephrotoxin is over-stated, and it has not been demonstrated that maintaining vancomycin serum levels within certain ranges will prevent its nephrotoxic effects, when they do occur.

Ototoxicity

Attempts to establish rates of vancomycin-induced ototoxicity are even more difficult due to the scarcity of quality evidence. The current consensus is that clearly related cases of vancomycin ototoxicity are rare. The association between vancomycin serum levels and ototoxicity is also uncertain. While cases of ototoxicity have been reported in patients whose vancomycin serum level exceeded 80 µg/mL, cases have been reported in patients with therapeutic levels as well. Thus, it also remains unproven that therapeutic drug monitoring of vancomycin for the purpose of maintaining "therapeutic" levels will prevent ototoxicity.

Interactions with other nephrotoxins

Another area of controversy and uncertainty concerns the question of whether, and, if so, to what extent, vancomycin increases the toxicity of other nephrotoxins. Clinical studies have yielded variable results, but animal models indicate that there probably is some increased nephrotoxic effect when vancomycin is added to nephrotoxins such as aminoglycosides. However, a dose- or serum level-effect relationship has not been established.

Antibiotic resistance

Intrinsic resistance

There are a few gram-positive bacteria that are intrinsically resistant to vancomycin: Leuconostoc and Pediococcus species, but these organisms are rare causes of disease in humans.[29] Most Lactobacillus species are also intrinsically resistant to vancomycin[29] (the exception is the finding of a few strains (but not all) of L. acidophilus[30]).

Most gram-negative bacteria are intrinsically resistant to vancomycin because their outer membrane is impermeable to large glycopeptide molecules[31] (with the exception of some non-gonococcal Neisseria species).[32]

Acquired resistance

Acquired microbial resistance to vancomycin is a growing problem, in particular, within healthcare facilities such as hospitals. With vancomycin as the last-line antibiotic for serious Gram-positive infections, there is the growing prospect that resistance will result in a return to the days when fatal bacterial infections were common.[citation needed] Vancomycin-resistant enterococcus (VRE) emerged in 1987. Vancomycin resistance emerged in more common pathogenic organisms during the 1990s and 2000s, including vancomycin-intermediate Staphylococcus aureus (VISA), vancomycin-resistant Staphylococcus aureus (VRSA), and vancomycin-resistant Clostridium difficile.[33][34] There is some suspicion that agricultural use of avoparcin, another similar glycopeptide antibiotic, has contributed to the emergence of vancomycin-resistant organisms.

One mechanism of resistance to vancomycin appears to be alteration to the terminal amino acid residues of the NAM/NAG-peptide subunits, normally D-alanyl-D-alanine, which vancomycin binds to. Variations such as D-alanyl-D-lactate and D-alanyl-D-serine result in only a 4-point hydrogen bonding interaction possible between vancomycin and the peptide. This loss of just one point of interaction results in a 1000-fold decrease in affinity.

In Enterococci this modification appears to be due to the expression of an enzyme that alters the terminal residue. Three main resistance variants have been characterised to date among resistant Enterococcus faecium and E. faecalis populations.

  • VanA - resistance to vancomycin and teicoplanin; inducible on exposure to these agents
  • VanB - lower-level resistance; inducible by vancomycin, but strains may remain susceptible to teicoplanin
  • VanC - least clinically important; resistance only to vancomycin; constitutive resistance

The development and use of novel antibiotics such as linezolid and daptomycin are expected to delay, but not halt, the emergence of bacteria resistant to all available antibiotics.

See also

References

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  1. ↑ Shnayerson, Michael; Plotkin, Mark (2003). The Killers Within: The Deadly Rise of Drug-Resistant Bacteria. Back Bay Books. ISBN 978-0316735667.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 Levine, D. (2006). "Vancomycin: A History". Clin Infect Dis. 42: S5–S12. doi:10.1086/491709. PMID 16323120. 
  3. ↑ 3.0 3.1 3.2 Moellering, RC Jr. (2006). "Vancomycin: A 50-Year Reassessment". Clin Infect Dis. 42 (Suppl 1): S3–S4. doi:10.1086/491708. PMID 16323117. 
  4. ↑ Griffith RS. (1981). "Introduction to vancomycin". Rev Infect Dis. 3: S2004. 
  5. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  6. ↑ Dewick, Paul M. (2002). Medicinal natural products: a biosynthetic approach. New York: Wiley. ISBN 0-471-49641-3. 
  7. ↑ 7.0 7.1 7.2 7.3 Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  8. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  9. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  10. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  11. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  12. ↑ Small PM, Chambers HF (1990). "Vancomycin for Staphylococcus aureus endocarditis in intravenous drug users". Antimicrob Agents Chemother. 34 (6): 1227–31. PMC 171789 Freely accessible. PMID 2393284. 
  13. ↑ Gonzalez C, Rubio M, Romero-Vivas J, Gonzalez M, Picazo JJ (1999). "Bacteremic pneumonia due to Staphylococcus aureus: a comparison of disease caused by methicillin-resistant and methicillin-susceptible organisms". Clin Infect Dis. 29 (5): 1171–7. doi:10.1086/313440. PMID 10524959. 
  14. ↑ 14.0 14.1 14.2 14.3 Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3
  15. ↑ Cantú TG, Yamanaka-Yuen NA, Lietman PS (1994). "Serum vancomycin concentrations: reappraisal of their clinical value". Clin Infect Dis. 18 (4): 533–43. PMID 8038306. 
  16. ↑ Lodise TP, Patel N, Lomaestro BM, Rodvold KA, Drusano GL (2009). "Relationship between initial vancomycin concentration‐time profile and nephrotoxicity among hospitalized patients". Clin Infect Dis. 49 (4): 507–514. doi:10.1086/600884. PMID 19586413.  line feed character in |author= at position 11 (help)
  17. ↑ Farber BF, Moellering RC Jr. (1983). "Retrospective study of the toxicity of preparations of vancomycin from 1974 to 1981". Antimicrob Agents Chemother. 23 (1): 138. PMC 184631 Freely accessible. PMID 6219616. 
  18. ↑ Drygalski A, Curtis BR (2007). "Vancomycin-Induced Immune Thrombocytopenia". N Engl J Med. 356 (9): 904. doi:10.1056/NEJMoa065066. PMID 17329697. 
  19. ↑ Edlund C, Barkholt L, Olsson-Liljequist B, Nord CE (1997). "Effect of vancomycin on intestinal flora of patients who previously received antimicrobial therapy". Clin Infect Dis. 25: 729–32. 
  20. ↑ Peláez T, Alcalá L, Alonso R; et al. (2002). "Reassessment of Clostridium difficile susceptibility to metronidazole and vancomycin". Antimicrob Agents Chemother. 46 (6): 1647–1650. doi:10.1128/AAC.46.6.1647-1650.2002. 
  21. ↑ http://www.nursingcenter.com/prodev/ce_article.asp?tid=745323
  22. ↑ Sivagnanam S, Deleu D. Red man syndrome. Crit Care 2003;7(2):119–120. PMID 12720556. (full text)
  23. ↑ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0721629210.
  24. ↑ 24.0 24.1 Cantu TG, Yamanaka-Yuen NA, Lietman PS. Serum vancomycin concentrations: reappraisal of their clinical value. Clin Infect Dis 1994;19(6):1180-2. PMID 8038306
  25. ↑ Moellering RC Jr. Monitoring serum vancomycin levels: climbing the mountain because it is there? Clin Infect Dis 1994;18(4):544-6. PMID 8038307
  26. ↑ Karam CM, McKinnon PS, Neuhauser MM, Rybak MJ. Outcome assessment of minimizing vancomycin monitoring and dosing adjustments. Pharmacotherapy 1999;19(3):257-66. PMID 10221365
  27. ↑ Geraci J (1977). "Vancomycin". Mayo Clin Proc. 52 (10): 631–4. PMID 909314. 
  28. ↑ Rybak M, Lomaestro B, Rotschafer JC; et al. (2009). "Therapeutic monitoring of vancomycin in adult patients: A consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists". American Journal of Health-System Pharmacy. 66 (1): 82–98. doi:10.2146/ajhp080434. PMID 19106348. 
  29. ↑ 29.0 29.1 Swenson JM, Facklam RR, Thornsberry C (1990). "Antimicrobial susceptibility of vancomycin-resistant Leuconostoc, Pediococcus and Lactobacillus species". Antimicrob Agents Chemother. 34: 543–49. 
  30. ↑ Hamilton-Miller JM, Shah S (1998). "Vancomycin susceptibility as an aid to the identification of lactobacilli". Lett Appl Microbiol. 26: 153–54. doi:10.1046/j.1472-765X.1998.00297.x. 
  31. ↑ Quintiliani R Jr, Courvalin P (1995). "Mechanisms of Resistance to Antimicrobial Agents". In Murray PR, Baron EJ, Pfaller MA, Tenover FC, Yolken RH. Manual of Clinical Microbiology (6th ed.). Washington DC: ASM Press. p. 1319. ISBN 1-55581-086-1. 
  32. ↑ Geraci JE, Wilson WR (1981). "Vancomycin therapy for infective enocarditis". Rev Infect Dis. 3(Suppl): S250–58. 
  33. ↑ Smith TL, Pearson ML, Wilcox KR, Cruz C, Lancaster MV, Robinson-Dunn B, et al. Emergence of vancomycin resistance in Staphylococcus aureus. Glycopeptide-Intermediate Staphylococcus aureus Working Group. N Engl J Med 1999;340(7):493-501. PMID 10021469
  34. ↑ McDonald LC, Killgore GE, Thompson A, et al. Emergence of an epidemic, toxin gene variant strain of Clostridium difficile responsible for outbreaks in the United States between 2000 and 2004. N Engl J Med 2005;353:2433-2441. PMID 16322603
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