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Plyss
Skeptic Friend
Netherlands
231 Posts |
 Posted - 04/01/2005 : 07:54:11
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Inspired by the Talk.origins post of the month runner up of last februari, i thought i'd expand upon one of the points made by the poster.
Pathogenic bacteria, both gram-positive and -negative rely on a structure called the cell-wall (also peptidoglycan or murein) to maintain membrane integrity. This structure forms a rigid jacket, not unlike chain-mail, that protects the bacterium from lysis due to osmotic stress or shearing forces.
(Free sample image from ConceptDraw)
The cell-wall consists of a meshwork of linear chains of carbohydrates crosslinked with peptides and is synthesised by a broad variety of enzymes acting together on both the inside and the outside of the inner membrane. This synthesis runs roughly as follows: A sugar-moiety with a penta-peptide attached to it is added to a phosphate-carrying, membrane bound hydrocarbon-chain. Once attached, another sugar-moiety is added, forming a molecule commonly named Lipid II. This Lipid II is transported accross the plasmamembrane where the two sugars with the penta-peptide are removed from the carrier-chain and added to a growing network of peptidoglycan.
(Image from Drs. Naomi Kramer)
This cell wall is essential for survival of the bacterium, and because humans cells lack such a structure, the synthesis machinery involved in making it forms a prime target for antibiotics. Examples of such antibiotics are abundant: Penicillin, fosfomycin, tunicamycin and bacitracin are just a few.
A special case is formed by the antibiotic vancomycin. Where some antibiotics target enzymes involved making the cell wall, vancomycin binds to a reaction intermediate. Specifically, it binds to the last two amino-acids of Lipid II, two D-alanine residues, thereby preventing Lipid II from being used in building more peptidoglycan. Because only minor amounts of Lipid II are present per bacterium even minor amounts of vancomycin completely abolish synthesis of
peptidoglycan and lead to cell death.
When enzymes are inhibited by antibiotics it is relatively easy for a bacterium to mutate in such a way as to render the enzyme immune to that antibiotic. This is however not the case when a complete pathway is blocked. Building up resistance to such an antibiotic required extensive change in multiple genes, while even change in a single one can render the entire pathway unusable, resulting in death of the bacterium.
This property of vancomycin has made it the antibiotic of choice in combating infections that are otherwise untreatable. Indeed, it is sometimes described as a "last-resort antibiotic".
Therefor, it came as an unfortunate surprise when the first strains of pathogens emerged that displayed resistance against vancomycin.
From Bug Bytes Volume 2 Number 19 - May 14, 1996
quote:
The mechanisms by which enterococci resist vancomycin are complex and include the VanA phenotype with high-level vancomycin and teicoplanin resistance, and the VanB phenotype with moderate to high-level resistance to vancomycin but continued susceptibility to teicoplanin. The genes required for expression of the VanA phenotype are carried on a trans-poson designated as Tn1546. Tn1546 contains a gene cluster of seven vancomycin-resistance genes of which five are required for expression of the VanA phenotype. These five genes are: vanA which codes for a ligase that results in cell wall precursors ending in the depsipeptide D-Ala-D-Lac instead of the normal D-Ala-D-Ala targeted by vancomycin; vanH which codes for a dehydrogenase; vanR and vanS which together regulate depsipeptide production; and vanX which codes for a protein required for resistance but of unknown function. In addition Tn1546 contains open reading frames ORF1 and ORF2, and genes vanY and vanZ which although involved in peptidoglycan synthesis are not necessary for vancomycin resistance.
In short, enterococci have gained the ability to use not the regular Lipid II ending in the amino acids D-ala-D-ala, but can now use a lipid II variety ending in a different motif, rendering it immune to vancomycin. To this purpose they've acquired 5 new proteins working in concert.
It may be argued however that, because the gene-cluster for vancomycin resistance can be transfered between bacteria, that it has been around from the beginning, designed by our loving Creator to inflict horrible infections onto people while desparate doctors stand powerless as their patients die despite their best efforts.
Interestingly though, a new vancomycin resistant pathogen has surfaced in recent years, named VISA (vancomycin intermediate Staphylococcus aureus) with a novel, borderline-resistance phenotype acquired without genetic exchange. The mechanism of this form of resistance remains as yet unknown, so it'll be interesting to see if it is in some way similar to the mechanism for the VanA form of resistance.
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Edited by - Plyss on 04/06/2005 00:47:59
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Dave W.
Info Junkie
USA
26020 Posts |
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Plyss
Skeptic Friend
Netherlands
231 Posts |
Posted - 04/01/2005 : 08:48:41 [Permalink]
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quote:
Originally posted by Dave W.
Hey! I was going to do this!
Mwhuahahaha! |
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beskeptigal
SFN Die Hard
USA
3834 Posts |
Posted - 04/02/2005 : 13:42:21 [Permalink]
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Don't know why I need to add this but it comes from some of my latest infection control work:
We now have CA-MRSA and HA-MRSA
CA: community acquired methicillin resistant staphylococcus aureus
HA: hospital acquired MRSA
The CA MRSA has acquired the methicillin resistance gene but retains susceptibility to other antibiotics in addition to Vancomycin. |
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Dude
SFN Die Hard
USA
6891 Posts |
Posted - 04/02/2005 : 19:01:54 [Permalink]
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quote:
The CA MRSA has acquired the methicillin resistance gene but retains susceptibility to other antibiotics in addition to Vancomycin.
There aren't many reported cases of vancomycin resistant staph.
Only 2 so far in the US, both in 2002.
And only 8 cases of vancomycin-intermediate SA.
http://www.cdc.gov/ncidod/hip/ARESIST/visa.htm
These two are much more serious than the vancomycin resistant enterococci. Fortunately the cases so far have all been treatable by other antibiotics. One of the big concerns for infectious disease is a strain of staph aureus that is more broadly resistant.
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Ignorance is preferable to error; and he is less remote from the truth who believes nothing, than he who believes what is wrong.
-- Thomas Jefferson
"god :: the last refuge of a man with no answers and no argument." - G. Carlin
Hope, n.
The handmaiden of desperation; the opiate of despair; the illegible signpost on the road to perdition. ~~ da filth |
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beskeptigal
SFN Die Hard
USA
3834 Posts |
Posted - 04/03/2005 : 22:17:00 [Permalink]
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quote:
Originally posted by Dude
quote:
The CA MRSA has acquired the methicillin resistance gene but retains susceptibility to other antibiotics in addition to Vancomycin.
There aren't many reported cases of vancomycin resistant staph.
Only 2 so far in the US, both in 2002.
And only 8 cases of vancomycin-intermediate SA.
http://www.cdc.gov/ncidod/hip/ARESIST/visa.htm
These two are much more serious than the vancomycin resistant enterococci. Fortunately the cases so far have all been treatable by other antibiotics. One of the big concerns for infectious disease is a strain of staph aureus that is more broadly resistant.
Ah.. but don't forget we live in a global world. |
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beskeptigal
SFN Die Hard
USA
3834 Posts |
Posted - 04/13/2005 : 02:22:38 [Permalink]
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Well it turns out we have had VRSA in the USA since 2002. Here's a case from 2004.quote:
STAPH. AUREUS, VRSA - USA (NEW YORK)
************************************
A ProMED-mail post
<http://www.promedmail.org>
ProMED-mail is a program of the
International Society for Infectious Diseases
<http://www.isid.org>
Date: Thu, 22 Apr 2004
From: ProMED-mail <promed@promedmail.org>
Source: Morb Mortal Wkly Rep 2004; 53: 322-3, 25 Apr [edited]
<http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5315a6.htm>
Vancomycin-resistant _Staphylococcus aureus_ -- New York, 2004
--------------------------------------------------------------
_Staphylococcus aureus_ is a common cause of hospital and community
acquired infections (1,2). The development of vancomycin-resistant
enterococci in 1988 led the way to the emergence of vancomycin-resistant
_S. aureus_ (VRSA) (minimum inhibitory concentration [MIC] >32 microg/mL
[3]), first recognized in 2002
(<http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5126a1.htm> 4-7). This report
describes the 3rd documented clinical isolate of VRSA from a patient in the
United States and provides evidence of failure to detect this VRSA by
commonly used automated antimicrobial susceptibility testing.
On 17 Mar 2004, a urine culture obtained from a resident of a long term
care facility yielded _S. aureus_. The isolate was tested for antimicrobial
susceptibility by using Microscan overnight panels (Dade Behring,
Deerfield, Illinois); vancomycin MIC was 4 microgram (mcg)/mL. Further
testing by Etest (AB Biodisk North America, Inc, Piscataway, New Jersey)
indicated that the isolate was resistant to vancomycin (MIC greater than
256 mcg/mL). After notification and subsequent analysis by the New York
State Department of Health (NYSDOH), the isolate was forwarded to the
Centers for Disease Control and Prevention (CDC), where it was confirmed to
be VRSA (vancomycin MIC = 64 mcg/mL, using the National Committee for
Clinical Laboratory Standards broth microdilution reference method). The
isolate contained both the mecA and vanA genes mediating oxacillin and
vancomycin resistance, respectively. The isolate was susceptible to
chloramphenicol, linezolid, minocycline, quinupristin-dalfopristin,
rifampin, and trimethoprim-sulfamethoxazole.
The patient remains in a long term care facility, and NYSDOH is
investigating the case. The goals of the investigation include assessment
of infection control practices and whether transmission to other patients,
health care providers, family, and other contacts has occurred. Previous
investigations of VRSA demonstrated no transmission among contacts
(<http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5140a3.htm> 5,6). This VRSA
isolate appears to be unrelated epidemiologically to the VRSA isolate
identified previously in Michigan and Pennsylvania
(<http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5140a3.htm> 5,6).
Although the New York isolate contained the vanA resistance gene, the
vancomycin MIC of the isolate appeared low when tested initially by an
automated method. Additional testing at CDC indicated that Microscan and
Vitek (bioMerieux, Hazelwood, Missouri) testing panels and cards available
in the US did not detect vancomycin resistance in this VRSA isolate.
Consequently, additional VRSA infections might have occurred but were
undetected by laboratories using automated methods. Potential VRSA isolates
should be saved for confirmatory testing, and clinical microbiology
laboratories must ensure that they are using susceptibility testing methods
that will detect VRSA. The most accurate form of vancomycin susceptibility
testing for staphylococci is a nonautomated MIC method (for example, broth
microdilution, agar dilution, or agar-gradient diffusion) in which the
organisms are incubated for a full 24 hours before reading results.
Therefore, when performing automated susceptibility testing of _S. aureus_
strains, particularly methicillin resistant _S. aureus_, laboratories
should include a vancomycin-agar screening plate containing 6 microg/mL of
vancomycin and examine the plate for growth after 24 hour incubation.
The public health response to identification of this VRSA infection is
ongoing. Use of proper infection control practices and appropriate
antimicrobial agent management can help limit the emergence and spread of
antimicrobial resistant microorganisms, including VRSA. CDC recommends
contact precautions when caring for patients with these infections,
including 1) placing the patient in a private room; 2) wearing gloves and a
gown during patient contact; 3) washing hands after contact with the
patient, infectious body tissues, or fluids; and 4) limiting the use of
patient-care items to individual patients. In addition, the number of
people caring for a patient with VRSA or vancomycin-intermediate _S.
aureus_ should be minimized (for example, by assigning dedicated staff to
care for the patient). Isolation of _S. aureus_ with confirmed or
presumptive vancomycin resistance should be reported immediately through
state and local health departments to the Division of Healthcare Quality
Promotion, National Center for Infectious Diseases, CDC, telephone
800-893-0485.
Reported by: M Kacica, MD, New York State Dept of Health. LC McDonald, MD,
Div of Healthcare Quality Promotion, National Center for Infectious
Diseases, CDC. Acknowledgments: This report is based in part on
contributions by C Scott, DJ Bopp, MS, NB Dumas, G Johnson, DJ
Kohlerschmidt, P Kurpiel, RJ Limberger, PhD, KA Musser, PhD, B Wallace, MD,
P Smith, MD, New York State Dept of Health.
References
1. CDC. National Nosocomial Infections Surveillance (NNIS) report, data
summary from January 1992--June 2001. Am J Infect Control 2001; 29: 404-21.
2. Lowy F. Staphylococcus aureus infections. N Engl J Med 1998; 339: 520-32.
3. National Committee for Clinical Laboratory Standards. Methods for
dilution antimicrobial susceptibility tests for bacteria that grow
aerobically, 6th ed. Approved standard, M7-A6. Wayne, Pennsylvania:
National Committee for Laboratory Standards, 2003.
4. CDC. Staphylococcus aureus resistant to vancomycin -- United States,
2002. MMWR 2002; 51: 565-7.
<http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5126a1.htm>
5. CDC. Vancomycin-resistant Staphylococcus aureus -- Pennsylvania, 2002.
MMWR 2002; 51: 902. <http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5140a3.htm>
6.Chang S, Sievert DM, Hageman JC, et al. Infection with
vancomycin-resistant Staphylococcus aureus containing the vanA resistance
gene. N Engl J Med 2003; 348: 1342-7.
7.Whitener CJ, Park SY, Browne FA, et al. Vancomycin-resistant
Staphylococcus aureus in the absence of vancomycin exposure. Clin Infect
Dis 2004; 38: 1049-55.
--
ProMED-mail
<promed@promedmail.org>
[The earlier reports of vancomycin resistance in _S. aureus_ referred
primarily to lower sensitivity to vancomycin rather than, as in this case,
true resistance. The issues regarding detecting the resistance by the
laboratorian are important to keep in mind. - Mod.LL]
[see also:
2002
---
Staph. aureus, VISA -UK-(Scotland) 20021220.6102
Staph. aureus, VRSA - USA (Michigan) 20020704.4665
1999
---
Vancomycin resist. S. aureus - China (Hong Kong) (04) 19991109.2008
1998
---
Staph. aureus, vancomycin resistant - USA (02) 19970829.1833
Staph. aureus, reduced susceptibility to Vancomycin - USA 19970826.1788]
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