535
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Sections 1-4 as of January 7, 2018.
Vancomycin, derived from the word “to vanquish", proved to be effective against most types of gram-positive bacteria <ref name="[5]" />. The FDA approved the drug in 1958 <ref name="[4]" />, despite concerns about possible toxicity and the fact that impurities in the drug caused red man syndrome - a hypersensitivity reaction resulting in red flushing and erythematous rashes on the face, neck and torso of patients <ref name= Mechanism "[6]">Sivagnanam, S. & Deleu, D. (2003). Red man syndrome. ''Critical Care, 7''(2), 119-120. [https://doi.org/10.1186/cc1871 doi:10.1186/cc1871]</ref>. Eli Lilly marketed vancomycin hydrochloride under the name Vancocin, until the patent ran out in the early 80s at which point generic versions of Action the drug became available <ref name="[4]" /><ref name="[5]" />.
== Mechanism of action and antimicrobial resistance == === Mechanism of action === Vancomycin kills and prevents the growth of gram-positive bacteria by inhibiting their cell wall synthesis <ref name="[9]" />. The cell walls of gram-positive bacteria are comprised of several layers of peptidoglycan, a mesh-like polymer consisting of sugars and amino acids. This layer provides mechanical support so that these bacteria can withstand osmotic pressures as large as 5-15 atm without lysing (rupturing) <ref name="[10]">Kahne, D., Leimkuhler, C., Lu, W., Walsh, C. (2005). Glycopeptide and Lipoglycopeptide Antibiotics. ''Chemical Reviews, 105''(2), 425-448. [https://doi.org/10.1021/cr030103a doi:10.1021/cr030103a]</ref>. A single peptidoglycan layer consists of many crosslinked glycan chains. A glycan chain is made up of repeating units of covalently bonded N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM) monomers joined together through transglycosylation. The newly elongated chains are mechanically weak until the pentapeptide chains on the NAM molecules are crosslinked. Crosslinking is effectuated by a family of transpeptidases, which use the amide group of the Lys<sub>3</sub> on one strand to attack the D-Ala<sub>4</sub> on the other strand, liberating a D-Ala<sub>5</sub> residue, and forming a Lys<sub>3</sub>-D-Ala<sub>4</sub> interstrand isopeptide bond which acts as a strengthening covalent cross-link between the two strands <ref name="[10]" />. Vancomycin belongs to a class of antibiotics which interferes in both the polymerization and the cross linking of glycan strands. It does this by binding firmly to the substrate of the transpeptidation enzymes, the D-Ala<sub>4</sub>-D-Ala<sub>5</sub> dipeptide, by means of five hydrogen bonds with its peptide backbone <ref name="[9]" /><ref name="[11]">Van Bambeke, F., Van Laethem, Y., Courvalin, P., Tulkens, P.M. (2004). Glycopeptide Antibiotics: from Conventional Molecules to New Derivatives. ''Drugs, 64''(9), 913-936. [https://doi.org/10.2165/00003495-200464090-00001 doi:10.2165/00003495-200464090-00001]</ref>. The formation of this complex prevents both transglycosylation and transpeptidation via steric hindrance <ref name="[11]" />. The two final two steps of bacterial peptidoglycan biosynthesis constitute a good target for any antimicrobial agent, as both processes are extracellular and thus accessible to compounds that are unable to penetrate the cell membrane. Furthermore, the peptidoglycan layer is vital enough to so important for survival that it is highly conserved across organisms, meaning that compounds such as vancomycin are effective against a large variety of gram-positive bacteria. Lastly, targeting a process that involves multiple, related enzymes, is advantageous as a single, spontaneous mutation in one enzyme will not lead to resistance<ref name="[10]" />. === Resistance to Vancomycin === Resistance to vancomycin and other GPAs (glycopeptide antibiotics) took over three decades to develop <ref name="[10]" /><ref name="[7]" />. This exceptionally large delay between introduction into the clinic and the emergence of resistance, is due in part to the relatively low clinical use of vancomycin during the period following its introduction <ref name="[7]" />. Indeed, once the first large outbreaks of β-lactam resistant strains of bacteria such as MRSA appeared in the 80s - causing a marked increase in vancomycin usage - vancomycin resistant bacterial strains quickly appeared as well <ref name="[10]" /><ref name="[7]" />. Two distinct forms of vancomycin resistance exist. The milder form of vancomycin resistance, exhibited for example by VISA (vancomycin intermediate staphylococcus aureus) strains, develops in patients undergoing prolonged vancomycin therapy. The prolonged exposure to vancomycin puts selective pressure on the pathogens. The treatment turns a heterogenous colony of bacteria with only a small subpopulation having a vancomycin MIC (minimum inhibitory concentration) greater than 2 µg/mL, into a homogenous colony with a MIC of 8 µg/mL. The resulting colony becomes very difficult to eradicate with vancomycin therapy <ref name="[12]">Gardete, S. & Tomasz, A. (2014). Mechanisms of vancomycin resistance in Staphylococcus aureus. ''The Journal of Clinical investigation, 124''(7), 2836-2840. [https://doi.org/10.1172/JCI68834 doi:10.1172/JCI68834]</ref>. The second, more serious form of vancomycin resistance, demonstrated by bacterial strains such as VRSA (vancomycin resistant staphylococcus aureus), is not due to spontaneous mutations of pathogens upon continued exposure to the drug <ref name="[10]" />.Instead, pathogenic microorganisms appear have directly copied the defense mechanisms of the antibiotic producing actinomycetes. This defense mechanism is used by the actinomycetes to avoid suicide during antibiotic production <ref name="[10]" /><ref name="[7]" /><ref name="Kahne[14]">Binda, E., Marinelli, F., Marcone, G.L. (2014). Old and New Glycopeptide Antibiotics: Action and Resistance. ''Antibiotics, 3''(4), 572-594. [https://doi.org/10.3390/antibiotics3040572 doi:10.3390/antibiotics3040572]</ref>. Pathogens resistant to GPAs obtain resistance through plasmid-borne copies of transposons coding for genes named ''van'', which reprogram the biosynthesis of cell walls, replacing the D-Ala-D-Ala peptide terminus with a D-alanyl-D-lactate (D-Ala-D-Lac) terminus <ref name="[14]" /><ref name="[10]" /><ref name="[13]">Miller, W.R., Munita, J.M., Arias, C.A. (2014). Mechanisms of antibiotic resistance in enterococci. ''Expert Review of Anti-Infective Therapy, 12''(10), 1221-1236. [https://doi.org/10.1586/14787210.2014.956092 doi:10.1586/14787210.2014.956092]</ref>. This small change reduces the binding affinity of vancomycin to the target around a 1000-fold, resulting in a vancomycin MIC ≥ 100 µg/mL making treatment with vancomycin impossible and effectively rendering the organism resistant <ref name="[10]" /><ref name="[7]" /><ref name="[13]" />. == Medical Use and TDM == Vancomycin is a glycopeptide antibiotic used as a last resort to treat severe, life-threatening infections caused by multidrug-resistant gram-positive bacteria, such as methicillin-resistant ''Staphylococcus aureus'' (MRSA) <ref name="[14]" />. Vancomycin can be administered intravenously or orally. When taken orally, vancomycin is absorbed very poorly into the bloodstream <ref name="[3]" />. Therefore, oral intake is only used for infections within the gastrointestinal tract, such as diarrhea caused by ''Clostridium difficile'', and to treat enterocolitis caused by certain types of bacteria <ref name="[15]">PubMed Health (2017). Vancomycin (By mouth). Accessed on 17 October 2017, at ''https://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0012602/?report=details''.</ref>. In all other cases vancomycin is administered intravenously <ref name="[16]">PubMed Health (2017). Vancomycin (By injection). Accessed on 17 October 2017, at ''https://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0012603/?report=details''.</ref>. Care must be taken to not administer the drug too fast, as this may lead to the patient developing red man syndrome <ref name="[6]" />. Most hospital protocols recommended a minimum vancomycin infusion time of 60 minutes <ref name="[6]" />. For patients with severe, deep-seated infections (including but not limited to meningitis, pneumonia osteomyelitis, endocarditis, bacteremia and prosthetic joint infection) a serum trough concentration of 15 to 20 µg/mL is recommended <ref name="[17]">Consgrove, S.E., Avdic, E., Dzintars, K. & Smith, J. (2015). Antibiotic Guide. ''Johns Hopkins Medicine, The Johns Hopkins Hospital Antimicrobial Stewardship Program.''</ref><ref name="[18]">Drew, R.H. & Sakoulas, G. (2017). Vancomycin: Parenteral dosing, monitoring, and adverse effects in adults. Accessed on 26 September 2017, at ''https://www.uptodate.com/contents/vancomycin-parenteral-dosing-monitoring-and-adverse-effects-in-adults.''</ref>. To achieve this concentration more rapidly an initial loading dose of 20-25 mg/kg is often given, followed by intermittent maintenance dosing of typically around 15-20 mg/kg every 8 to 12 hours <ref name="[17]" />. Patients with less severe infections (soft tissue infections) do not require a loading dose, and are started immediately on intermittent dosing with the aim of achieving a minimum serum trough concentration of 10-15 µg/mL <ref name="[18]" />. Trough concentrations are measured as these constitute the most practical and accurate indicator for treatment effectiveness and toxicity. Peak levels are rarely measured and are not clinically relevant <ref name="[17]" />. {| class="wikitable"!Target group!Loading Dose!Target Trough Concentration|-!Patients with deep-seated infections|20 – 25 mg / kg|15 – 20 µg/mL|-!Patients without severe infections| -|10 – 15 µg/mL|}<sub>''Table 1. Vancomycin dosing for different classes of patients with normal renal function <ref name="[17]" />.''</sub> There is large interpatient variability in vancomycin pharmacokinetics <ref name="[19]">Carter, B.L., Damer, M.K., Walroth, T.A., Buening, N.R., Foster, D.R. (2015). A systematic Review of Vancomycin Dosing and Monitoring in Burn Patients. ''Journal of Burn Care & Research, 36'', 641-650. [https://doi.org/10.1097/BCR.0000000000000191 doi:10.1097/BCR.0000000000000191]</ref>. The rate of clearance of vancomycin depends on the following factors; pathogen susceptibility to the drug, disease severity, the site of the infection, patient weight, age, gender and renal function <ref name="[18]" />. As vancomycin is largely cleared through the kidneys, the effect of renal function is especially great. Groups of patients demonstrating rapid clearance, such as young children with naturally high renal function and burn patients, require significantly more frequent dosing than patients with normal renal function to achieve the same target trough concentrations <ref name="[17]" /><ref name="[18]" /><ref name="[19]" />. In contrast, patients with impaired renal function may require dose reductions or extended dosing intervals in order to stay within the therapeutic range <ref name="[17]" /><ref name="[18]" />. For optimal treatment it is essential that every patient receives the correct dose. If the concentration of vancomycin in the body is too low, the treatment is ineffective and the chance that bacteria develop resistance to vancomycin increases <ref name="[12]" /><ref name="[20]">Abdul-Aziz, M.H., Lipman, J., Mouton, J.W., Hope, W.W., Roberts, J.A. (2015). Applying Pharmacokinetic/Pharmacodynamic Principles in Critically Ill Patients: Optimizing Efficacy and Reducing Resistance Development. ''Seminars in Respiratory and Critical Care Medicine, 36''(1), 136-53. [https://doi.org/10.1055/s-0034-1398490 doi:10.1055/s-0034-1398490]</ref>. A concentration of vancomycin that is too high, has been linked to nephrotoxicity and ototoxicity <ref name="[17]" />. Correct dosing of vancomycin is difficult due to the drug’s marked pharmacokinetic variability. Therapeutic drug monitoring (TDM) is the practice of measuring the concentration of a specific drug in the bloodstream at designated time intervals with the aim of using this data to optimize the individual dosing regimens of patients. TDM is of strong help for correctly dosing vancomycin <ref name="[21]">Kang, J.S. & Lee, M.H. (2009). Overview of Therapeutic Drug Monitoring. ''Korean Journal of Internal Medicine, 24''(1), 1-10. [https://doi.org/10.3904/kjim.2009.24.1.1 doi:10.3904/kjim.2009.24.1.1]</ref>. Currently, hospital protocols recommend once-weekly monitoring of vancomycin levels for patients with stable renal function, and more frequent monitoring for those with changing renal function or those who are hemodynamically unstable <ref name="[17]" />. The introduction of a biosensor for vancomycin would allow for more frequent monitoring and TDM for all patients which would contribute strongly to patient health and recovery. == Lab Protocols == Vancomycin hydrochloride may cause skin irritation, breathing difficulties and can be harmful if ingested. Protective eyewear, clothing and gloves have to be worn when working with the compound, and inhaling the dust/fumes/vapours/sprays of the compound is to be avoided <ref name="[22]">Cayman Chemical (2014). Safety Data Sheet Vancomycin Hydrochloride.</ref>. Dry vancomycin hydrochloride powder should be stored at 20-25°C in order to be kept in optimal condition <ref name="[3]" />. Vancomycin hydrochloride dissolved in human blood plasma should be stable for at least six months when stored at -80°C. Stable meaning that the solution loses less than 10% of its initial vancomycin concentration. With the incorporation of up to four freeze-thaw cycles it should be stable for at least four months if kept at -80°C. Vancomycin hydrochloride should furthermore be stable in plasma for at least 24 hours when kept at a temperature of 4°C <ref name="[23]" >Zhang, M., Moore, G.A., Young, S.W. (2014). Determination of Vancomycin in Human Plasma, Bone and Fat by Liquid Chromatography/Tandem Mass Spectrometry. ''Journal of Analytical & Bioanalytical Techniques, 5''(3), 196. [https://doi.org/10.4172/2155-9872.1000196 doi:10.4172/2155-9872.1000196]</ref>.
== References ==
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