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!style="text-align:left;"|Solubility
|0.225 gmg/L <ref name="[1]" /> in water
|-
!style="text-align:left;"|Half life
=== History ===
In the 1950s, only few options were available for the treatment of penicillin-resistant staphylococcal infections. To remedy this, Eli Lilly and Company started a program with the aim of discovering new antibiotics. Eventually vancomycin, first called compound 05865, was discovered in 1952 in a soil sample from the jungles in Borneo. The discovery was made by E.C. Kornfield, an organic chemist who worked at Eli Lilly <ref name="[4]">Flynn Pharma LTD (2013). ''A short history of vancomycin.''</ref><ref name="[5]">Levine, D.P. (2006). Vancomycin: A History. ''Clinical Infectious Diseases, 42''(1), 5-12. [https://doi.org/10.1086/491709 doi:10.1086/491709]</ref>.
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="[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 the drug became available <ref name="[4]" /><ref name="[5]" />.
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 µgmg/mLL, into a homogenous colony with a MIC of 8 µgmg/mLL. 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="[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 µgmg/mL L 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 µgmg/mL L 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 µgmg/mL L <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" style="margin-bottom:0"
!Target group
!Loading Dose
|-
!Patients with deep-seated infections
|20 – 25 mg / kg|15 – 20 µgmg/mLL
|-
!Patients without severe infections
| -
|10 – 15 µgmg/mLL|}<div style="margin-bottom:1em"><sub>''Table 1. Vancomycin dosing for different classes of patients with normal renal function <ref name="[17]" />.''</sub></div>
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]" />.
== 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>.
== State of the Art ==
The SensUs competition wants to stimulate the development of molecular biosensing devices, which are small devices that can be used at the bedside of patients or even at home. Currently no handheld or table-top point-of-care devices for detecting vancomycin are available on the market. The devices listed below in Table 2 are all large instruments which can only be found in laboratory environments.
{| class="wikitable" style="margin-bottom:0"
!Company
!Product
!Test name
!Sample Volume
!Reportable range
!Precision
!Time to Result
|-
|Abbott
|Architect <ref name="[24]">iVancomycin Architect System (2008). Leaflet ''iVancomycin''. Abbott.</ref>
|iVancomycin
|20 μL
|3 - 100 mg/L
|CV <10%
|16 min.
|-
|Roche
|Cobas c311/511 <ref name="[25]">Cobas Vancomycin Generation 3 (2016). Leaflet ''19 Vancomycin Cobas''. Roche Diagnostics.</ref>
|VANC3
|2 μL
|4 - 80 mg/L
|CV <11%
|10 min.
|-
|Beckman Coulter
|AU480 <ref name="[26]">Emit 2000 Vancomycin Assay (2010). Leaflet ''Emit 2000 Vancomycin Assay''. Beckman Coulter.</ref>
|Emit ® 2000 Vancomycin Assay
|2.4 μL
|2 - 50 mg/L
|CV <5%
|8-9 min.
|}<div style="margin-bottom:1em"><sub>''Table 2: Selection of currently available systems for measuring vancomycin.''</sub></div>
All products in Table 2 make use of enzyme immunoassays to detect vancomycin in blood plasma or serum, these are explained in more detail in the next section. Almost all plasma stabilising anticoagulants are compatible with the assays - EDTA K2 or K3, Li -heparin, etc. - as vancomycin does not react with any of these reagents <ref name="[24]" /><ref name="[25]" /><ref name="[26]" />.
The cost of running a single vancomycin assay on the Abbott Architect is €3.50 <ref name="[24]" /><ref name=”[40]”>This list price was received by email from Abbott, The Netherlands.</ref>.
== Past, Present and Future Sensing Methods ==
The first immunoassays were developed back in 1950s. These were radioimmunoassays (RIAs) which made use of radioactive labels to measure the concentration of an analyte in a sample <ref name="[27]">Wu, A.H.B. (2006). A selected history and future of immunoassay development and applications in clinical chemistry. ''Clinica chimica acta, 369''(2), 119-124. [https://doi.org/10.1016/j.cca.2006.02.045 doi:10.1016/j.cca.2006.02.045]</ref>. Due to the inherent difficulties of working with radioactive materials, RIAs have since been largely replaced by other methods, e.g. enzyme immunoassays (EIAs) <ref name="[27]" /><ref name="[28]">Abbott (2008). ''Learning Guide Immunoassay.'' Abbott Laboratories.</ref>. Immunoassays (IAs) can be split into two broad categories, homogeneous and heterogeneous <ref name="[29]">Engvall, E. (1980). Enzyme immunoassay ELISA and EMIT. ''Methods in Enzymology, 70'', 419-439. [https://doi.org/10.1016/S0076-6879(80)70067-8 doi:10.1016/S0076-6879(80)70067-8]</ref>. Homogeneous IAs allow for measuring the extent of a reaction in a solution containing both the free and antibody-bound components, while heterogeneous IAs require that the two be separated prior to measuring <ref name="[30]">Jenkins, S.H. (1992). Homogeneous enzyme immunoassay. ''Journal of Immunological Methods, 150''(1-2), 91-97. [https://doi.org/10.1016/0022-1759(92)90067-4 doi:10.1016/0022-1759(92)90067-4]</ref><ref name="[31]">Khanna, P. (1991). Homogeneous enzyme immunoassay. In: Prince, C.P., Newman, D.J. ''Principles and Practice of Immunoassay'' (326-364). London: Palgrave Macmillan. [https://doi.org/10.1007/978-1-349-11234-0_12 doi:10.1007/978-1-349-11234-0_12]</ref>. Homogeneous assays are typically faster and easier to automate but less sensitive than heterogeneous assays<ref name="[30]" /><ref name="[31]" />.
The Roche cobas c311/511 has several different tests, immunoassays, for measuring vancomycin in a sample. These include an immunoassay based on the kinetic interaction of microparticles in solution (KIMS) and a homogeneous enzyme immunoassay called EMIT (Enzyme Multiplied Immunoassay Technique) which can also found on the Beckman Coulter AU480. The EMIT assay is based on competition between free vancomycin molecules in the sample and vancomycin-enzyme conjugates for antibody binding sites. The enzyme used to label vancomycin is glucose-6-phosphate dehydrogenase (G6PDH). It turns NAD<sup>+</sup> into NADH in its active state, but becomes inactive when bound to an antibody. In this way the presence of vancomycin in a sample can be determined based on enzyme activity. There is a direct relationship between the amount of vancomycin in a sample and the buildup of NADH, which causes an absorbance change that can be measured spectrophotometrically <ref name="[4]" /><ref name="[25]" /><ref name="[32]">Roche Diagnostics (2011). ''Therapeutic drug monitoring. Contributing to better patient Care.''</ref>.
The Abbott architect makes use of a heterogenous EIA called CMIA (Chemiluminescent Microparticle Immunoassay), which is a modified form of the well known ELISA (enzyme-linked immunosorbent assay) <ref name="[33]">Ilyas, M. & Ahmad, I. (2014). Chemiluminescent microparticle immunoassay based detection and prevalence of HCV infection in district Peshawar Pakistan. ''Virology Journal, 11''. [https://doi.org/10.1186/1743-422X-11-127 doi:10.1186/1743-422X-11-127]</ref>. The CMIA for vancomycin is based on competition between free vancomycin in the sample and an acridinium-labeled vancomycin conjugate. They compete for the binding sites on anti-vancomycin antibody coated paramagnetic microparticles during the incubation step. After this step the reaction mixture is washed to get rid of any unbound acridinium-labeled vancomycin, and pre-trigger and trigger solutions are added to cause a chemiluminescent reaction with the bound acridinium-labeled vancomycin. An indirect relationship exists between the amount of vancomycin in the sample and the units of light detected by the Abbott Architect <ref name="[2]" /><ref name="[28]" />.
The trend we are currently seeing in all areas of healthcare is to move away from large institutions such as hospitals, and into a world of more decentralized healthcare. This requires the development of small, portable, easy-to-use and inexpensive point-of-care testing (POCT) devices, which will complement services from centralized laboratories. The first generation of such POCT devices is already on the market for a limited number of biomarkers, such as the Abbott i-Stat <ref name="[34]">i-STAT HANDHELD (2017). Abbott Point of Care. Assessed on 19 December 2017, at ''https://www.pointofcare.abbott/int/en/offerings/istat/istat-handheld''.</ref> and Roche Cobas h252 <ref name="[35]">Roche (2017). Cobas h 252 POC system. Assessed on 19 December 2017, at ''http://www.cobas.com/home/product/point-of-care-testing/cobas-h-232.html''.</ref>. However, none of these is presently able to measure vancomycin.
Several avenues for improving biosensing devices further are currently being explored in research. For example, researchers are exploring if smartphones can be used as readout instruments, since smartphone cameras are now sensitive enough to measure the light given off by a biosensing assay <ref name="[38]">Herberman, R.B. (1983). Natural killer cells and tumor immunity. ''Survey of Immunologic Research, 2''(3), 306-308.</ref><ref name="[39]">Fu, Q., Wu, Z., Xu, F., Li, X., Yao, C. Xu, M., Sheng, L., Yu, S., Tang, Y. (2016). A portable smart phone-based plasmonic nanosensor readout platform that measures transmitted light intensities of nanosubstrates using an ambient light sensor. ''Lab on a Chip, 16''(10), 1927-33. [https://doi.org/10.1039/C6LC00083E doi:10.1039/C6LC00083E]</ref>. Furthermore research is being done on methods to measure analytes directly in the skin, so that blood sampling will not be necessary anymore. Commercial devices are already available for measuring glucose in the skin (CGM = continuous glucose monitoring), but such devices are not yet available for other substances such as antibiotic drugs. Research is being done on novel sampling methods, e.g. the use of microneedles to detect biomarkers in dermal interstitial fluid in extremely small (<1nL) volumes <ref name="[36]">Ito, Y., Inagaki, Y., Kobuchi, S., Takada, K., Sakaeda, T. (2016). Therapeutic Drug Monitoring of Vancomycin in Dermal Interstitial Fluid Using Dissolving Microneedles. ''International Journal of Medical Sciences, 13''(4), 271-276. [https://doi.org/10.7150/ijms.13601 doi:10.7150/ijms.13601]</ref><ref name="[37]">Ranamukhaarachchi, S.A., Padeste, C., Dübner, M., Häfeli, U.O., Stoeber, B., Cadarso, V.J. (2016). Integrated hollow microneedle-optofluidic biosensor for therapeutic drug monitoring in sub-nanoliter volumes. ''Scientific Reports, 6''. [https://doi.org/10.1038/srep29075 doi:10.1038/srep29075]</ref>.
== References ==
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