Vancomycin toxicity

Introduction:
Vancomycin is an example of a glycopeptide antibiotic. It works as an antibiotic by inhibiting cell wall synthesis via the mechanism of peptidoglycan inhibition. Peptidoglycan is a key component of the bacterial cell wall and without it, the cell wall is not able to function and lyses; therefore vancomycin is classed as bactericidal. Vancomycin prevents the transglycolysation step in the polymerization of peptidoglycan. In normal peptidoglycan there are two repeating carbohydrate units called NAG (N-acetylglucosamine) and NAM (N-acetylmuramic acid). Transpeptidase is an enzyme that cross links the short peptide chains that are found on NAM to link the NAM/NAG residues; this cross linking process is a process that strengthens peptidoglycan and hence the cell wall of the bacteria. The mechanism of action of vancomycin disrupts this transpeptidisation; this means that the peptidoglycan monomers cannot polymerise and make the long chains required for the formation of the bacterial cell wall. Vancomycin binds specifically to the terminal D-Alanyl-D-Alanine motif on the terminal pentapeptides of the NAG/NAM peptides through forming 5 hydrogen bonds hence blocking the transpeptidase enzyme binding and cross linking adjacent peptides. This disruption of the cell wall polymerisation halts the formation of a fully functional bacterial cell wall which is vital in a living bacteria.

vancomycin.jpg

Here is an animation showing how vancomycin disrupts the cell wall synthesis:

Adpated from:
http://pharmacologycorner.com/vancomycin-mechanism-action-animation/

Because of it's mechanism of action, vancomycin is only effective against Gram positive bacteria; the vancomycin structure means that it is too large to penetrate Gram negative bacteria. Because of it's large side effect profile, use of vancomycin is restricted to bacteria that are resistant or hypersensitive to β-lactam antibiotics which are the usual front line treatment for such bacterial infections. It is also the anti-bacterial of choice in treating resistant Staphyloccus aureus infections such as methicillin resistant Staphyloccus aureus (MRSA), though there are more synthetic theraupeutics emerging for the treatment of MRSA with smaller side effect profiles.
Vancomycin is administered usually intravenously over a long infusion except in the case of treating a gastrointestinal infection of Clostridium difficile when it is administered orally.
As previously mentioned, the use of vancomycin is restricted because of the side effects profile and as it is one of the last line treatments available in the management of MRSA. Though some resistant strains have been found, new antibiotics such as linezolid (a synthetic antibiotic) and Quinupristin/dalfopristin (a combination therapy involving two seperate antibiotics, both strepogramin antibiotics) are being used because resistance issues with them have not arisen to date. Some of the side effects that are associated with vancomycin include nephrotoxicity and ototoxicity and with regards the skin several adverse effects have been recorded and they will now be discussed in a little more detail....

Skin Toxicity

Red Man Syndrome (RMS):

Because of the increasing incidence of MRSA, there is also an increase in the use of vancomycin and the most common hypersensitivity reaction that is associated with intravenous administration of the drug is RMS (sometimes also known as Red Neck Syndrome). RMS is associated with pruritis(itching) and erythema(redness) of the face, neck and torso (usually upper torso but can spread). This cause of RMS is thought to be partially due to histamine release and is most commonly found in patients in which the vancomycin dose was infused in less than 1 hour. Slow infusion of the drug is crucial in preventing many of the skin related toxic side effects related to the drug though cases of RMS have also been reported from infusions of the drug that were taken over a long period of time which is recommended for minimization and even elimination of these side effects. Less frequent side effects associated with RMS are severe hypotension and another adverse skin reaction, angiodema. Angiodema is a subcutaneous swelling that can be likened to hives but underneath the skin rather than on it; the cause of angiodema is unknown but it is thought to be mediated by histamine release and other chemical mediators.

The main symptoms of RMS, like the rare angiodema side effect, are caused by histamine release. This is not an IgE induced allergic reaction though, the histamine release is mediated solely through direct interaction with vancomycin or products of vancomycin metabolism within the body. The symptoms of RMS usually appear in the patient 4-10 minutes after the slow infusion has begun but can appear even after the infusion has ended.
The drug induced histamine release is mediated via an increase in IP3 (inositol triphosphate) and hence release of intracellular calcium in mast cells and basophils. When IP3 binds to the IP3 receptor, a calcium channel, and activate it, there is a huge influx of intracellular calcium to mast cells and basophils that contain histamine. The influx of calcium causes the release of the histamine; this causes the erythema and pruritis associated with RMS. The increase in IP3 that is documented through experimentation and research is directly linked to the vancomycin and is thought to be the mechanism through which RMS is related to vancomycin administration.
Anti-histamines can be used prophylactically and after the RMS has come to light to combat RMS symptoms and side effects and in extreme cases desensitization would be used as a method of overcoming the condition. Desensitization is a way of overcoming an allergic reaction to a particular substance by first administering a small dose and then gradually increasing the dose to a comfortable level so the reaction will no longer be an issue.

Erythema of the face:
erythema.jpg



Phlebitis:

Phlebitis is described as an inflammation of a vein that is usually caused by drug administration. Phlebitis has been observed in patients administered with vancomycin and it is thought to occur because of the low pH of the drug. Vancomycin is known to have a pH of between 2.8 and 4.5 making it extremely acidic. The interaction of the acidic therapeutic causes a direct irritation to the vascular wall and hence an immune response is mounted via histamine release from mast cells. The blood neutralises the vancomycin but phlebitis becomes a problem when it comes in contact with the vascular walls directly. Symptoms of the condition are similar to those that are experienced for RMS, erythema and pruritis, but much less severe; erythema and inflammation are generally experienced at the site of injection of the vancomycin. NSAIDs are recommended for treatment of the swelling and pain of the condition.

Toxic Epidermal Necrosis (TEN):

Necrosis is defined as the premature death of a living body tissue. Toxic epidermal necrosis is a very rare and dangerous condition in which is differentiated to skin necrosis by the fact that it is just not skin dying, in this condition the dermal and epidermal layers become detached from one another; also this condition is not localised to the site of injection, it occurs all over the body. The condition is rare but is induced by reaction to medications such as sulfonamides and cephlasporins and though rare, this form of skin toxicity has been observed after vancomycin administration; it has also been reported that cases of TEN have been caused by viral infections and Mycoplasma pneunomia. Although TEN affects most of the body, the mucous membranes are worst hit so the mouth, eyes and genital areas are the most gravely affected when suffering with the condition. Though rare, TEN is an extremely serious and life-threatening disease state and it has a very high mortality rate, between 25-35%, and this figure increases in the elderly and those who have a significant area of their body affected by the epidermal detachment. Many people that are affected by TEN and survive must live with the repercussions of the condition. Sequelae (a pathological condition coming about as a results of a disease state) that are associated with TEN are most commonly affiliated with the eye and the changes that are observed in the conjunctival epithelium and in the worse case of events can lead to blindness.

Keratinocytes are the most predominant cell type in the epidermis and in TEN (and Steven Johnson syndrome (SJS)- a less severe condition similar to TEN) programmed cell death (apoptosis) of keratinocytes followed by necrosis is thought to cause of the epidermal detachment in TEN. Pathological analysis of the blistering fluid in the early stage of the condition shows that cytotoxic T-lymphocytes and CD8+ T-lymphocytes are the most predominant cell types found in the fluid and this would assume that MHC1 that is activated by the drug in question initiates expansion of these immune cells and hence the initiation of the immune response. There is also evidence to suggest that granzyme B has a role in initiating the apoptosis of the keratinoctyes. Granzyme is a protease that is released from granules within cytotoxic T-cells and natural killer cells. There is evidence to suggest that granzyme B has some of the cytotoxic activity in the skin that causes the immune reaction and subsequent necrosis but like all of the suggested mechanisms for TEN, nothing has been concretely set down as a full mechanism of action for the condition.

Because the mechanism of TEN is unknown, many pathways are explored and examined for their possible role in the condition in order to maximise knowledge for treatment and analysis. Another ligand that is indicated in the disease for it's possible role in initiating necrosis is the FAS ligand (fasL), a member the tumousr necrosis factor (TNF) family. It is an important protein that is associated with the immune system and binding of the ligand to the appropriate receptor activates necrosis. Elevated levels of the fasL are consistently found in samples of skin that are taken pre-detachment which could signal for their inclusion in a possible cause of condition.
Though it is not classed as a drug that is of high risk of causing TEN, cases of probable vancomycin induced TEN have been reported so it's inclusion as a possible side effect and possible type of toxicity cannot be ignored.

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Blistering commonly is an early sign of TEN




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Mucous membranes, like the mouth are regularly the worst affected in TEN





TEN_icky.jpg
Detachment of the dermal and the epidermal layers of the skin





Conclusion:

It is clear to see that there are multiple possible adverse skin toxicity reactions that are possible side effects when vancomycin is administered to a patient. These reactions would be amplified in patients that are immunosuppressed and especially in patients that have limited renal function. Risk of mortality in such toxic reactions, especially in the case in TEN, is increased in the case of patients that are suffering from other serious conditions and illnesses. Though the mechanisms of some of the toxicity reactions are still unknown, on the most part, treatment of this reactions is generally considerably easier and improves greatly after withdrawal of the vancomycin as a therapeutic.

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References:

Introduction:
Information:
Image:
Adapted from:
Amination:

Skin Toxicity:
Red Man Syndrome (RMS):
  • Vancomycin-Induced Histamine Release and Red Man Syndrome: Comparison of 1- and 2-Hour Infusion. Daniel P. Healy, Jan V. Sahai, Stephen H. Fuller and Ronald E.Polk. Antimicrobial Agents and Chemotherapy April 1990.
  • http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001849/
  • Mechanisms of vancomycin-induced histamine release from rat peritoneal mast cells. Yasufumi Horinouchi, Kihachiro Abe, Keiji Kubo and Masuichiro Oka. Inflammation Research. Volume 40.
  • Severe local vancomycin induced skin necrosis. Diane W. M. Hoelen, David H. T. Tjan, Roel van Vugt, Y. Geert van der Meer and Arthur R. H. van Zanten. British Journal of Clinical Pharmacology 2007
  • Red Man Syndrome. Soupramanien Sivagnanam and Dirk Deleu. Critical Care Journal

Phlebitis:


Toxic Epidermal Necrolysis:
  • The Current Understanding of Steven-Johnson Syndrome and Toxic Epidermal Necrolysis. Dr. Maja Mockenhaupt. Medscape Education. Link: http://www.medscape.org/viewarticle/751622_4
  • Toxic Epidermal Necrolysis and Stevens-Johnson Syndrome. Thomas Harr and Lars E. French. Orphanet Journal of Rare Diseases 2010
  • Probable vancomycin associated toxic epidermal necrolysis. Craycraft ME, Arunakul VL, Humeniek JM. Journal of Pharmacotherapy.
  • Pharmacology. 5th edition. Rang, Dale, Ritter and Moore.