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Questions And Answer

• Overview

  Vancomycin is a complex tricyclic glycopeptide antibiotic produced by Streptococcus orientalis^{[1, 2]}. Vancomycin was first discovered from a soil sample in the interior jungle of Borneo in the 1950s, and its usage was very limited due to the presence of impurities that caused toxicities in the earlier preparations. However, the use of vancomycin was reconsidered after the emergence of methicillin-resistant Staphylococci in the 1970s, and its usage increased from the 1980s after purer preparations were made in late 1970s^[3]. Now, vancomycin has become the most common injectable drug of choice to treat methicillin-resistant Staphylococci species and drug resistant Enterococcus species^[4].
  
  Figure 1 The chemical structure of vancomycin
  VCM is generally prescribed to combat severe infections caused by Gram-positive bacteria, to fight microorganisms that are resistant to other antimicrobial agents or still indicated to patients who are allergic to penicillins and cephalosporins^{[1, 5]}. As a consequence, it is very much used in intensive care units (ICU) for the treatment of not only hospital infections and sepsis, but also of pneumonia cases, empyema, endocarditis, osteomyelitis, soft tissue abscesses among others^{[1, 6, 7]}.
  This drug is not the first-choice agent owing to its adverse effects like hypotension and tachycardia, phlebitis, nephrotoxicity, ototoxicity^[7], hypersensibility reactions, chills, exanthema and fever1, and the fact that peripheral IV complications are a major concern^[8]. The literature reveals that the use of inappropriate doses and prolonged therapyes increase the risk of toxicity that, in turn, favors the onset of adverse effects^[9-11]. Therefore, the people who use antibiotics in animals and humans must be vigilant about the adverse. Therefore, the people who use antibiotics in animals and humans must be vigilant about the adverse effects and the proper doses—especially in case of last-line antibiotics such as vancomycin.
  3 doses; however, higher doses may be prescribed1. Although the established pediatric doses vary according to the age range described below^{[1, 3]}, no consensus has been reached regarding the adequate dose of vancomycin for children.;

• Indication and Administration

  Vancomycin is active against most strains of Clostridia, resistant strains), coagulase-negative Staphylococci, and Viridans group Staphylococci and Enterococci. Vancomycin is not effective against Gram-negative bacteria^[12]. Vancomycin is one of the antibiotics of last resort, used only after treatment with other antibiotics has failed in the treatment of life-threatening infections by Gram-positive bacteria. Even though vancomycin has great potential in treating infections in animals, the use of vancomycin in veterinary medicine is limited because it is expensive and requires continuous intravenous infusion^[13]. Powdered vancomycin is reconstituted in sterile water, which results in a dark-colored solution, and it is further diluted in 5% dextrose or saline when it is administered. The reconstituted solution is stable for 14 days either at room temperature or in a refrigerator. Additionally, 125 mg and 250 mg vancomycin tablets are available for oral administration^[14].  ;

• Pharmacodynamic

  The factors that affect the activity of vancomycin are its tissue distribution, its protein-binding, inoculum size, and resistant organisms. The volume of distribution in humans is 0.4–1 L/kg; in dogs, 0.4–5.5 L/kg[15]. The binding of vancomycin to protein has a range from 10% to 50%. A 1–8-fold increase in the minimum inhibitory concentration (MIC) has been shown in several in vitro assessments as a result of the presence of albumin, whereas the presence of serum has had a more variable effect^[16]. It is evident in an in vitro pharmacodynamic model that the time taken to kill is longer when the inoculum size is high (9.5 log10 CFU/g) compared to a moderate inoculum (5.5 log10 CFU/g): 48 versus 72 h, respectively, for both the methicillin sensitive Staphylococci and methicillin-resistant Staphylococci organisms isolated from human patients^[16,17].
  Vancomycin penetrates into most body spaces, and the penetrability is dependent on the degree of inflammation present. The concentration of vancomycin in different body spaces is different^[18]. The inflamed meninges improve the penetration of vancomycin into the cerebral spinal fluid, with reported concentrations of 6.4–11.1 mg/L, whereas uninflamed meninges have resulted in low concentrations of 0–3.45 mg/L in humans^[19]. Furthermore, it has been shown in a rabbit model that a high concentration of vancomycin is present in the cerebral spinal fluid of inflamed meninges^[20]. Therapeutic concentrations of vancomycin in ascitic, pericardial, pleural, and synovial fluids are greater than 2.5 mg/L in humans^[21].
  More than 80% and 50% of a vancomycin dose is excreted unchanged in the urine (mostly by way of glomerular filtration) within 24 h after administration in humans and dogs, respectively, and the concentration of vancomycin in liver tissue and bile is below detectable levels. Vancomycin has a distribution phase of 30 min to 1 h. The half-life of vancomycin in patients with normal creatinine clearance in humans is about 6 h; dogs, 2 h; horses, 3 h^[22]. ;

• Brand Name(s) in US

  Vancocin, Vancoled ;

• Mode of action

  The mechanism of action of this antimicrobial agent is via the inhibition of bacterial cell wall biosynthesis or, more specifically, the inhibition of peptidoglycan biosynthesis. It is, therefore, bactericidal for reproductive bacteria^[1]. The bacterial cell wall contains peptidoglycan that encircles the whole bacteria. In Gram-positive bacteria this substance is more significantly present, and it forms large and insoluble layers on the outer part of the cell membrane, totaling up to 40 layers which consist of multiple skeletons of amino sugars: N-acetylglucosamine and N-acetylmuramic^[24]. The latter contains lateral short peptide residues with cross-links, which form a high-level resistant polymeric chain. The drug inhibits this polymerization or the transglycosylase reaction once it binds with high affinity to the C-terminal D-alanyl D-alanine residues of lipid-linked cell wall precursors and blocks the linkage to the glycopeptide polymer1. As a result, it hinders the cross-links of peptides from binding to tetrapeptide side chains; namely, it prevents its linkage to the growing tip of the peptidoglycan^[24]. ;

• Resistance issue

  Antibiotic use either as therapy, in the prevention of bacterial diseases, or as performance enhancers has resulted in antibiotic-resistant microorganisms in pathogens and among bacteria of the endogenous microflora of animals. Antibiotic-resistant bacteria present in animals can be transmitted to humans via contact or via the food chain. Furthermore, resistance genes of animal bacteria can be transferred to human pathogens in the intestinal flora of humans. The development of intermediate and high levels of resistance to vancomycin for Staphylococcus aureus was reported for the first time in Japan in 1997^[25]. According to guidelines of the Clinical Laboratory Standards Institute, susceptibility break points of vancomycin are <4 mcg/mL for Enterococcus, <1 mcg/mL for Streptococcus, and <4 mcg/mL for Staphylococcus. However, in 2006, the vancomycin MIC breakpoints for S. aureus were lowered to 2 ug/mL for “susceptible”, 4–8 ug/mL for “intermediate”, and 16 ug/mL for “resistant”^[26]. Enterococci should be regularly tested in vitro for susceptibility to vancomycin for determination of MIC. Enterococci are deemed susceptible to vancomycin if MICs are <4 ug/mL; they are considered as intermediate level resistance to vancomycin if MICs are 8 to 16 ug/mL; and as complete resistance to vancomycin if MICs are >16 ug/mL. ;

• Side effects

  Prolonged intravenous use of vancomycin may cause neutropenia, thrombophlebitis, rash, fever, anemia, thrombocytopenia, and ototoxic reactions in humans and animals. Vancomycin should be administered intravenously in diluted form, because it is highly irritable for the tissues. It may cause local phlebitis at the site of injection in animals^[14]. Vancomycin should be infused for over 1h to reduce the risk of the histamine release-associated “red man” syndrome in humans. It is advised not to administer intravenous rapidly, so as to avoid acute adverse reaction in animals^[4]. The major drawback of vancomycin usage is auditory damage in humans; however, tinnitus and deafness might improve once the treatment is ceased. In addition to that, nausea, chills, phlebitis, severe hypotension, wheezing, dyspnoea, urticaria, and pruritus have been observed with the treatment of vancomycin in humans^[27–30]. In some instances, neutropenia was detected with prolonged therapy^[31].
  There is a potential for nephrotoxicity and ototoxicity with vancomycin in animals^[32]. Toxicities are minimal in vancomycin monotherapy at conventional dosages of 1 g (15 mg/kg) every 12 h in humans^[33]. However, increased incidence of nephrotoxicity has been established with doses of 4 g/day or higher. As a result of elevated dosage, serum concentrations may increase, which may lead to toxicity^[34]. Vancomycin increases the risk of nephrotoxicity in humans with drugs such as amphotericin, capreomycin, cyclosporine, cisplatin, colistimethate, polymyxins, and tacrolimus. ;

• References

  1. GUPTA A, BIYANI M, KHAIRA A. Vancomycin nephrotoxicity: myths and facts. Neth J Med 2011; 69: 379-383.
  2. DEHORITY W. Use of vancomycin in pediatrics. Pediatr Infect Dis J 2010; 29: 462-464.
  3. Moellering, R.C., Jr. Vancomycin: A 50-year reassessment. Clin. Infect. Dis. 2006, 42, S3–S4.
  4. Mark, G.P. Saunders Handbook of Veterinary Drugs Small and Large Animal, 3rd ed.; Saunders: Philadelphia, PA, USA, 2011.
  5. HICKS RW, HERNANDEZ J. Perioperative pharmacology: a focus on vancomycin. AORN J 2011; 93: 593-599.
  6. PLAN O, CAMBONIE G, BARBOTTE E, MEYER P, DEVINE C, MILESI C, PIDOUX O, BADR O, PICAUD JC. Arch Dis Child Fetal Neonatal 2008; 93: 418-421.
  7. BADRAN EF, SHAMAYLEH A, IRSHAID YM. Int J Clin Pharmacol Ther 2011; 49: 252-257.
  8. ROSZELL S, JONES C. J Infusion Nurs 2010; 33: 112-118.
  9. NUNN MO, CORALLO CE, AUBRON C, POOLE S, DOOLEY MJ, CHENG AC. Ann Pharmacother 2011; 45: 757-763.
  10. PRITCHARD L, BAKER C, LEGGETT J, SEHDEV P, BROWN A, BAYLEY BK. Am J Med 2010; 123: 1143-1149.
  11. KHOTAEI GT, JAM S, SEYED AS, MOTAMED F, NEJAT F, TAGHI M, ASHTIANI H, IZADYAR M. Acta Med Iran 2010; 48: 91-94.
  12. Bennett, P.N.; Brown, M.J. Vancomycin, Clinical Pharmacology, 9th ed.; Churchill Livingstone: London, UK, 2000.
  13. John, F.P.; Baggot, J.D.; Walker, R.D. Glycopeptides: Vancomycin, Teicoplanin, and Avoparcin, Antimicrobial Therapy in Veterinary Medicine, 3rd ed.; Blackwell Publishing Professional: Ames,
  14. IA, USA, 2000.
  15. Levison, M.E.; Levison, J.H. Infect. Dis. Clin. N. Am. 2009, 23, 791–815.
  16. Cantu, T.G.; Dick, J.D.; Elliott, D.E.; Humphrey, R.L.; Kornhauser, D.M. Protein binding of vancomycin in a patient with immunoglobulin A myeloma. Antimicrob. Agents Chemother. 1990, 34, 1459–1461.
  17. Micek, S.T. Clin. Infect. Dis. 2007, 45, S184–S190.
  18. Koteva, K.; Hong, H.L.; Wang, X.D.; Nazi, I.; Hughes, D.; Naldrett, M.J.; Buttner, M.J.; Wright, G.D. A. Nat. Chem. Biol. 2010, 6, 327–329.
  19. Albanese, J.; Leone, M.; Bruguerolle, B.; Ayem, M.L.; Lacarelle, B.; Martin, C. Antimicrob. Agents Chemother. 2000, 44, 1356–1358.
  20. Nau, R.; Sörgel, F.; Eiffert, H. Clin. Microbiol. Rev. 2010, 23, 858–883.
  21. Matzneller, P.; Burian, A.; Zeitlinger, M.; Sauermann, R. Pharmacology 2016, 97, 233–244.
  22. Forouzesh, A.; Moise, P.A.; Sakoulas, G. Vancomycin ototoxicity: A reevaluation in an era of increasing doses. Antimicrob. Agents Chemother.
  23. 2009, 53, 2483–2486.
  24. CHAMBERS HF. Antimicrobial agents: Protein Synthesis Inhibitors and miscellaneous antibacterial agents. In: Goodman and Gilman's the pharmacological basis of therapeutics 11th edition. Edited by Joel G. Hardman, Lee E. Limbird. New York, McGraw-Hill, 2010; pp. 1074-1077.
  25. Chen, C.Y.; Huang, Y.C. Review: New epidemiology of Staphylococcus aureus infection in Asia. Clin. Microbiol. Infect. 2014, 20, 605–623.
  26. Tenover, F.C., Jr.; Moellering, R.C. Clin. Infect. Dis. 2007, 44, 1208–1215.
  27. Brummett, R.E.; Fox, K.E. Antimicrob. Agents Chemother. 1989, 33, 791–796.
  28. Elting, L.S.; Rubenstein, E.B.; Kurtin, D.; Rolston, K.V.; Fangtang, J.; Martin, C.G.; Raad, I.I.; Whimbey, E.E.; Manzullo, E.; Bodey, G.P. Mississippi mud in the 1990s: Risks and outcomes of vancomycin-associated toxicity in general oncology practice. Cancer 1998, 83, 2597–2607.
  29. Stanley, D.; McGrath, B.J.; Lamp, K.C.; Rybak, M.J. Pharmacotherapy 1994, 14, 35–39.
  30. Tange, R.A.; Kieviet, H.L.; Marle, J.V.; Sjoback, D.B.; Ring,W. An experimental study of vancomycin-induced cochlear damage. Arch. Otorhinolaryngol. 1989, 246, 67–70.
  31. Pai, M.P.; Mercier, R.C.; Koster, S.A. Epidemiology of vancomycin-induced neutropenia in patients receiving home intravenous infusion therapy. Ann. Pharmacother. 2006, 40, 224–228.
  32. Bishop, T. Vancomycin. In The Veterinary Formulary, 6th ed.; Pharmaceutical Press: London, UK, 2005.
  33. Ray, A.S.; Haikal, A.; Hammoud, K.A.; Yu, S.L. Vancomycin and the Risk of AKI: A Systematic Review and Meta-Analysis. CJASN 2016, 11, 2132–2140.
  34. Bailie, G.R.; Neal, D. Vancomycin ototoxicity and nephrotoxicity. Med. Toxicol. Advers. Drug Exp. 1988, 3, 376–386.
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