Dear Label_Name,

Greetings! I hope you are well.

I am writing on behalf of an international publishing house, Science and Education Publishing, USA (http://www.sciepub.com).

Science and Education Publishing (SciEP) is a multidisciplinary open access publisher of Journals covering the fields of Science, Technology and Medicine. All SciEP publications are subject to high-quality peer review, editorial and production processes and are freely available online.

Welcome to the April, 2013 edition of SciEP newsletter, providing monthly summaries of articles on science & education related topics of interest to scientist and professionals. The mission of our journals is to provide an open access forum for publishing new findings on issues pertinent to scientific and academic field. We also invite you to submit original research papers, review articles, short reports, or case studies are considered for publication in our Multidisciplinary Journals.

American Journal of Public Health Research
DOI: 10.12691/ajphr-1-1-3

The Implementation of a Tele-Homecare System with Service Oriented Architecture and HL7 Message Transmission Standard
Ching-Sung Wang

American Journal of Medical and Biological Research
DOI: 10.12691/ajmbr-1-1-2

The Influence of Ethanol on Pyruvate Kinases Activity in Vivo, in Vitro, in Silico
Lelevich Sergey Vladimirovich, Khrustalev Vladislav Victorovich, Barkovsky Eugene Victorovich, Shedogubova Tatyana Aleksandrovna

American Journal of Medical Sciences and Medicine
DOI: 10.12691/ajmsm-1-1-1

Clinical and Histological Features in Wegener Granulomatosis
Li Cavoli Gioacchino, Passantino Rita, Bono Luisa, Tortorici Calogera, Ferrantelli Angelo, Giammarresi Carlo, Rotolo Ugo

American Journal of Infectious Diseases and Microbiology
DOI: 10.12691/ajidm-1-1-2

The Curse of Lymphatic Filariasis: Would the Continual Use of Diethylcarbamazine Eliminate this Scourge in Papua New Guinea?
Anne Lanham, Lillian Mwanri

We have released issues of some journals on February 2013.
American Journal of Public Health Research
American Journal of Medical Sciences and Medicine
American Journal of Medical and Biological Research
American Journal of Pharmacological Sciences
American Journal of Clinical Medicine Research
American Journal of Nursing Research
American Journal of Cancer Prevention
American Journal of Medicine Studies
American Journal of Infectious Diseases and Microbiology
American Journal of Cardiovascular Disease Research
American Journal of Biomedical Research
American Journal of Mechanical Engineering
American Journal of Microbiological Research
Journal of Preventive Medicine
American Journal of Food and Nutrition
American Journal of Hypertension Research
American Journal of Sports Science and Medicine
Journal of Cancer Research and Treatment
American Journal of Zoological Research
Journal of Biomedical Engineering and Technology
American Journal of Microbiological Research
Biomedical Science and Engineering

We are pleased to announce that submissions are now being accepted for peer review for all the journals across all our subject areas in SciEP.

Please submit your manuscript via our online submission system:
http://www.sciepub.com/author/signin

To unsubscribe from our mailing list, please click on the following link: unsubscribe

I am looking forward to hearing from you.

Kind regards,

David Rain
Email:join@sciepub.com
Science and Education Publishing (http://www.sciepub.com)

The Action of Amoxicillin-Clavulanate on Hepatocytes

Omar Rashid Sadeq

Faculty of Dentistry, Arab American University, Jenin., (AAUJ), Palestine, P.O Box 240 Jenin, 13 Zababdeh

Abstract: The oral antibiotic amoxicillin is third generation penicillin combined to clavulanate, widely employed in medicine and dentistry for treatment of mild-to-moderate bacterial infections. Clavulanate is not indicated alone because it lacks antibacterial activity, so it is added to amoxicillin in order to inactivate beta-lactamse enzyme which is the major cause of penicillin resistance. Beta- lactamase is produced by many microorganisms, it destroys beta lactam ring of beta lactam antibiotics, therefore amoxicillin-clavulante is indicated as an extended antibiotic that covers many gram positive a and a significant number of gram negative microorganisms which produce beta-lactamse. This compound amoxicillin-clavulanate is available in multiple dose variations, typically as 250, 500 to 875 mg amoxicillin with 125 mg of clavulanate potassium, given two to three times daily for 7 to 10 days. The combination is provided in many trade formulation namely moclav and agumentin. Amoxicillin is in general use because it is the most effective and least toxic antibiotic, however it can cause some unwanted effects particularly allergic, GIT and renal effects. The purpose of recent study is to estimate possibility toxic effect of amoxicillin-clavulanate on hepatocytesand its revesibility, about 64 infectious patients of several ages were investigated, 35 of them are men and the 29 are women, for about 3 weeks. Complete blood count (CBC) and serum of alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (AP) and gamma glutamyltranspeptidase (gamma-GT) are taken before, and after completion of treatment. The main finding of this research is that amoxicillin-clavulanate has a toxic effect on hepatocytes, represented mainly by reversible cholestatic hepatitis in patients older 50 years, who experience fatigue, GIT upset, prurituts and jaundice. The hepatic injury has occurred in elderly men more than in women.

Keywords: amoxicillin, clavulanate, beta-lactamase, moclav, agumentin, alkaline phosphatase, gamma glutamyltranspeptidase, alanine transaminase, aspartate transaminase, prurituts, jaundice

Citation: Omar Rashid Sadeq, The Action of Amoxicillin-Clavulanate on Hepatocytes. American Journal of Pharmacological Sciences, 5 (1). 8-10. January 2017. doi:10.12691/ajps-5-1-2

1. Methodology

64 patients were included in the research study, patients were suffering from acute upper respiratory infections such as tonsillitis, laryngitis, nasopharyngitis as well as, sinusitis, gingivitis and periodontitis, both sexes of patients are divided into 3 groups according to severity and treatment period with amoxicillin-clavulanate, in each group are 22 patients aged from 20 to 60 years of old.

The patients of first group, treated by amoxicillin-clavulanate (625 mg 3 times daily) therapy for about 1 weeks.

The second group, patients medicated by amoxicillin-clavulante (625 mg 3 times daily) therapy for about 2 weeks.

The third group treated by amoxicillin-clavulante (625 mg 3 times daily) therapy for about 3 weeks,

All patients were examined to exclude hepatic, renal as well as cardiac impairments, CBC and hepatic enzymes are taken before and after treatment. The patients were asked after treatment about their complaints.

2.Methods of Investigation & Discussion

Investigations show that the first and second groups who were treated by amoxicillin-clavulante at a dose of 625 mg 3 times daily for 1and 2 weeks respectively have not significant deviation in their CBC, Gamma- GT, ALT, AST and AP enzymes, patients were asked if they have had GIT symptoms or other problems, they didn’t demonstrate any complaints, pruritus and jaundice have not been noted.

The third group was treated for 3 weeks, because of their prolonged infectious process, that accompanies with many symptoms of intoxication syndrome, such as fever, arthragia, myalgia, coughing, nausea, vomiting and headache, in these patients systemic complications such as pneumonia, meningitis and endocarditis were excluded.

About 13 patients aged from 50-60 years of the third investigated group who were medicated by the same dose of amoxicillin- calvulanate for 3 weeks have eosinophilia, as well as patients experience fatigue, fever, skin rash and arthralgia, the mechanism of eosinophila and allergic symptoms mentioned above is unknown but it seems to be of immunologic origin.

Hepatic enzymes elevations above their normal values are also seen, in about 7 patients (5 of them are men) the AP and Gama- GT serum are markedly increased, indicating cholestatic hepatic injury, after excluding bone abnormalities in these patients, with a slight elevation of ALT and AST.

In 4 patients (3 of them are men) the serum of ALT and AST are significantly elevated, showing hepatocellular injury, in these patients the AP serum is still around its normal range, but Gamma-GT is slightly increased.

In 2 male patients of this group high levels of all hepatic enzymes are noted (AP, Gamma-GT, ALT and AST), indicating that the hepatic injury in these two patients is mixed, The hepatic injury in this group is more common in elderly people, and in men rather than in women.

The remaining patients of the third group who are under 50 years of old didn’t show any significant deviation. (see Table 1).

Table 1. Analysis of Patients Treated With Amoxicillin-Clavulanate In A Period of 3 Weeks

Additional analysis were taken from the third group one week after completion of amoxicillin-clavulanate therapy, including CBC and hepatic enzymes, to ensure reversibility of hepatic injury, the results shows that CBC and hepatic enzymes return to their normal values a week after treatment with amoxicillin-clavulanate therapy, indicating temporary hepatic injury caused by medication, (See Table 2).

Table 2. Analysis of Patients of Third Group One Week After Completion of Treatment

According to the above data amoxicillin-calvulante does not produce hepatic injury in infectious patients treated for a period of either 1 or 2 weeks, but it is hepatotoxic in elderly people treated for 3 weeks, the mechanism of injury is not linked to amoxicillin by its self , but the hepatic cell injury here is associated with clavulanate, because other beta lactamase inhibitors (tazobactam and subactam) have not been reported to cause a similar hepatic injury, although it has been manifested with other penicillins when combined with clavulanate (ticarcillin/clavulanate).

The hepatic injury is reversible because hematologic and hepatic alterations normalize following a week after treatment.

3.Conclusion

1. Amoxicillin-clavulanate is a safe antibiotic in an infectious patients until 50 years in a period of 1- 2 weeks.

2. Amoxicillin-clavulanate is currently the most common cause of clinically apparent, drug induced acute hepatic injury in elderly patients treated at a dose of 625mg tid for 3 weeks.

3. The type of hepatic injury caused by amoxicillin-clavulanate is usually reversible cholestatic rather than hepatocellular or mixed character.

4. The mechanism by which amoxicillin-clavulanate induce eosinophilia is not well understood but it is thought to be of immunologic origin.

5. It is better to replace clavulanate by other beta lactamase inhibitors such as tazobactam to avoid hepatic injury caused by clavulanate in elderly patients.

References

[1]   | DeLemos AS, Ghabril M, Rockey DC, Gu J, Barnhart HX, Fontana RJ, Kleiner DE, et al; Drug-Induced Liver Injury Network (DILIN). Amoxicillin-clavulanate-induced liver injury. Dig Dis Sci. 2016 Mar 22.
[2]   | Björnsson ES. Hepatotoxicity by Drugs: The Most Common Implicated Agents. Int J MolSci 2016; 17.
[3]   | Ferrer P, Amelio J, Ballarín E, Sabaté M, Vidal X, Rottenkolber M, Schmiedl S, et al; PROTECT Work Package 2.. Systematic Review and Meta-Analysis: Macrolides and Amoxicillin/Clavulanate-induced Acute Liver Injury. Basic ClinPharmacolToxicol 2015 Dec 26.
[4]   | Moreno L, Sánchez Delgado J, Vergara M, Casas M, Miquel M, Dalmau B. Recurrent drug-induced liver injury (DILI) with ciprofloxacin and amoxicillin/clavulanic. Rev EspEnferm Dig. 2015 Dec; 107: 767-8.
[5]   | Kim SH, Saide K, Farrell J, Faulkner L, Tailor A, Ogese M, Daly AK, et al. Characterization of amoxicillin- and clavulanic acid-specific T cells in patients with amoxicillin-clavulanate-induced liver injury. Hepatology 2015; 62: 887-99.
[6]   | Mengual-Moreno E, Lizarzábal-García M, Ruiz-Soler M, Silva-Suarez N, Andrade-Bellido R, Lucena-González M, Bessone F, et al. [Case reports of drug-induced liver injury in a reference hospital of Zulia state, Venezuela]. Invest Clin 2015; 56: 3-12. Spanish.
[7]   | Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-1352.e7.
[8]   | Björnsson ES. Drug-induced liver injury: an overview over the most critical compounds. Arch Toxicol 2015; 89: 327-34.
[9]   | Fontana RJ. Pathogenesis of idiosyncratic drug-induced liver injury and clinical perspectives. Gastroenterology 2014; 146: 914-28.
[10]   | Devarbhavi H, Andrade RJ. Drug-induced liver injury due to antimicrobials, central nervous system agents, and nonsteroidal anti-inflammatory drugs. Semin Liver Dis. 2014; 34: 145-61.
[11]   | Romero-Gómez M, Moreno-Casares A, et al. HLA Alleles Influence the Clinical Signature of Amoxicillin-Clavulanate Hepatotoxicity. PLoS One 2013; 8: e68111.
[12]   | Moseley RH. Hepatotoxicity of antimicrobials and antifungal agents. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 463-82.
[13]   | Sistanizad M, Peterson GM. Drug-induced liver injury in the Australian setting. J Clin Pharm Ther 2013; 38: 115-20.
[14]   | Beraldo DO, Melo JF, Bonfim AV, Teixeira AA, Teixeira RA, Duarte AL. Acute cholestatic hepatitis caused by amoxicillin/clavulanate. World J Gastroenterol 2013; 19: 8789-92.
[15]   | Sánchez-Ruiz-Granados E, Bejarano-García A, Uceda-Torres E. Recurrent cholestasis by amoxicillin-clavulanic acid: the importance of a correct diagnosis of hepatotoxicity. Rev EspEnferm Dig 2012; 104: 616-7.
[16]   | Petri WA Jr. Penicillins, cephalosporins, and other β-lactam antibiotics. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman &Gilman’s the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1477-1504.
[17]   | Herrero-Herrero JI, García-Aparicio J. Corticosteroid therapy in a case of severe cholestasic hepatitis associated with amoxicillin-clavulanate. J Med Toxicol 2010; 6: 420-3.
[18]   | Domínguez Jiménez JL, Marín Moreno M, Bernal Blanco E, Puente Gutiérrez JJ, GuioteMalpartida S, de la Mata García M. [Acute cholestatic hepatitis induced by amoxicillin-clavulanic acid]. GastroenterolHepatol 2008; 31: 46. Spanish.
[19]   | Sabaté M, Ibáñez L, Pérez E, Vidal X, Buti M, Xiol X, Mas A, et al. Risk of acute liver injury associated with the use of drugs: a multicentre population survey. Aliment PharmacolTher 2007; 25:1401-9.
[20]   | Cundiff J, Joe S. Amoxicillin-clavulanic acid-induced hepatitis. Am J Otolaryngol 2007; 28: 28-30.
[21]   | Fontana RJ, Shakil AO, Greenson JK, Boyd I, Lee WM. Acute liver failure due to amoxicillin and amoxicillin/clavulanate. Dig Dis Sci 2005; 50: 1785-90.
[22]   | Martí J. [Cholestatic hepatitis due to amoxicillin-clavulanic acid with positive re-exposure]. EnfermInfeccMicrobiolClin 2003; 21: 322-3. Spanish.
[23]   | Thiim M, Friedman LS. Hepatotoxicity of antibiotics and antifungals. Clin Liver Dis 2003 ; 7: 381-99, vi-vii.
[24]   | Jordán T, González M, Casado M, Suárez JF, Pulido F, Guerrero E, Esteban J. [Amoxicillin-clavulanic acid induced hepatotoxicity with progression to cirrhosis.] Gastroenterol Hepatol 2002; 25: 240-3. Spanish.
[25]   | Sgro C, Clinard F, Ouazir K, et al. Incidence of drug-induced hepatic injuries: A French population-based study. Hepatology. 2002; 36(2):451-455.23. Boyd IW.
[26]   | Comment: history of drug-induced hepatitis and risk of amoxicillin/clavulanate-induced hepatotoxicity. Ann Pharmacother 2001; 35: 1677.
[27]   | Schey R, Avni Y, Bruck R, Shirin H. History of drug-induced hepatitis and risk of amoxicillin/clavulanate-induced hepatotoxicity. Ann Pharmacother 2001; 35: 1142-3.
[28]   | Berg P, Hahn EG. Hepatotoxic reactions induced by beta-lactamase inhibitors. Eur J Med Res 2001; 6: 535-42.
[29]   | Soza A, Riquelme F, Alvarez M, Duarte I, Glasinovic JC, Arrese M. [Hepatotoxicity by amoxicillin/clavulanic acid: case report] Rev Med Chil 1999; 127: 1487-91. Spanish.
[30]   | Zimmerman, HJ. Hepatotoxicity from drugs in common use. Semin Liver Dis 1990;10: 322-338.