Review on Lyophilization of Anti-biotics

Abstract

The process of Lyophilization is carried out in pharmaceutical solutions inorder to produce an acceptable and stable product has been a practice employed to manufacture many marketed injectable formulations. Lyophilization which is based on the principle of sublimation of ice is a process of removal of water by, conversion of ice directly from solid to vapour without passing through a liquid phase. It includes the processes like freezing, sublimation and desorption. The present marketed formulation is taking more amount of time to get lyophilized and is facing problem of cake integrity during transport and upon prolonged storage. So the present work is designed to formulate a lyophilized Piperacillin tazobactam powder for injection, with decreased lyophilization time, increased stability and make the product more economical. Thus, the important objective of this research is to formulate a stable lyophilized formulation with desired characteristics, by combining with different excipients

Keywords

Lyophilization, Aniti-biotics, Dosage form

Introduction

Antibiotics

The greatest drugs of the 20th century to therapeutics are Anti-biotics. The drugs are designed in such a manner that they have the ability to inhibit/kill the infecting organism and there should not be any l effect on the recipient. Such type of action is known as chemotherapy. Chemotherapy is the treatment of disease by the use of chemical substances, especially the treatment of tumor by cytotoxic and other drugs. The basis of selective microbial toxicity is the action of the drug on a component of the cell wall or folate synthesis that is not found in the host. Waksman coined the word anti-biotic during 1942; Previously they were called lysins, bacteriolytic agents [1-5].

Principles of Freeze Drying

The process consists of three steps or processes:

• Freezing

• Sublimation

• Desorption

Freezing

Formulation is cooled during this stage. Pure crystalline ice forms from the liquid, thereby resulting in a freeze concentrate of the remainder of the liquid to a more viscous state. Ultimately this highly concentrated and viscous solution solidifies yielding a solid product. Small ice crystals produce pores with lower volume-surface area, thus resulting in lower diffusion and sublimation rates [5,6].

Primary drying

As the drying proceeds, thickness of the frozen layer decreases and the thickness of partially dried solid increases. The transfer of heat is generally done by conduction or radiation. Convection effect is negligible, due to low air density. After sublimation, vapour molecules get collected in the condenser. The condenser provides a surface for the water vapour to re-solidify on it. Condenser temperatures are typically below -500°C [7,8].

Secondary drying

During this process, traces of remaining water are removed. Bound moisture will be found in the product, even after all the ice has sublimed during primary drying. 7-8% of residual moisture may be present in the product, but the product appears dry. The bound water is desorbed from the product. The relatively small amount of bound water remaining in the matrix is removed by desorption. Temperature is increased more than that in primary drying. The temperature of the solid is raised to as high as 500°C to 600°C [9,10].

Excipients in A Lyophilized Formulation

Most freeze dried products contain several components in addition to active pharmaceutical ingredients (API). These additional components, known as excipients, are intended to serve a specific function, normally related to stability or process. They are as follows:

Bulking agents

Bulking agents are intended to be inert and improve product elegance and blow-out of product is prevented. The structured of lyophilized cake is important, since proper cake formation leads to proper pore formation, that provides the means for vapour to escape from the product during drying. (Ex: Mannitol, Lactose)

Buffering agents

Sodium hydroxide, Sodium bicarbonate.

Tonicity adjusters

Parenteral formulations must be isotonic with the blood plasma, so as to avoid damage to tissues. However, not all drugs at their recommended dosage are isotonic with blood, thus requiring the addition of a tonicity adjusting agent. (Ex: Sodium chloride, Glycine, Glycerol).

Surfactants

Generally surfactants are added to improve wetting and reconstitution behavior, and to stabilize proteins during freezing. Surfactants are generally added to low dose products to minimize losses due to surface adsorption (i.e. when the total amount of drug loss is a significant percentage of the drug in solution). (Ex: Polysorbate 80) [11-30].

Process Overview

In freeze drying, solution is filled into vials; a special slotted rubber closure is inserted halfway into the vial, which allows escape of water vapour. Vials are placed on trays and transferred to freeze dryer. Trays of product are placed on shelves containing internal channels, allowing circulation of silicone oil. The solution is frozen by circulation of silicon oil through internal channels in shelf assembly. When the product is solidified sufficiently, the pressure in freeze-dry chamber is reduced. After this pressure is reached, heat is applied to the product by increasing the temperature of circulating fluid. As drying proceeds, a receding boundary can be observed in the vial as the thickness of the frozen layer decreases, and the thickness of partially dried solid increases. It happens due to direct sublimation of ice in the primary drying phase of lyophilization. The concentration gradient of water vapour between the drying front and condenser is the driving force for removal of water during lyophilization. After primary drying, additional drying is necessary to remove any water that did not freeze during the freeze process. This phase is required to remove water adsorbed to or trapped by the solid matrix. This phase is called secondary drying and consists of water removal by diffusion and desorption. When the product is sufficiently dry, vials are usually stoppered in place by hydraulic compression of shelf stack which pushes vials to fully inserted position.

Determining Drying Endpoints

The drying boundary in vials moved to the bottom of the product reveals that no ice is visible in the product. As the heat input to the product is increased, evaporate cooling keeps the product temperature well below the temperature of its surrounding atmosphere. When the primary drying is complete, the product temperature rises to equal the temperature of its environment.

Drug Excipients Compatibility Study

Excipient compatibility study gives valuable information about potential incompatibilities between API and excipients [31-40]. Compatibility between API and excipients can be affected by many factors such as moisture content, physical form, particle size, morphology etc. The stressed storage conditions used to accelerate reactions between API and excipients are carefully selected such that, measurable changes occur in short time frame, while ensuring that such data remains applicable to ambient conditions. In the present study, compatibility of Piperacillin and Tazobactam with excipients like Sodium Bicarbonate, Mannitol, Lactose and Dextrose was studied for a period of one month. The drugs and excipients were taken in 1:2 (50 mg + 100 mg) ratio and loaded for stability studies at 25 ± 20°C/60 ± 5% RH and 40 ± 20°C/75 ± 5% RH accelerated temperatures and related humidity. The samples were analyzed for drug stability by HPLC method [41-50].

The drug is analyzed by HPLC by dissolving the contents with 10 ml of water for injection.

Formulation

Procedure

Required quantities of drugs and excipients are collected and weighed accurately. Water for injection (A) was freshly collected and the temperature is maintained at 12 ± 20°C. 10 ml of this WFI (from A) was taken in a separate beaker and to this 2 gm of Piperacillin was added slowly followed by 100 mg of Sodium Bicarbonate with constant stirring (B) [51-60]. In another beaker 5 ml of WFI (from A) was taken and to this 0.25 gm of Tazobactam was added slowly followed by 20 mg of Sodium Bicarbonate with constant stirring (C). This Tazobactam solution (C) is added to the above Piperacillin solution (B) [61-65]. To this required quantity of selected bulking agent was added. Final volume was made up to 20 ml with WFI (from A) and mixed properly until completely dissolved using a sonicator. pH was checked and adjusted with Sodium bicarbonate to 5.5-7.0 if required. 0.22 μ Millipore syringe filter is used to filter this solution. The solution is filled into vials. The vials are partially stoppered and loaded into trays of the lyophilizer. The lyophilization cycle was started and after the cycle is completed the vials are removed from the trays and are stored at suitable temperature for further analysis [65-75].

The bulking agents used are:

• Mannitol

• Lactose

• Dextrose

Development of Lyophilization Cycle

The solution is filled into vials. The vials are partially stoppered and loaded into trays of the lyophilizer. Different lyophilization cycles were tried to optimize the cycle which produces stable and uniform cake [76-82].

Conclusion

The present research work was designed to develop a lyophilized Piperacillin/Tazobactam powder for injection with improved stability and being more economical when compared to the present marketed formulation [83-90]. The marketed formulation has problem of stability upon prolonged storage and is also taking more time for the process of lyophilization to get completed. Therefore the present work was focused on overcoming the drawbacks associated with the present marketed formulation and to formulate a stable product that is found to be economical. To improve the stability and cake characteristics of the lyophilized formulation, three bulking agents were selected in different concentrations. Three different lyophilization cycles were carried out using different combinations of these excipients and drugs. From the results it was revealed that, lyophilization cycle 3 and formulation F2 with 5% mannitol produced good results as the formulation exhibited a good cake structure and evaluation factors were found to be with in the USP limits. From the results a conclusion can be reached that, the use of bulking agents produced stable injectable dosage form of Piperacillin tazobactam with improved cake structure and decreased lyophilization time [91-100].

Summary

Piperacillin is an extended spectrum beta–lactam antibiotic of the ureidopenicillin class, useful in treating many gram positive and gram negative pathogens, including Pseudomonas aeruginosa. Tazobactam is a compound that inhibits the action of bacterial β-lactamases. It is combined with the Piperacillin. This combination is available as lyophilized powder for injection. Preformulation studies of the drugs were performed for their description, solubility, pH, water content, melting point, assay and the results were found to be within the limits. Compatibility of the drugs with excipients was determined. The drugs were formulated by using various excipients such as mannitol, lactose and dextrose in different concentrations and were lyophilized. A total of six formulations with different concentrations of excipients were prepared and were lyophilized using three different lyophilization cycles.

Finally it was concluded that lyophilization cycle 3 was the best process, with F2-5% mannitol being the best formulation passing all the tests. Hence, F2 with 5% mannitol was selected as the best formulation for the lyophilization of Piperacillin/Tazobactam combination.

References

1. Tsompos C, et al. The Effect of the Antioxidant Drug “U-74389G” on Uterus Inflammation during Ischemia Reperfusion Injury in Rats. J Pharm Sci Emerg Drugs. 2015;3:1.
2. Swapnil S, et al. Healing Potential of Citrullus Lanatus in Acetic Acid Induced Ulcerated Rats. J Pharm Sci Emerg Drugs. 2015;3:1.
3. Patel MN, et al. Synthesis, Characterization and Biological Elucidation of Mixed Ligand Cu(II) Complexes as Artificial Metallonucleases. J Pharm Sci Emerg Drugs. 2015;3:1.
4. Ibrahim NAE. Ideal and Effective Preceptor in Pharmacy Practice. Ethical. J Pharma Care Health Sys. 2015;S2:e001.
5. DeSear KE, et al. Evaluation of an Interactive Educational Model to Enhance Antimicrobial Stewardship at an Academic Medical Center. J Pharma Care Health Sys. 2015;S2:S2-001.
6. Sealy P. Team Based Learning Strategy Applied to Pharmacy Based Courses. J Pharma Care Health Sys. 2015;S2:S2-002.
7. Dameh M. Report of Second Year Pharmacy Students’ Experience after Using a Virtual Dispensing Program. J Pharma Care Health Sys. 2015;S2:003.
8. Shawaqfeh MS. Gamification as a Learning Method in Pharmacy Education. J Pharma Care Health Sys. 2015;S2:004.
9. Ma C, et al. Impact of Advanced Pharmacy Practice Experiential Student-Led Seminars on Competencies of Retail Pharmacy Students Enrolled in Introductory Pharmacy Practice Experience. J Pharma Care Health Sys. 2015;S2:005.
10. Bruno O, et al. Availability of Essential Medicines and Supplies during the Dual Pull-Push System of Drugs Acquisition in Kaliro District, Uganda. J Pharma Care Health Sys. 2015;S2:006.
11. Thompson M, Gilliam E, Nuffer W (2015) Longitudinal Assessment of Students’ Communication and Professionalism Skills across All Levels of a Pharm D Curriculum. J Pharma Care Health Sys S2:007.
12. Barakat K. Computer-Aided Drug Design. J Pharma Care Health Sys. 2014;1:e113.
13. Aminabhavi TM. Oral Insulin Therapy for Diabetic Treatment. J Pharma Care Health Sys. 2014;1:e114.
14. Sharif SI. Mentoring in Pharmacy Education and Practice. J Pharma Care Health Sys. 2014;1:e115.
15. Moustafa MAA. Towards Pharmaceutical Care Services in Saudi Arabia, Personal Experience. J Pharma Care Health Sys. 2014;1:e116.
16. Moultry AM. Pharmacy: An Evolving Profession without the Status. J Pharma Care Health Sys. 2014;1:e117.
17. Alkhateeb FM. Availability and Perceived Value of Bachelor of Science Programs in Pharmaceutical Marketing and Management in the United States. J Pharma Care Health Sys. 2014;1:e118.
18. Barakat K. Do We Need Small Molecule Inhibitors for the Immune Checkpoints? J Pharma Care Health Sys. 2014;1:e119.
19. Scheer F, et al. Pharmacokinetics of Piperacillin and Ciprofloxacin in Critically Ill Patients Undergoing Continuous Venovenous Haemodialysis or Haemodiafiltration. J Pharma Care Health Sys. 2014; 1:118.
20. Feng X, et al. Future Medicine for Today’s Cancer Patients: Therapeutic Application of Pharmacogenomics in Oncology. J Pharma Care Health Sys. 2014;1:119.
21. Kumari KP, et al. Stability Indicating RP-HPLC method Development and Validation of Salicylic Acid in Choline Magnesium Trisalicilate (Trilisate) Tablets. J Pharma Care Health Sys. 2014;1:120.
22. Abreu MR, et al. Salivary Glands of Female Ticks Rhipicephalus sanguineus Like a Potential Source of Molecules with Inhibitory Action: In vivo study with Walker 256 Tumor Cells. J Pharma Care Health Sys. 2014;1:121.
23. Greenspan FM. Urinary Incontinence: Patients Health Care. J Pharma Care Health Sys. 2014;1:122.
24. Pine M, et al. Using Clinically-Enhanced Claims Data to Discern Current Patterns of Inpatient Care and Identify Opportunities for Improvement. J Pharma Care Health Sys. 2014;1:123.
25. Ogino D, et al. Distribution Differences of Medical and Clinical Research and Clinical Trial Information by Hospital Size in Japan. J Pharma Care Health Sys. 2014;1:124.
26. Feng X. Angiogenesis and Antiangiogenesis Therapies: Spear and Shield of Pharmacotherapy. J Pharma Care Health Sys. 2014;1:e110
27. Aminabhavi TM. Is Cancer Treatment Through Targeted Delivery a Better Solution? J Pharma Care Health Sys. 2014;1:e111.
28. Mitchelmore BR, et al. Incorporating Clinical Expertise and The Clinical Presentation in Evidence-Based Medicine. J Pharma Care Health Sys. 2014;1:e112.
29. Janknegt R InforMatrix Aromatase Inhibitors in Breastcancer. J Pharma Care Health Sys. 2014;1:111.
30. Hassali MA, et al. Strengthening Pharmacy Practice Research: The Need for Combining both Qualitative and Quantitative Methodology. J Pharma Care Health Sys. 2014;1:112.
31. Godman B, et al. Initiatives among Authorities to Improve the Quality and Efficiency of Prescribing and the Implications of Prescribing and the Use of Medicines; Findings and Implications. J Pharma Care Health Sys. 2014;1:113.
32. Janknegt R. Biologicals in the Treatment of Plaque Psoriasis: Drug Selection by Means of the SOJA Method. J Pharma Care Health Sys. 2014;1:114.
33. Veronin MA, et al. Patient-centered Health Care Delivery Uniting MTM, EHRs and Patients: Opportunities for Pharmacists. J Pharma Care Health Sys. 2014;1:115.
34. Alkhaldi N, et al. A Five Year Review of Patient Focussed Medicine Information Queries at a Large UK Teaching Trust: Assessing the Trends, Predicting the Future. J Pharma Care Health Sys. 2014;1:116.
35. Menaa F. Emulsions Systems for Skin Care: From Macro to Nano-Formulations. J Pharma Care Health Sys. 2014;1:e104.
36. Sharif SI. Improving and Assessing Writing Skills and Practices of Pharmacy Students. J Pharma Care Health Sys. 2014;1:e105.
37. Banh HL. Are we Still Treating the Numbers? J Pharma Care Health Sys. 2014;1:e106.
38. Alkhateeb FM and Albers L. As Provider Status Looms, will PharmD Programs Lag Behind Regulation? J Pharma Care Health Sys. 2014; 1:e107.
39. Banh HL. Pharmacy Practice in Alberta, Canada. J Pharma Care Health Sys. 2014;1:e101.
40. Hedaya MA. The Need for Tamper-Resistant and Abuse-Deterrent Formulations. J Pharma Care Health Sys. 2014;1:e102.
41. Sharif SI. Team-Based Learning in Pharmaceutical Education. J Pharma Care Health Sys. 2014;1:e103.
42. Patel S, et al. Effectiveness of Pharmacy Run Anticoagulation Clinics Compared to Large Clinical Trials of New Oral Anticoagulants. J Pharma Care Health Sys. 2014;1:101.
43. Dhiman GJ and Amber KT. The Sunshine Act and the Academic Institution. J Pharma Care Health Sys. 2014;1:102.
44. Lakshmi PK, et al. Transdermal Permeation Enhancement of Lamotrigine Using Terpenes. J Pharma Care Health Sys. 2014;1:103.
45. Stuart B, et al. Anticipating Part D Phase Changes: How Heart Failure Patients Respond to the Medicare Drug Benefit Design. J Pharma Care Health Sys. 2014;1:104.
46. Tucker R, Duffy J. The Role of Community Pharmacists in the Management of Skin Problems. J Pharma Care Health Sys. 2014;1:105.
47. McConaha JL. Evaluation of Student Pharmacist and Pharmacist Impact on Disease State Management and Patient Satisfaction in Adult Patients with Asthma. J Pharma Care Health Sys. 2014;1:106.
48. Sharif A, et al. Development and Optimization of Dimethicone-based Cream Containing Muscat Hamburg Grape Extract: In-vitro Evaluation. J Pharma Care Health Sys. 2014;1:107.
49. Chihara T, et al. Dietary Administration of Aloe Vera Gel Extract Inhibits Intestinal Polyp Formation in Min Mice Fed a High-Fat Diet. Pharm Anal Acta. 2015;6:340.
50. Chow SC and Lin M. Analysis of Two-Stage Adaptive Seamless Trial Design. Pharm Anal Acta. 2015;6:341.
51. Nasr JJ, et al. Stability-Indicating Spectrophotometric Determination of Aceclofenac Using Multivariate Calibration. Pharm Anal Acta. 2015;6:342.
52. Napoleone E. Children and ADRs (Adverse Drug Reactions). Ital J Pediatr. 2010;36:4.
53. Napoleone E and Radice S. From pharmacovigilance to therapy amelioration in paediatric patients: The role of the clinical pharmacologists and family paediatricians. Part of a series on Paediatric Pharmacology, guest edited by GianvincenzoZuccotti, Emilio Clementi, and Massimo Molteni. Pharmacol Res. 2012;65: 168-170.
54. Arroll B. Antibiotics for upper respiratory tract infections: an overview of Cochrane reviews. Respir Med. 2005;99:255-261.
55. Schneider-Lindner V, et al. Secular trends of antibacterial prescribing in UK paediatric primary care. J AntimicrobChemother. 2011;66:424-433.
56. Holstiege J, et al. Systemic antibiotic prescribing to paediatric outpatients in 5 European countries: a population-based cohort study. BMC Pediatr. 2014;14:174.
57. Bottaro G, et al. 5 days Cefaclor vs. 10 days amoxicillin/clavulanate in the treatment of childhood streptococcal pharyngitis. Data from a randomized clinical trial. Minerva Pediatr. 2015;64:341-346.
58. Barash J. Group A streptococcal throat infection-to treat or not to treat? ActaPaediatr 2009;98:434-436.
59. Pellegrino P, et al. Pharmacovigilance knowledge in family paediatricians. A survey study in Italy. Health Policy. 2013;113:216-220.
60. Napoleone E. The FIMP-MCRN (Family Paediatricians-Medicines for Children Research Network): generating evidence and safety at the point of care. Evid Based Child Health. 2011;6:37.
61. Napoleone E. Excellence in Family Paediatricians: the FIMP-MCRN (Medicines for Children Research Network) becomes a member of ENPR-EMA (European Network of Paediatric Research at the European Medicines Agency). Ital J Pediatr. 2011;37:7.
62. Napoleone E and Mele G Medicines for children: the proactive approach of the FIMP-MCRN (Family Paediatricians-Medicines for Children Research Network). ActaPediatrica. 2010;99:113.
63. Napoleone E and Mele G. The FIMP Medicines for Children Research Network. Ital J Pediatr 2011;36:46.
64. Napoleone E and Scasserra C. Pharmacovigilance in Pediatric Age: The Role of Family Pediatricians-Medicines for Children Research Network (FP-MCRN). J Pharmacovigilance. 2015;3:168.
65. Sandor GK, et al.  Antimicrobial treatment options in the management of odontogenic infections. J Can Dent Assoc.  1998;64:508-514.
66. Brook I. Microbiology and management of endodontic infections in children. J Pediatr Dent 2003;28:13-17.
67. Sands T, et al. Odontogenic infections: Part two. Microbiology, antibiotics and management. Oral Health. 2003;85:11-23.
68. Peedikayil FC. Antibiotics: Use and misuse in pediatric dentistry. J Indian SocPedodPrev Dent 2011;29:282-287.
69. Baker KA and Fotos PG. The management of odontogenic infections. A rationale for appropriate chemotherapy. Dent Clin North Am.  1994;38:689-706.
70. Cope AL, et al. General dental practitioners′ perceptions of antimicrobial use and resistance: A qualitative interview study. Br Dent J. 2014;217:E9.
71. Pallasch TJ. Global antibiotic resistance and its impact on the dental community. Calif Dent Assn J. 2014;28:215-233.
72. Fine DH, et al. Clinical use of antibiotics in dental practice. Int J Antimicrob Agents. 2011;9:235-238.
73. Jain MK and Oswal S. Antibiotics in dentistry-An art and science. Ann Dent Speciality. 2013;1:20-25.
74. Henry M, et al. Effect of Penicillin in postoperative endodontic pain and swelling in symptomatic necrotic teeth. J Endod. 2001;27:117-123.
75. Wilson W, et al. Prevention of infective endocarditis: A guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation. 2007;116:1736-1754.
76. Bresco-Salinas M, et al. Antibiotic susceptibility of the bacteria causing odontogenic infections. Med Oral Patol Oral Cir Bucal. 2011;11:E70-E75.
77. Kirkwood KL. Update on antibiotics used to treat orofacial infections. Alpha Omegan. 2003;96:28-34.
78. Ellison SJ. The role of phenoxymethylpenicillin, amoxicillin, metronidazole and clindamycin in the management of acute dentoalveolar abscesses–a review. Br Dent J. 2009;206:357-362.
79. Lewis MA. Why we must reduce dental prescription of antibiotics: European Union Antibiotic Awareness Day. Br Dent J. 2008;205:537-538.
80. Mangundjaja S and Hardjewinata K. Clindamycin versus ampicillin in the treatment of odontogenic infections. ClinTher. 1990;12:242-249.
81. Kupfer SR. Prevention of dry socket with clindamycin. A retrospective study. N Y State Dent J. 1995;61:30-33.
82. Dolui SK, et al. Ofloxacin-induced reversible arthropathy in a child. J Postgrad Med. 2011;53:144-145.
83. Warnke PH, et al. Penicillin compared with other advanced broad spectrum antibiotics regarding antibacterial activity against oral pathogens isolated from odontogenic abscesses. J CraniomaxillofacSurg. 2008;36:462-467.
84. Campagna JD, et al. TheUse of Cephalosporins in Penicillin-allergic Patients A Literature Review. J Emerg Med. 2012;42:612-620.
85. Laxminarayan R, et al. Antibiotic resistance—the need for global solutions. The Lancet Infectious Diseases. 2013;13:1057-1098.
86. Pollack LA and Srinivasan A. Core elements of hospital antibiotic stewardship programs from the Centers for Disease Control and Prevention. Clinical Infectious Diseases. 2014;59:S97-S100.
87. Piddock LJ. The crisis of no new antibiotics—what is the way forward? The Lancet Infectious Diseases. 2012;12:249-253.
88. Fair RJ and Tor Y. Antibiotics and bacterial resistance in the 21st century. Perspectives in Medicinal Chemistry. 2014;6:25.
89. Nordmann P, et al. Carbapenem resistance in Enterobacteriaceae: here is the storm! Trends in Molecular Medicine. 2012;18:263-272.
90. Huh AJ and Kwon YJ “Nanoantibiotics”: a new paradigm for treating infectious diseases using nanomaterials in the antibiotics resistant era. Journal of Controlled Release. 2011;156:128-145.
91. Ansell J, et al. Pharmacology and management of the vitamin K antagonists: American collage of chest physicians’ evidence based clinical practice guidelines. Chest. 2011;133:160S-198S.
92. January CT, et al. AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Circulation. 2014;130:e199-267.
93. Holbrook AM, et al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med. 2005;165: 1095-1106.
94. Juurlink DN. Drug interactions with warfarin: what clinicians need to know. CMAJ. 2007;177:369-371.
95. Zhang Q, et al. Amoxicillin/clavulanic acid-warfarin drug interaction: a randomized controlled trial. Br J Clin Pharmacol. 2011;71:232-236.
96. Kelly M, et al. Formation of rectus sheath hematoma with antibiotic use and warfarin therapy: a case report. Am J Geriatr Pharmacother. 2011;3:266-269.
97. Larsen TR, et al. Acute warfarin toxicity: An unanticipated consequence of amoxicillin/clavulanate administration. Am J Case Rep. 2011;15:45-48.
98. Shimodaira M, et al. An oblique muscle hematoma as a rare cause of severe abdominal pain: a case report. BMC Research Notes. 2013;6:18.
99. Narum S, et al. Warfarin-associated bleeding events and concomitant use of potentially interacting medicines reported to the Norwegian spontaneous reporting system. British Journal of Clinical Pharmacology. 2011;71:254-262.
100. Baillargeon J, et al. Concurrent use of warfarin and antibiotics and the risk of bleeding in older adults. Am J Med. 2012;125:183-189.