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Enhanced Bleeding With Cefoxitin or Moxalactam: Statistical Analysis Within a Defined Population of 1493 Patients

Enhanced Bleeding With Cefoxitin or Moxalactam: Statistical Analysis Within a Defined Population... Abstract • Most cases of β-lactam-associated coagulopathy occur in patients with other risk factors. This study analyzed temporally related clinical bleeding events in 1493 patients who received one antibiotic for at least three days. Univariate and multivariate analyses controlled for condition variables (nutritional status, renal, hepatic, or hematologic dysfunction, intensive care unit stay) and treatment variables (use of antiplatelet agents, anticoagulants, vitamin K, antitumor chemotherapy or antiulcer therapy, steroids) that could have been associated with bleeding independently. Rates of bleeding ranged from 0% (chloramphenicol sodium succinate, vancomycin hydrochloride, erythromycin lactobionate) to 8.2% (cefoxitin) to 22.2% (moxalactam disodium). Multiple logistic regression analyses revealed that only moxalactam (odds ratio, 9.9) and cefoxitin (odds ratio, 2.1) exhibited significantly higher likelihoods of bleeding than other agents. This study statistically confirms increased risk of bleeding with moxalactam, heretofore reported only anecdotally. Cefoxitin may carry risks greater than previously believed. (Arch Intern Med 1986;146:2159-2164) References 1. Clancy CM, Gleckman RH: Hypoprothrombinemia and bleeding associated with cefamandole. Lancet 1983;1:250.Crossref 2. Hooper CA, Haney BB, Stone HH: Gastrointestinal bleeding due to vitamin K deficiency in patients on parenteral cefamandole. Lancet 1980;1: 39.Crossref 3. Panwalker AP, Rosenfeld J: Hemorrhage, diarrhea and superinfection associated with the use of moxalactam. J Infect Dis 1983;147:171-172.Crossref 4. Jones SR, Kimbrough RC: Moxalactam and hemorrhage. Ann Intern Med 1983;99:126.Crossref 5. Rahal JJ Jr, Simberkoff MS, Landesman SH: Prospective evaluation of moxalactam therapy for gram-negative bacillary meningitis. J Infect Dis 1984;149:562-567.Crossref 6. Fishman L, Marsh WR: Prolonged bleeding time associated with moxalactam administration. Neurosurgery 1984;14:735-736.Crossref 7. Weitekamp MR, Aber RC: Prolonged bleeding time and bleeding diatheses associated with moxalactam administration. JAMA 1983;249:69-71.Crossref 8. Srinivasan S, Francke EL, Neu HC: Use of moxalactam in therapy of infections due to multiresistant bacteria, abstract 365. Program and abstracts of the 20th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC, Sept 22-24, 1980. 9. Bach MC: Prolonged bleeding time associated with 'low dose' moxalactam therapy. JAMA 1984;251:3082.Crossref 10. Shenkenberg TD, Mackowiak PA, Smith JW: Coagulopathy and hemorrhage associated with cefoperazone therapy in a patient with renal failure. South Med J 1985;78:488-489.Crossref 11. Shatth SJ, Bennett JS, McDonough M, et al: Carbenicillin and penicillin G inhibit platelet function in vitro by impairing the interaction of agonists with the platelet surface. J Clin Invest 1980;44:329-337.Crossref 12. Ballard JO, Barnes SG, Sattler FR: Comparison of the effects of mezlocillin, carbenicillin, and placebo on normal hemostasis. Antimicrob Agents Chemother 1984;25:153-156.Crossref 13. Somani P, Freimer EH, Smith MR, et al: Bleeding abnormalities and β-lactam penicillins, abstract 959. Program and abstracts of the 24th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC, Oct 8-10, 1984. 14. Somani P, Smith MR, Gohara A, et al: The effects of mezlocillin, ticarcillin and placebo on blood coagulation and bleeding time in normal volunteers. J Antimicrob Chemother 1983;11( (suppl C) ):33-41.Crossref 15. Natelson EA, Brown CH III, Bradshaw MW, et al: Influence of cephalosporin antibiotics on blood coagulation and platelet function. Antimicrob Agents Chemother 1976;9:91-93.Crossref 16. Alexander DP, Russo ME, Fohrman DE, et al: Nafcillin-induced platelet dysfunction and bleeding. Antimicrob Agents Chemother 1983;23: 59-62.Crossref 17. Gentry LO, Jemsek JG, Natelson EA: Effects of sodium piperacillin on platelet function in normal volunteers. Antimicrob Agents Chemother 1981;19:532-533.Crossref 18. Fedder IL, Holmes S, Vlasses SH, et al: Effect of intravenous carbenicillin, cefoxitin and cefamandole on ADP-induced platelet aggregation and shape change. Thromb Res 1983;32:215-222.Crossref 19. Brown CH III, Natelson EA, Bradshaw MW, et al: The hemostatic defect produced by carbenicillin. N Engl J Med 1974;291:265-271.Crossref 20. Brown AE, Quesada O, Murrer JA, et al: Assessment of coagulation problems in patients with cancer receiving empiric antibiotic therapy, abstract C-355. Program and abstracts of the 19th Meeting of the American Society of Clinical Oncology, San Diego, May 22-24,1983. 21. Cristano P: Hypoprothrombinemia associated with cefoperazone treatment. Drug Intell Clin Pharm 1984;18:314-316. 22. Cohen MS, Washton HE, Barranco SF: Multicenter trial of cefoperazone sodium in the United States. Am J Med 1984;77:35-41.Crossref 23. Lerner PI, Lubin A: Coagulopathy with cefazolin in uremia. N Engl J Med 1974;290:1324. 24. Papa MZ, Amsterdam E, Schniederman J, et al: Hemorrhagic complications encountered on a surgical service. Am J Surg 1984;147:378-381.Crossref 25. Schuster DP, Rowley H, Feinstein S, et al: Prospective evaluation of the risk of upper gastrointestinal bleeding after admission to a medical intensive care unit. Am J Med 1984;76:623-630.Crossref 26. Zuckerman GR, Cornette GL, Clouse RE, et al: Upper gastrointestinal bleeding in patients with chronic renal failure. Ann Intern Med 1985;102:588-592.Crossref 27. Fainstein V, Bodey GP, McCredie KB, et al: Coagulation abnormalities induced by β-lactam antibiotics in cancer patients. J Infect Dis 1983; 148:745-750.Crossref 28. Morris DL, Fabricius PJ, Ambrose NS, et al: A high incidence of bleeding is observed in a trial to determine whether addition of metronidazole is needed with latamoxef for prophylaxis in colorectal surgery. J Hosp Infect 1984;5:398-408.Crossref 29. Klippel AP, Pitsinger B: Hypoprothrombinemia secondary to antibiotic therapy and manifested by massive gastrointestinal hemorrhage. Arch Surg 1968;96:266-268.Crossref 30. Reddy J, Bailey RR: Vitamin K deficiency developing in patients with renal failure treated with cephalosporin antibiotics. NZ Med J 1980;92:378-380. 31. Pineo GF, Gallus AS, Hirsch J: Unexpected vitamin K deficiency in hospitalized patients. Can Med Assoc J 1973;109:880-883. 32. Malpass TW, Harker LA: Acquired disorders of platelet dysfunction. Semin Hematol 1980;17:242-258. 33. Weiss HJ: Platelet physiology and abnormalities of platelet function. N Engl J Med 1975;293:531-541, 580-588.Crossref 34. McCabe WR, Jackson GG: Gram-negative bacteremia. Arch Intern Med 1962;110:847-855.Crossref 35. Lemeshow S, Hosmer DW: Estimating odds ratios with categorically scaled covariates in multiple logistic regression analysis. Am J Epidemiol 1984;119:147-151. 36. Ham JM: Hypoprothrombinemia in patients undergoing prolonged intensive care. Med J Aust 1971;2:716-718. 37. Kozak AJ, Bertino JS, Reese RE, et al: Hypoprothrombinemia associated with concurrent use of cefamandole in a rural teaching hospital, abstract 1216. Program and abstracts of the 24th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC, Oct 8-10,1984. 38. Neu HC: Adverse effects of new cephalosporins. Ann Intern Med 1983;98:415-416. 39. Bang NU, Kammer RB: Hematologic complications associated with β-lactam antibiotics. Rev Infect Dis 1983;5( (suppl 2) ):S380-S393.Crossref 40. Bang NU, Tessler SS, Heidenreich RO, et al: Effects of moxalactam on blood coagulation and platelet function. Rev Infect Dis 1982;4( (suppl) ): S546-S554.Crossref 41. Lipsky JJ, Lewis JC, Novick WJ: Production of hypoprothrombinemia by moxalactam and 1-methyl 5-thiotetrazole in rats. Antimicrob Agents Chemother 1984;25:380-381.Crossref 42. Lipsky JJ: N-methyl thiotetrazole inhibition of the gamma carboxylation of glutamic acid: Possible mechanism for antibiotic-induced hypoprothrombinemia. Lancet 1983;1:192-193.Crossref 43. Lipsky JJ: Latamoxef-associated hypoprothrombinemia. Lancet 1983;1:624.Crossref 44. Wold JS, Buening MK, Hanasono GK: Latamoxef-associated hypoprothrombinemia. Lancet 1983;1:408.Crossref 45. Conly JM, Ramotar K, Chubb H, et al: Hypoprothrombinemia in febrile, neutropenic patients with cancer: Association with antimicrobial suppression of intestinal microflora. J Infect Dis 1984;150:202-212.Crossref 46. Andrassy K, Bechtold H, Ritz E: Hypoprothrombinemia caused by cephalosporins. J Antimicrob Chemother 1985;15:133-135.Crossref 47. Lipsky JJ, Lewis JC, Novick WJ Jr: The role of the 2-methyl, 1,3,4-thiadiazole, 5-thiol leaving group in cefazolin-induced hypoprothrombinemia, abstract 703. Program and abstracts of the 25th Interscience Conference on Antimicrobial Agents and Chemotherapy, Minneapolis, Sept 29-Oct 2, 1985. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Internal Medicine American Medical Association

Enhanced Bleeding With Cefoxitin or Moxalactam: Statistical Analysis Within a Defined Population of 1493 Patients

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Publisher
American Medical Association
Copyright
Copyright © 1986 American Medical Association. All Rights Reserved.
ISSN
0003-9926
eISSN
1538-3679
DOI
10.1001/archinte.1986.00360230079013
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Abstract

Abstract • Most cases of β-lactam-associated coagulopathy occur in patients with other risk factors. This study analyzed temporally related clinical bleeding events in 1493 patients who received one antibiotic for at least three days. Univariate and multivariate analyses controlled for condition variables (nutritional status, renal, hepatic, or hematologic dysfunction, intensive care unit stay) and treatment variables (use of antiplatelet agents, anticoagulants, vitamin K, antitumor chemotherapy or antiulcer therapy, steroids) that could have been associated with bleeding independently. Rates of bleeding ranged from 0% (chloramphenicol sodium succinate, vancomycin hydrochloride, erythromycin lactobionate) to 8.2% (cefoxitin) to 22.2% (moxalactam disodium). Multiple logistic regression analyses revealed that only moxalactam (odds ratio, 9.9) and cefoxitin (odds ratio, 2.1) exhibited significantly higher likelihoods of bleeding than other agents. This study statistically confirms increased risk of bleeding with moxalactam, heretofore reported only anecdotally. Cefoxitin may carry risks greater than previously believed. (Arch Intern Med 1986;146:2159-2164) References 1. Clancy CM, Gleckman RH: Hypoprothrombinemia and bleeding associated with cefamandole. Lancet 1983;1:250.Crossref 2. Hooper CA, Haney BB, Stone HH: Gastrointestinal bleeding due to vitamin K deficiency in patients on parenteral cefamandole. Lancet 1980;1: 39.Crossref 3. Panwalker AP, Rosenfeld J: Hemorrhage, diarrhea and superinfection associated with the use of moxalactam. J Infect Dis 1983;147:171-172.Crossref 4. Jones SR, Kimbrough RC: Moxalactam and hemorrhage. Ann Intern Med 1983;99:126.Crossref 5. Rahal JJ Jr, Simberkoff MS, Landesman SH: Prospective evaluation of moxalactam therapy for gram-negative bacillary meningitis. J Infect Dis 1984;149:562-567.Crossref 6. Fishman L, Marsh WR: Prolonged bleeding time associated with moxalactam administration. Neurosurgery 1984;14:735-736.Crossref 7. Weitekamp MR, Aber RC: Prolonged bleeding time and bleeding diatheses associated with moxalactam administration. JAMA 1983;249:69-71.Crossref 8. Srinivasan S, Francke EL, Neu HC: Use of moxalactam in therapy of infections due to multiresistant bacteria, abstract 365. Program and abstracts of the 20th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC, Sept 22-24, 1980. 9. Bach MC: Prolonged bleeding time associated with 'low dose' moxalactam therapy. JAMA 1984;251:3082.Crossref 10. Shenkenberg TD, Mackowiak PA, Smith JW: Coagulopathy and hemorrhage associated with cefoperazone therapy in a patient with renal failure. South Med J 1985;78:488-489.Crossref 11. Shatth SJ, Bennett JS, McDonough M, et al: Carbenicillin and penicillin G inhibit platelet function in vitro by impairing the interaction of agonists with the platelet surface. J Clin Invest 1980;44:329-337.Crossref 12. Ballard JO, Barnes SG, Sattler FR: Comparison of the effects of mezlocillin, carbenicillin, and placebo on normal hemostasis. Antimicrob Agents Chemother 1984;25:153-156.Crossref 13. Somani P, Freimer EH, Smith MR, et al: Bleeding abnormalities and β-lactam penicillins, abstract 959. Program and abstracts of the 24th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC, Oct 8-10, 1984. 14. Somani P, Smith MR, Gohara A, et al: The effects of mezlocillin, ticarcillin and placebo on blood coagulation and bleeding time in normal volunteers. J Antimicrob Chemother 1983;11( (suppl C) ):33-41.Crossref 15. Natelson EA, Brown CH III, Bradshaw MW, et al: Influence of cephalosporin antibiotics on blood coagulation and platelet function. Antimicrob Agents Chemother 1976;9:91-93.Crossref 16. Alexander DP, Russo ME, Fohrman DE, et al: Nafcillin-induced platelet dysfunction and bleeding. Antimicrob Agents Chemother 1983;23: 59-62.Crossref 17. Gentry LO, Jemsek JG, Natelson EA: Effects of sodium piperacillin on platelet function in normal volunteers. Antimicrob Agents Chemother 1981;19:532-533.Crossref 18. Fedder IL, Holmes S, Vlasses SH, et al: Effect of intravenous carbenicillin, cefoxitin and cefamandole on ADP-induced platelet aggregation and shape change. Thromb Res 1983;32:215-222.Crossref 19. Brown CH III, Natelson EA, Bradshaw MW, et al: The hemostatic defect produced by carbenicillin. N Engl J Med 1974;291:265-271.Crossref 20. Brown AE, Quesada O, Murrer JA, et al: Assessment of coagulation problems in patients with cancer receiving empiric antibiotic therapy, abstract C-355. Program and abstracts of the 19th Meeting of the American Society of Clinical Oncology, San Diego, May 22-24,1983. 21. Cristano P: Hypoprothrombinemia associated with cefoperazone treatment. Drug Intell Clin Pharm 1984;18:314-316. 22. Cohen MS, Washton HE, Barranco SF: Multicenter trial of cefoperazone sodium in the United States. Am J Med 1984;77:35-41.Crossref 23. Lerner PI, Lubin A: Coagulopathy with cefazolin in uremia. N Engl J Med 1974;290:1324. 24. Papa MZ, Amsterdam E, Schniederman J, et al: Hemorrhagic complications encountered on a surgical service. Am J Surg 1984;147:378-381.Crossref 25. Schuster DP, Rowley H, Feinstein S, et al: Prospective evaluation of the risk of upper gastrointestinal bleeding after admission to a medical intensive care unit. Am J Med 1984;76:623-630.Crossref 26. Zuckerman GR, Cornette GL, Clouse RE, et al: Upper gastrointestinal bleeding in patients with chronic renal failure. Ann Intern Med 1985;102:588-592.Crossref 27. Fainstein V, Bodey GP, McCredie KB, et al: Coagulation abnormalities induced by β-lactam antibiotics in cancer patients. J Infect Dis 1983; 148:745-750.Crossref 28. Morris DL, Fabricius PJ, Ambrose NS, et al: A high incidence of bleeding is observed in a trial to determine whether addition of metronidazole is needed with latamoxef for prophylaxis in colorectal surgery. J Hosp Infect 1984;5:398-408.Crossref 29. Klippel AP, Pitsinger B: Hypoprothrombinemia secondary to antibiotic therapy and manifested by massive gastrointestinal hemorrhage. Arch Surg 1968;96:266-268.Crossref 30. Reddy J, Bailey RR: Vitamin K deficiency developing in patients with renal failure treated with cephalosporin antibiotics. NZ Med J 1980;92:378-380. 31. Pineo GF, Gallus AS, Hirsch J: Unexpected vitamin K deficiency in hospitalized patients. Can Med Assoc J 1973;109:880-883. 32. Malpass TW, Harker LA: Acquired disorders of platelet dysfunction. Semin Hematol 1980;17:242-258. 33. Weiss HJ: Platelet physiology and abnormalities of platelet function. N Engl J Med 1975;293:531-541, 580-588.Crossref 34. McCabe WR, Jackson GG: Gram-negative bacteremia. Arch Intern Med 1962;110:847-855.Crossref 35. Lemeshow S, Hosmer DW: Estimating odds ratios with categorically scaled covariates in multiple logistic regression analysis. Am J Epidemiol 1984;119:147-151. 36. Ham JM: Hypoprothrombinemia in patients undergoing prolonged intensive care. Med J Aust 1971;2:716-718. 37. Kozak AJ, Bertino JS, Reese RE, et al: Hypoprothrombinemia associated with concurrent use of cefamandole in a rural teaching hospital, abstract 1216. Program and abstracts of the 24th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC, Oct 8-10,1984. 38. Neu HC: Adverse effects of new cephalosporins. Ann Intern Med 1983;98:415-416. 39. Bang NU, Kammer RB: Hematologic complications associated with β-lactam antibiotics. Rev Infect Dis 1983;5( (suppl 2) ):S380-S393.Crossref 40. Bang NU, Tessler SS, Heidenreich RO, et al: Effects of moxalactam on blood coagulation and platelet function. Rev Infect Dis 1982;4( (suppl) ): S546-S554.Crossref 41. Lipsky JJ, Lewis JC, Novick WJ: Production of hypoprothrombinemia by moxalactam and 1-methyl 5-thiotetrazole in rats. Antimicrob Agents Chemother 1984;25:380-381.Crossref 42. Lipsky JJ: N-methyl thiotetrazole inhibition of the gamma carboxylation of glutamic acid: Possible mechanism for antibiotic-induced hypoprothrombinemia. Lancet 1983;1:192-193.Crossref 43. Lipsky JJ: Latamoxef-associated hypoprothrombinemia. Lancet 1983;1:624.Crossref 44. Wold JS, Buening MK, Hanasono GK: Latamoxef-associated hypoprothrombinemia. Lancet 1983;1:408.Crossref 45. Conly JM, Ramotar K, Chubb H, et al: Hypoprothrombinemia in febrile, neutropenic patients with cancer: Association with antimicrobial suppression of intestinal microflora. J Infect Dis 1984;150:202-212.Crossref 46. Andrassy K, Bechtold H, Ritz E: Hypoprothrombinemia caused by cephalosporins. J Antimicrob Chemother 1985;15:133-135.Crossref 47. Lipsky JJ, Lewis JC, Novick WJ Jr: The role of the 2-methyl, 1,3,4-thiadiazole, 5-thiol leaving group in cefazolin-induced hypoprothrombinemia, abstract 703. Program and abstracts of the 25th Interscience Conference on Antimicrobial Agents and Chemotherapy, Minneapolis, Sept 29-Oct 2, 1985.

Journal

Archives of Internal MedicineAmerican Medical Association

Published: Nov 1, 1986

References