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Search Health Information    Trimethoprim/Sulfamethoxazole

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Trimethoprim/Sulfamethoxazole

Drug Information

The antibiotic combination of trimethoprim and sulfamethoxazole (TMP/SMX) is used to treat a wide variety of bacterial infections and some infections due to parasites . Bactrim, Cotrim, and Septra are brand names for products containing identical amounts of TMP/SMX. Bactrim DS and Septra DS contain twice as much TMP and SMX as Bactrim and Septra.

Common brand names:

Bactrim DS, Cotrim DS, Septra DS, SMZ-TMP DS

Summary of Interactions with Vitamins, Herbs, & Foods

Types of interactions: Beneficial Adverse Check

Replenish Depleted Nutrients

  • Calcium

    Sulfonamides, including sulfamethoxazole, can decrease absorption of calcium, magnesium, and vitamin B12.1 This is generally not a problem when taking sulfamethoxazole for two weeks or less. People taking sulfamethoxazole for longer than two weeks should ask their doctor about nutrient monitoring and supplementation.

    Note:Since sulfamethoxazole is often prescribed in combination with trimethoprim (for example, in Bactrim or Septra), it may be easy to associate this interaction with trimethoprim. However, this interaction is not known to occur with trimethoprim alone.

    The interaction is supported by preliminary, weak, fragmentary, and/or contradictory scientific evidence.
  • Folic Acid

    Sulfonamides, including sulfamethoxazole, can interfere with the activity of folic acid, vitamin B6, and vitamin K.3 This is generally not a problem when taking sulfamethoxazole for two weeks or less. People taking sulfamethoxazole for longer than two weeks should ask their doctor about nutrient monitoring and supplementation.

    Note:Since sulfamethoxazole is often prescribed in combination with trimethoprim (for example, in Bactrim or Septra), it may be easy to associate this interaction with trimethoprim. However, this interaction is not known to occur with trimethoprim alone.

    The interaction is supported by preliminary, weak, fragmentary, and/or contradictory scientific evidence.
  • Magnesium

    Sulfonamides, including sulfamethoxazole , can decrease absorption of calcium, magnesium, and vitamin B12.9 This is generally not a problem when taking sulfamethoxazole for two weeks or less. People taking sulfamethoxazole for longer than two weeks should ask their doctor about nutrient monitoring and supplementation.

    The interaction is supported by preliminary, weak, fragmentary, and/or contradictory scientific evidence.
  • Vitamin B12

    Sulfonamides, including sulfamethoxazole , can decrease absorption of calcium, magnesium, and vitamin B12.11 This is generally not a problem when taking sulfamethoxazole for two weeks or less. People taking sulfamethoxazole for longer than two weeks should ask their doctor about nutrient monitoring and supplementation.

    The interaction is supported by preliminary, weak, fragmentary, and/or contradictory scientific evidence.
  • Vitamin B6

    Sulfonamides, including sulfamethoxazole, can interfere with the activity of folic acid, vitamin B6, and vitamin K.13 This is generally not a problem when taking sulfamethoxazole for two weeks or less. People taking sulfamethoxazole for longer than two weeks should ask their doctor about nutrient monitoring and supplementation.

    Note:Since sulfamethoxazole is often prescribed in combination with trimethoprim (for example, in Bactrim or Septra), it may be easy to associate this interaction with trimethoprim. However, this interaction is not known to occur with trimethoprim alone.

    The interaction is supported by preliminary, weak, fragmentary, and/or contradictory scientific evidence.

Reduce Side Effects

  • Probiotics

    A common side effect of antibiotics is diarrhea , which may be caused by the elimination of beneficial bacteria normally found in the colon. Controlled studies have shown that taking probiotic microorganisms—such as Lactobacillus casei, Lactobacillus acidophilus, Bifidobacterium longum, or Saccharomyces boulardii—helps prevent antibiotic-induced diarrhea.19

    The diarrhea experienced by some people who take antibiotics also might be due to an overgrowth of the bacterium Clostridium difficile, which causes a disease known as pseudomembranous colitis. Controlled studies have shown that supplementation with harmless yeast—such as Saccharomyces boulardii 20 or Saccharomyces cerevisiae (baker’s or brewer’s yeast)21—helps prevent recurrence of this infection. In one study, taking 500 mg of Saccharomyces boulardii twice daily enhanced the effectiveness of the antibiotic vancomycin in preventing recurrent clostridium infection.22 Therefore, people taking antibiotics who later develop diarrhea might benefit from supplementing with saccharomyces organisms.

    Treatment with antibiotics also commonly leads to an overgrowth of yeast (Candida albicans) in the vagina ( candida vaginitis ) and the intestines (sometimes referred to as “dysbiosis”). Controlled studies have shown that Lactobacillus acidophilus might prevent candida vaginitis.23

  • Brewer’s Yeast

    A common side effect of antibiotics is diarrhea , which may be caused by the elimination of beneficial bacteria normally found in the colon. Controlled studies have shown that taking probiotic microorganisms—such as Lactobacillus casei, Lactobacillus acidophilus, Bifidobacterium longum, or Saccharomyces boulardii—helps prevent antibiotic-induced diarrhea.34

    The diarrhea experienced by some people who take antibiotics also might be due to an overgrowth of the bacterium Clostridium difficile, which causes a disease known as pseudomembranous colitis. Controlled studies have shown that supplementation with harmless yeast—such as Saccharomyces boulardii 35 or Saccharomyces cerevisiae (baker’s or brewer’s yeast)36—helps prevent recurrence of this infection. In one study, taking 500 mg of Saccharomyces boulardii twice daily enhanced the effectiveness of the antibiotic vancomycin in preventing recurrent clostridium infection.37 Therefore, people taking antibiotics who later develop diarrhea might benefit from supplementing with saccharomyces organisms.

    Treatment with antibiotics also commonly leads to an overgrowth of yeast (Candida albicans) in the vagina ( candida vaginitis ) and the intestines (sometimes referred to as “dysbiosis”). Controlled studies have shown that Lactobacillus acidophilus might prevent candida vaginitis.38

    The interaction is supported by preliminary, weak, fragmentary, and/or contradictory scientific evidence.

Support Medicine

  • Probiotics

    A common side effect of antibiotics is diarrhea , which may be caused by the elimination of beneficial bacteria normally found in the colon. Controlled studies have shown that taking probiotic microorganisms—such as Lactobacillus casei, Lactobacillus acidophilus, Bifidobacterium longum, or Saccharomyces boulardii—helps prevent antibiotic-induced diarrhea.49

    The diarrhea experienced by some people who take antibiotics also might be due to an overgrowth of the bacterium Clostridium difficile, which causes a disease known as pseudomembranous colitis. Controlled studies have shown that supplementation with harmless yeast—such as Saccharomyces boulardii 50 or Saccharomyces cerevisiae (baker’s or brewer’s yeast)51—helps prevent recurrence of this infection. In one study, taking 500 mg of Saccharomyces boulardii twice daily enhanced the effectiveness of the antibiotic vancomycin in preventing recurrent clostridium infection.52 Therefore, people taking antibiotics who later develop diarrhea might benefit from supplementing with saccharomyces organisms.

    Treatment with antibiotics also commonly leads to an overgrowth of yeast (Candida albicans) in the vagina ( candida vaginitis ) and the intestines (sometimes referred to as “dysbiosis”). Controlled studies have shown that Lactobacillus acidophilus might prevent candida vaginitis.53

Reduces Effectiveness

  • none

Potential Negative Interaction

  • Potassium

    TMP/SMX has been reported to elevate potassium and other constituents of blood (creatinine and BUN).59 In particular, people with impaired kidney function should be closely monitored by their prescribing doctor for these changes. People taking sulfamethoxazole or TMP/SMX should talk with their prescribing doctor before taking any potassium supplements or potassium-containing products, such as No Salt, Salt Substitute, Lite Salt, and even high-potassium foods (primarily fruit).

  • PABA

    PABA (para-aminobenzoic acid) may interfere with the action of sulfamethoxazole. It should not be taken together with trimethoprim/sulfamethoxazole.

    The interaction is supported by preliminary, weak, fragmentary, and/or contradictory scientific evidence.

Explanation Required 

  • Folic Acid

    The use of multivitamin supplements containing folic acid diminishes the occurrence of birth defects associated with trimethoprim. According to one study,63 pregnant women who took folic acid–containing multivitamin supplements in addition to their prescription drugs had fewer babies with heart defects and deformities of the upper lip and mouth.

    The combination drug trimethoprim/sulfamethoxazole (TMP/SMX) has been rarely associated with folic acid-deficiency anemia.64 This action may be due to trimethoprim-induced folic acid depletion.65 Trimethoprim and TMP/SMX should be used with caution in patients with folic acid deficiency, for which blood tests are available. Folic acid replacement does not interfere with the antibacterial activity of trimethoprim66 or TMP/SMX.67

  • Vitamin K

    Several cases of excessive bleeding have been reported in people who take antibiotics.68 , 69 , 70 , 71 This side effect may be the result of reduced vitamin K activity and/or reduced vitamin K production by bacteria in the colon. One study showed that people who had taken broad-spectrum antibiotics had lower liver concentrations of vitamin K2 (menaquinone), though vitamin K1 (phylloquinone) levels remained normal.72 Several antibiotics appear to exert a strong effect on vitamin K activity, while others may not have any effect. Therefore, one should refer to a specific antibiotic for information on whether it interacts with vitamin K. Doctors of natural medicine sometimes recommend vitamin K supplementation to people taking antibiotics. Additional research is needed to determine whether the amount of vitamin K1 found in some multivitamins is sufficient to prevent antibiotic-induced bleeding. Moreover, most multivitamins do not contain vitamin K.

    The interaction is supported by preliminary, weak, fragmentary, and/or contradictory scientific evidence.
The Drug-Nutrient Interactions table may not include every possible interaction. Taking medicines with meals, on an empty stomach, or with alcohol may influence their effects. For details, refer to the manufacturers’ package information as these are not covered in this table. If you take medications, always discuss the potential risks and benefits of adding a new supplement with your doctor or pharmacist.

References

1. Holt GA. Food & Drug Interactions. Chicago: Precept Press, 1998, 248–49, 250–1.

2. Holt GA. Food & Drug Interactions. Chicago: Precept Press, 1998, 248–49, 250–1.

3. Holt GA. Food & Drug Interactions. Chicago: Precept Press,1998, 248–49, 251–2.

4. Holt GA. Food & Drug Interactions. Chicago: Precept Press, 1998, 248–49, 251–2.

5. Young LY, Koda-Kimble MA, eds. Applied Therapeutics: The Clinical Use of Drugs. Vancouver, WA: Applied Therapeutics, 1988, 911.

6. Kahn SB, Fein SA, Brodsky I. Effects of trimethoprim on folate metabolism in man. Clin Pharmacol Ther 1968;9:550–60.

7. Young LY, Koda-Kimble MA, eds. Applied Therapeutics: The Clinical Use of Drugs. Vancouver, WA: Applied Therapeutics, 1988, 911.

8. Safrin S, Lee BL, Sande MA. Adjunctive folinic acid with trimethoprim-sulfamethoxazole for pneumocystis carinii pneumonia in AIDS patients is associated with an increased risk of therapeutic failure and death. J Infect Dis 1994;170:912–7.

9. Holt GA. Food & Drug Interactions. Chicago: Precept Press, 1998, 248–49, 250–1.

10. Holt GA. Food & Drug Interactions. Chicago: Precept Press, 1998, 248–49, 250–1.

11. Holt GA. Food & Drug Interactions. Chicago: Precept Press, 1998, 248–49, 250–1.

12. Holt GA. Food & Drug Interactions. Chicago: Precept Press, 1998, 248–49, 250–1.

13. Holt GA. Food & Drug Interactions. Chicago: Precept Press,1998, 248–49, 251–2.

14. Holt GA. Food & Drug Interactions. Chicago: Precept Press, 1998, 248–49, 251–2.

15. Young LY, Koda-Kimble MA, eds. Applied Therapeutics: The Clinical Use of Drugs. Vancouver, WA: Applied Therapeutics, 1988, 911.

16. Kahn SB, Fein SA, Brodsky I. Effects of trimethoprim on folate metabolism in man. Clin Pharmacol Ther 1968;9:550–60.

17. Young LY, Koda-Kimble MA, eds. Applied Therapeutics: The Clinical Use of Drugs. Vancouver, WA: Applied Therapeutics, 1988, 911.

18. Safrin S, Lee BL, Sande MA. Adjunctive folinic acid with trimethoprim-sulfamethoxazole for pneumocystis carinii pneumonia in AIDS patients is associated with an increased risk of therapeutic failure and death. J Infect Dis 1994;170:912–7.

19. Elmer GW, Surawicz CM, McFarland LV. Biotherapeutic agents. A neglected modality for the treatment and prevention of selected intestinal and vaginal infections. JAMA 1996;275:870–6 [review].

20. Elmer GW, Surawicz CM, McFarland LV. Biotherapeutic agents. A neglected modality for the treatment and prevention of selected intestinal and vaginal infections. JAMA 1996;275:870–6 [review].

21. Schellenberg D, Bonington A, Champion CM, et al. Treatment of Clostridium difficile diarrhoea with brewer’s yeast. Lancet 1994;343:171–2.

22. Surawicz CM, Elmer GW, Speelman P, et al. Prevention of antibiotic-associated diarrhea by Saccharomyces boulardii: A prospective study. Gastroenterol 1989;96:981–8.

23. Elmer GW, Surawicz CM, McFarland LV. Biotherapeutic agents. A neglected modality for the treatment and prevention of selected intestinal and vaginal infections. JAMA 1996;275:870–6 [review].

24. Elmer GW, Surawicz CM, McFarland LV. Biotherapeutic agents. A neglected modality for the treatment and prevention of selected intestinal and vaginal infections. JAMA 1996;275:870–6 [review].

25. Elmer GW, Surawicz CM, McFarland LV. Biotherapeutic agents. A neglected modality for the treatment and prevention of selected intestinal and vaginal infections. JAMA 1996;275:870–6 [review].

26. Schellenberg D, Bonington A, Champion CM, et al. Treatment of Clostridium difficile diarrhoea with brewer’s yeast. Lancet 1994;343:171–2.

27. Surawicz CM, Elmer GW, Speelman P, et al. Prevention of antibiotic-associated diarrhea by Saccharomyces boulardii: A prospective study. Gastroenterol 1989;96:981–8.

28. Elmer GW, Surawicz CM, McFarland LV. Biotherapeutic agents. A neglected modality for the treatment and prevention of selected intestinal and vaginal infections. JAMA 1996;275:870–6 [review].

29. Elmer GW, Surawicz CM, McFarland LV. Biotherapeutic agents. A neglected modality for the treatment and prevention of selected intestinal and vaginal infections. JAMA 1996;275:870–6 [review].

30. Elmer GW, Surawicz CM, McFarland LV. Biotherapeutic agents. A neglected modality for the treatment and prevention of selected intestinal and vaginal infections. JAMA 1996;275:870–6 [review].

31. Schellenberg D, Bonington A, Champion CM, et al. Treatment of Clostridium difficile diarrhoea with brewer’s yeast. Lancet 1994;343:171–2.

32. Surawicz CM, Elmer GW, Speelman P, et al. Prevention of antibiotic-associated diarrhea by Saccharomyces boulardii: A prospective study. Gastroenterol 1989;96:981–8.

33. Elmer GW, Surawicz CM, McFarland LV. Biotherapeutic agents. A neglected modality for the treatment and prevention of selected intestinal and vaginal infections. JAMA 1996;275:870–6 [review].

34. Elmer GW, Surawicz CM, McFarland LV. Biotherapeutic agents. A neglected modality for the treatment and prevention of selected intestinal and vaginal infections. JAMA 1996;275:870–6 [review].

35. Elmer GW, Surawicz CM, McFarland LV. Biotherapeutic agents. A neglected modality for the treatment and prevention of selected intestinal and vaginal infections. JAMA 1996;275:870–6 [review].

36. Schellenberg D, Bonington A, Champion CM, et al. Treatment of Clostridium difficile diarrhoea with brewer’s yeast. Lancet 1994;343:171–2.

37. Surawicz CM, Elmer GW, Speelman P, et al. Prevention of antibiotic-associated diarrhea by Saccharomyces boulardii: A prospective study. Gastroenterol 1989;96:981–8.

38. Elmer GW, Surawicz CM, McFarland LV. Biotherapeutic agents. A neglected modality for the treatment and prevention of selected intestinal and vaginal infections. JAMA 1996;275:870–6 [review].

39. Elmer GW, Surawicz CM, McFarland LV. Biotherapeutic agents. A neglected modality for the treatment and prevention of selected intestinal and vaginal infections. JAMA 1996;275:870–6 [review].

40. Elmer GW, Surawicz CM, McFarland LV. Biotherapeutic agents. A neglected modality for the treatment and prevention of selected intestinal and vaginal infections. JAMA 1996;275:870–6 [review].

41. Schellenberg D, Bonington A, Champion CM, et al. Treatment of Clostridium difficile diarrhoea with brewer’s yeast. Lancet 1994;343:171–2.

42. Surawicz CM, Elmer GW, Speelman P, et al. Prevention of antibiotic-associated diarrhea by Saccharomyces boulardii: A prospective study. Gastroenterol 1989;96:981–8.

43. Elmer GW, Surawicz CM, McFarland LV. Biotherapeutic agents. A neglected modality for the treatment and prevention of selected intestinal and vaginal infections. JAMA 1996;275:870–6 [review].

44. Elmer GW, Surawicz CM, McFarland LV. Biotherapeutic agents. A neglected modality for the treatment and prevention of selected intestinal and vaginal infections. JAMA 1996;275:870–6 [review].

45. Elmer GW, Surawicz CM, McFarland LV. Biotherapeutic agents. A neglected modality for the treatment and prevention of selected intestinal and vaginal infections. JAMA 1996;275:870–6 [review].

46. Schellenberg D, Bonington A, Champion CM, et al. Treatment of Clostridium difficile diarrhoea with brewer’s yeast. Lancet 1994;343:171–2.

47. Surawicz CM, Elmer GW, Speelman P, et al. Prevention of antibiotic-associated diarrhea by Saccharomyces boulardii: A prospective study. Gastroenterol 1989;96:981–8.

48. Elmer GW, Surawicz CM, McFarland LV. Biotherapeutic agents. A neglected modality for the treatment and prevention of selected intestinal and vaginal infections. JAMA 1996;275:870–6 [review].

49. Elmer GW, Surawicz CM, McFarland LV. Biotherapeutic agents. A neglected modality for the treatment and prevention of selected intestinal and vaginal infections. JAMA 1996;275:870–6 [review].

50. Elmer GW, Surawicz CM, McFarland LV. Biotherapeutic agents. A neglected modality for the treatment and prevention of selected intestinal and vaginal infections. JAMA 1996;275:870–6 [review].

51. Schellenberg D, Bonington A, Champion CM, et al. Treatment of Clostridium difficile diarrhoea with brewer’s yeast. Lancet 1994;343:171–2.

52. Surawicz CM, Elmer GW, Speelman P, et al. Prevention of antibiotic-associated diarrhea by Saccharomyces boulardii: A prospective study. Gastroenterol 1989;96:981–8.

53. Elmer GW, Surawicz CM, McFarland LV. Biotherapeutic agents. A neglected modality for the treatment and prevention of selected intestinal and vaginal infections. JAMA 1996;275:870–6 [review].

54. Elmer GW, Surawicz CM, McFarland LV. Biotherapeutic agents. A neglected modality for the treatment and prevention of selected intestinal and vaginal infections. JAMA 1996;275:870–6 [review].

55. Elmer GW, Surawicz CM, McFarland LV. Biotherapeutic agents. A neglected modality for the treatment and prevention of selected intestinal and vaginal infections. JAMA 1996;275:870–6 [review].

56. Schellenberg D, Bonington A, Champion CM, et al. Treatment of Clostridium difficile diarrhoea with brewer’s yeast. Lancet 1994;343:171–2.

57. Surawicz CM, Elmer GW, Speelman P, et al. Prevention of antibiotic-associated diarrhea by Saccharomyces boulardii: A prospective study. Gastroenterol 1989;96:981–8.

58. Elmer GW, Surawicz CM, McFarland LV. Biotherapeutic agents. A neglected modality for the treatment and prevention of selected intestinal and vaginal infections. JAMA 1996;275:870–6 [review].

59. Alappan R, Perazella MA, Buller GK. Hyperkalemia in hospitalized patients treated with trimethoprim-sulfamethoxazole. Ann Intern Med 1996;124:316–20.

60. Alappan R, Perazella MA, Buller GK. Hyperkalemia in hospitalized patients treated with trimethoprim-sulfamethoxazole. Ann Intern Med 1996;124:316–20.

61. Perazella MA. Drug-induced hyperkalemia: Old culprits and new offenders. Am J Med 2000;109:307–14 [review].

62. Alappan R, Perazella MA, Buller GK. Hyperkalemia in hospitalized patients treated with trimethoprim-sulfamethoxazole. Ann Intern Med 1996;124:316–20.

63. Hernández-Díaz S, Werler MM, Walker AM, Mitchell AA. Folic acid antagonists during pregnancy and the risk of birth defects. New Engl J Med 2000;343:1608–14.

64. Sahai J. Urinary tract infections. In Applied Therapeutics: The Clinical Use of Drugs, 6th ed. Vancouver, WA: Applied Therapeutics, 1995, 63–6.

65. Kahn SB, Fein SA, Brodsky I. Effects of trimethoprim on folate metabolism in man. Clin Pharmacol Ther 1968;9:550–60.

66. Threlkeld DS, ed. Systemic Anti-Infectives, Miscellaneous Anti-Infectives, Trimethoprim. In Facts and Comparisons Drug Information. St. Louis, MO: Facts and Comparisons, Aug 1992, 408–a.

67. Sahai J. Urinary tract infections. In Applied Therapeutics: The Clinical Use of Drugs, 6th ed. Vancouver, WA: Applied Therapeutics, 1995, 63–6.

68. Suzuki K, Fukushima T, Meguro K, et al. Intracranial hemorrhage in an infant owing to vitamin K deficiency despite prophylaxis. Childs Nerv Syst 1999;15:292–4.

69. Huilgol VR, Markus SL, Vakil NB. Antibiotic-induced iatrogenic hemobilia. Am J Gastroenterol 1997;92:706–7.

70. Bandrowsky T, Vorono AA, Borris TJ, Marcantoni HW. Amoxicllin-related postextraction bleeding in an anticoagulated patient with tranexamic acid rinses. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996;82:610–2.

71. Kaiser CW, McAuliffe JD, Barth RJ, Lynch JA. Hypoprothrombinemia and hemorrhage in a surgical patient treated with cefotetan. Arch Surg 1991;126:524–5.

72. Conly J, Stein K. Reduction of vitamin K2 concentration in human liver associated with the use of broad spectrum antimicrobials. Clin Invest Med 1994;17:531–9.

73. Suzuki K, Fukushima T, Meguro K, et al. Intracranial hemorrhage in an infant owing to vitamin K deficiency despite prophylaxis. Childs Nerv Syst 1999;15:292–4.

74. Huilgol VR, Markus SL, Vakil NB. Antibiotic-induced iatrogenic hemobilia. Am J Gastroenterol 1997;92:706–7.

75. Bandrowsky T, Vorono AA, Borris TJ, Marcantoni HW. Amoxicllin-related postextraction bleeding in an anticoagulated patient with tranexamic acid rinses. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996;82:610–2.

76. Kaiser CW, McAuliffe JD, Barth RJ, Lynch JA. Hypoprothrombinemia and hemorrhage in a surgical patient treated with cefotetan. Arch Surg 1991;126:524–5.

77. Conly J, Stein K. Reduction of vitamin K2 concentration in human liver associated with the use of broad spectrum antimicrobials. Clin Invest Med 1994;17:531–9.

78. Suzuki K, Fukushima T, Meguro K, et al. Intracranial hemorrhage in an infant owing to vitamin K deficiency despite prophylaxis. Childs Nerv Syst 1999;15:292–4.

79. Huilgol VR, Markus SL, Vakil NB. Antibiotic-induced iatrogenic hemobilia. Am J Gastroenterol 1997;92:706–7.

80. Bandrowsky T, Vorono AA, Borris TJ, Marcantoni HW. Amoxicllin-related postextraction bleeding in an anticoagulated patient with tranexamic acid rinses. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996;82:610–2.

81. Kaiser CW, McAuliffe JD, Barth RJ, Lynch JA. Hypoprothrombinemia and hemorrhage in a surgical patient treated with cefotetan. Arch Surg 1991;126:524–5.

82. Conly J, Stein K. Reduction of vitamin K2 concentration in human liver associated with the use of broad spectrum antimicrobials. Clin Invest Med 1994;17:531–9.

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