- Email: [email protected]
Analysis of prothrombin time prolongation in north American cefotetan clinical trials: Questions and answers
Schentag et al
with n o r m a l v i t a m i n K status. In surveillance studies, N M T T - c o n t a i n i n g antibiotics were no m o r e freq u e n t l y associated with h y p o p r o t h r o m b i n e m i a or bleeding t h a n antibiotics t h a t lack this moiety.
10.
11.
References 1. Joehl RJ,'Rasback DA, Ballard JO, Weitekamp MR, Sattler FR. Moxalactam: evaluation of clinical bleeding in patients with abdominal infection. Arch Surg 1983; 118: 1259-61. 2. Pakter RL, Russell TR, Mielke CH, West D. Coagulopathy associated with the use of moxalactam. JAMA 1982; 248: 1100-2. 3. Baxter JG, Marble DA, Whitfield LR, Wels PB, Walczak P, Schentag JJ. Clinical risk factors for prolonged PT/PTT in abdominal sepsis patients treated with moxalactam or tobramycin plus clindamycin. Ann Surg 1985; 201: 96-102. 4. Schentag JJ, Welage LS, Grasela TH, Adelman MH. Determinants of antibiotic-associated hypoprothrombinemia. Pharmacotherapy 1987; 7: 80-6. 5. Sattler FR, Weitekamp MR, Ballard JO. Potential for bleeding with the new beta-lactam antibiotics. Ann Intern Med 1986; 105: 924-31. 6. Lipsky JJ, N-methyl-thio-tetrazole inhibition of the gamma carboxylation of glutamic acid: possible mechanism for antibiotic-associated hypoprothrombinemia. Lancet 1983; 2: 192-3. 7. Kerremans AL, Lipsky JJ, Van Loon J, Gallego MO, Weinshilbourn RM. Cephalosporin-induced hypoprothrombinemia: possible role for thiol methylation of 1-methyltetrazole-5thiol and 2-methyl-l,3,4-thiadiazole-5-thiol. J Pharmacol Exp Ther 1985; 235: 382-8. 8. Uotila L, Suttie JW. Inhibition of vitamin K-dependent carboxylase in vitro by cefamandole and its structural analogs. J Infect Dis 1983; 150: 571-8. 9. Aronoff GR, Wolen RL, Obermeyer BD, Black HR. Pharmacokinetics and protein binding of cefamandole and its 1-
12. 13.
14. 15.
16.
17. 18.
19.
methyl H-tetrazole-5 thiol side chain in subjects with normal and impaired renal function. J Infect Dis 1986; 153: 1069-74. Jusko WJ. Guidelines for collection and analysis of pharmacokinetic data. In: Evans W, Schentag J, Jusko W, eds. Applied pharmacokinetics. Spokane, WA: Applied Therapeutics, Inc., 1986: 9-84. Grasela TH, Schentag JJ. A clinical pharmacy oriented drug surveillance network. I: Program description. Drug Intell Clin Pharm 1987; 21: 902-8. Barza M, Furie B, Brown AE, Furie BC. Defects in vitamin Kdependent carboxylation associated with moxalactam treatment. J Infect Dis 1986; 153:1166-9. Morris DL, Fabricius PJ, Ambrose NS, Scammell B, Burdon DW, Keighley MR. 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. Ham FM. Hypoprothrombinemia in patients undergoing prolonged intensive care. Med J Aust 1971; 2: 716-8. Schentag JJ, Vari AJ, Winslade NE, et al. Treatment with aztreonam or tobramycin in critical care patients with nosocomial gram-negative pneumonia. Am J Med 1985; 78 (suppl 2A): 34-42. Brown RB, Klar J, Lemeshow S, Teres D, Pastides H, Sand M. Enhanced bleeding with cefoxitin and moxalactam. Statistical analysis within a defined population of 1493 patients. Arch Intern Med 1986; 146: 2159-64. Lipsky JJ, Lewis JC, Novick WJ. Production of hypoprothrombinemia by moxalactam and 1-methyl-5-thiotetrazole in rats. Antimicrob Agents Chemother 1984; 25: 380-1. Mackie IJ, Walshe K, Cohen H, et al. Effects of N-methyl thiotetrazole cephalosporin on haemostasis in patients with reduced serum vitamin K ~concentrations. J Clin Pathol 1986; 39: 1245-9. Weitekamp MR, Caputo GM, AI-Mondhiry HAB, Aber RC. The effects of latamoxef, cefotaxime, and cefoperazone on platelet function and coagulation in normal volunteers. J Antimicrob Chemother 1985; 16: 95-101.
FOCUS
Analysis of Prothrombin Time Prolongation in North American Cefotetan Clinical Trials: Questions and Answers
Neil H. Goldstein, M D , Wilmington, Delaware
Q: What has Stuart's experience been with hypoprothrombinemia associated with cefotetan? A: We undertook a retrospective analysis of prothrombin time prolongation in the North American cefotetan therapeutic clinical trials. All patients enrolled in these trials From the Division of Clinical and Medical Affairs, Stuart Pharmaceuticals, Wilmington, Delaware. Requests for reprints should be addressedto Neil H. Goldstein, MD, 'Division of Clinical and Medical Affairs, Stuart Pharmaceuticals,New Murphy Roadand Concord Pike, Wilmington,Delaware 19897.
44
who had a pretherapy and end or post-therapy prothrombin time were included in this analysis. Table I shows demographics for the cefotetan and comparator drug patients. The types of infections treated are shown for each drug. The cefotetan trials included patients with intraabdominal, gynecologic, skin and soft tissue, and gonococcal infections. Cefoxitin was used in all but the gonococcal trials. Moxalactam was one of our early comparators and only appears in the early intraabdomi-
The American Journal of Surgery
Symposium on the New Cephalosporins
TABLE I
Patients With R e p e a t e d P r o t h r o m b i n Times: Population C h a r a c t e r i s t i c s * Cefotetan (n = 890)
Cefoxitin (n = 138)
Moxalactam (n = 81)
Ceftriaxone (n = 73)
179 (20) 270 (30) 228 (26) 2 ! 3 (24)
42 (30.4) 57 (41.3) 39 (28.3) 0
44 (54) 37 (46) 0 0
0 0 0 73 (100)
Male
459 (52)
62 (45)
25 (31)
61 (84)
Female Age (yr) Range
431 (48)
76 (55)
56 (69)
12 (16)
16-931 35 28
16-84 33.5 28
16-895 39 29.5
17-44 w 25.5 24.5
41 (4)7 77 (9) 31 (3)
18 (13) 13 (9) 3 (2)
5 (6) 5 (6) 8 (10)
0 0 0
Parameter Infection type
Intraabdominal Gynecologic Skin, soft tissue Gonococcal Sex
Mean Median General condition
Poor, critical Alcohol abuse Cancer history Therapy duration (d) Range Mean Median
1-37
2-23
i-12
1
5.4 5
6.3 6
5.8 6
1 1
* Values in parentheses are percentages. 1, n = 879 patients. t n = 76 patients. w n = 72 patients. n = 889 patients.
nal and gynecologic trials. Ceftriaxone was a recent comparator and only appears in the gonococcal trials. The male to female ratios show a preponderance of women in the moxalactam group, most likely due to the proportion of gynecologic infections treated, and a preponderance of men treated for gonorrhea in the ceftriaxone group. The age ranges and mean and median ages for the first three groups are comparable. The ceftriaxone patients were younger. The general condition of the patient as indicated by the investigator showed a slightly higher percentage of patients in poor to critical condition in the cefoxitin group and none in the ceftriaxone group. The rates for alcohol abuse were again similar in the first three groups. The cancer rate was a little higher in the moxalactam group and was lowest in the ceftriaxone group. Not all the can: cers were clearly active at the time of entry into the study. Finally, duration of therapy was also quite similar, except for the shorter therapy in the ceftriaxone group. Despite the differences in types of infections treated, the cefotetan, cefoxitin, and moxalactam patients were fairly similar in their demographics. Ceftriaxone, however, had been used primarily for healthy male outpatients with gonorrhea. Table II shows the pretherapy laboratory values for the different treatment groups: T h e pretherapy creatinine ranges and percentage of patients with creatinine levels greater than 1.5 mg/dl were similar for the first three groups. The protocols discouraged the entering of patients with a creatinine level greater than 2.5 mg/dl. About half the patients in the first three groups had pzetherapy anemia as defined by a hemoglobin level of less than 14 g/dl in men or 12 g/dl in women. There were a
Volume 155 (5A), May 31, 1988
few patients with pretherapy platelet counts under 100,000 cells/mm 3. All the groups also had some patients with pretherapy prothrombin times above 14 seconds. This table, in addition to the previous one, indicates that the cefotetan, cefoxitin, and moxalactam patients were relatively similar in their pretherapy risk factors for coagulopathy. Table III shows the percentage of patients with prothrombin time elevations for each group. An increased prothrombin time was defined as an increase Of more than 1 second in patients who had a pretherapy prothrombin time less than or equal to 14 seconds and a follow-up prothrombin time greater than or equal to 15 seconds at end or post-therapy. It was believed that this definition would be more likely to identify patients with an antibiotic-induced prothrombin time elevation, since these patients all had essentially normal pretherapy prothrombin times. All elevations meeting this definition for the pr Othrombin time increase were included in the analysis regardless of whether the investigator reported the increase as drug-related. The data indicate a 2.5 percent rate of prothrombin time elevation for cefotetan compared with 1.6 percent for cefoxitin, 5.1 percent for moxalactam, and 4.2 percent for ceftriaxone. For the comparators, the total numbers are relatively small. In addition, although the first two tables show similar pretherapy risk profiles for the first three groups, these patient groups were heterogenous. The cefotetan patients, for instance, represent patients treated for several types of infections whose results were compared with those of several different agents. Therefore, although adverse-reaction data can be pooled to provide an overall view and suggest possible trends, a formal statistical anal-
45
Goldstein
T A B L E II
Patients With Repeated PrOthrombin Times: Laboratory Data* Data
Pretherapy creatinine (mg/dl) Range Mean Median Total Pretherapy creatihine ( > ! . 5 mg/dl) Pretherapy aner~ia t Total Pretherapy platelets ( < 100,000 cells/mm 3) Total Pretherapy prothrombin time (>14 s)
Cefotetan (n = 890)
Cefoxiti'n (n = 138)
Moxalactam (n = 81)
Ceftriaxone ( n = 73)
0.3-6.3 1 1 864 40 (5)
0.4-4.6 1.1 i 132 9 (7)
O. 1-2.9 1 0.9 77 6 (8)
0.7-1.5 1.1 1.1 72 0
385 (43) 886 10 (1)
84 (61) 137 0
34 (42)
7 (10) 72 0
813 51 (6)
134 12 (9)
69 3 (4)
2 (3)
2" i3')
* Values in parentheses are percentages. t Anemia defined as a hemoglobin level below 14 g/dl for men and below 12 g/dl for women.
TABLE III
Patients With Increased Prothrombin Time: Antibiotic Groups
Treatment
Cefotetan Cefoxitin Moxalactam Ceftriaxone
Patients With Repeated Prothrombin Times (PT) Patients With PT Total Increase T Number" n % 839 126 78 71
21 2 4 3
2.5 1.6 5.1 4.2
* Patients with a pretherapy prothrombin time of < 14 seconds and a repeated prothrombin time. T Patients with a greater than 1 second increase in prothrombin time, to 15 seconds or more,
ysis is difficult due to the intertrial differences. What is most important, however, is to examine the clinical consequence of the prothrombin time elevations. Each case report form for patients who fulfilled the definition of prothrombin time prolongation shown in Table III was individually examined, and all use of vitamin K was recorded. In addition, if the antibiotic was discontinued prematurely for the prothrombin time elevation or bleeding, this was recorded. Transfusions were included if they were given for prothrombin time elevation or clinical bleeding. Preoperative and immediate postoperative transfusions at the start of antibiotic therapy stated to be for chronic anemia or to replace surgical losses, or subsequent transfusions stated to be for chronic
46
anemia, were not included as required interventions if there was no evidence of clinical bleeding. Bleeding was reported if it was described anywhere in the case report form. Microscopic hematuria alone was not included, since many of the patients had indwelling Foley catheters. This analysis found that the only therapy given the 21 cefotetan patients was vitamin K, which was administered to 3 patients (14 percent). Two of these three patients had prothrombin time elevations of less than 10 seconds. In the third patient, the prothrombin time returned to within normal limits 1 day after receiving vitamin K. All of the cefotetan patients completed their course of antibiotics and none had evidence of clinical bleeding. Three of the four moxalactam patients required some type of intervention. Two received vitamin K, and one of these also had the antibiotic stopped prematurely. The third patient required a premature discontinuation of the antibiotic and transfusions for clinical gastrointestinal bleeding. There was no treatment given for prothrombin time elevations in the cefoxitin or ceftriaxone patients. In conclusion, a retrospective analysis of patients with follow-up prothrombin times indicates similar pretherapy risk factors for the cefotetan, cefoxitin, and moxalactam patients. The ceftriaxone patients were enrolled only in gonococcal trials and Were younger and healthier. Patients with prothrombin time elevations were identified in all the treatment groups, even the relatively healthy ceftriaxone patients. More importantly, however, the only bleeding seen was in a patient given moxalactam. The majority of that group also received therapy, including prematurely stopping the antibiotic and giving vitamin K. The onty therapy given for the cefotetan patients was vitamin K in three patients.
The American Journal of Surgery
with n o r m a l v i t a m i n K status. In surveillance studies, N M T T - c o n t a i n i n g antibiotics were no m o r e freq u e n t l y associated with h y p o p r o t h r o m b i n e m i a or bleeding t h a n antibiotics t h a t lack this moiety.
10.
11.
References 1. Joehl RJ,'Rasback DA, Ballard JO, Weitekamp MR, Sattler FR. Moxalactam: evaluation of clinical bleeding in patients with abdominal infection. Arch Surg 1983; 118: 1259-61. 2. Pakter RL, Russell TR, Mielke CH, West D. Coagulopathy associated with the use of moxalactam. JAMA 1982; 248: 1100-2. 3. Baxter JG, Marble DA, Whitfield LR, Wels PB, Walczak P, Schentag JJ. Clinical risk factors for prolonged PT/PTT in abdominal sepsis patients treated with moxalactam or tobramycin plus clindamycin. Ann Surg 1985; 201: 96-102. 4. Schentag JJ, Welage LS, Grasela TH, Adelman MH. Determinants of antibiotic-associated hypoprothrombinemia. Pharmacotherapy 1987; 7: 80-6. 5. Sattler FR, Weitekamp MR, Ballard JO. Potential for bleeding with the new beta-lactam antibiotics. Ann Intern Med 1986; 105: 924-31. 6. Lipsky JJ, N-methyl-thio-tetrazole inhibition of the gamma carboxylation of glutamic acid: possible mechanism for antibiotic-associated hypoprothrombinemia. Lancet 1983; 2: 192-3. 7. Kerremans AL, Lipsky JJ, Van Loon J, Gallego MO, Weinshilbourn RM. Cephalosporin-induced hypoprothrombinemia: possible role for thiol methylation of 1-methyltetrazole-5thiol and 2-methyl-l,3,4-thiadiazole-5-thiol. J Pharmacol Exp Ther 1985; 235: 382-8. 8. Uotila L, Suttie JW. Inhibition of vitamin K-dependent carboxylase in vitro by cefamandole and its structural analogs. J Infect Dis 1983; 150: 571-8. 9. Aronoff GR, Wolen RL, Obermeyer BD, Black HR. Pharmacokinetics and protein binding of cefamandole and its 1-
12. 13.
14. 15.
16.
17. 18.
19.
methyl H-tetrazole-5 thiol side chain in subjects with normal and impaired renal function. J Infect Dis 1986; 153: 1069-74. Jusko WJ. Guidelines for collection and analysis of pharmacokinetic data. In: Evans W, Schentag J, Jusko W, eds. Applied pharmacokinetics. Spokane, WA: Applied Therapeutics, Inc., 1986: 9-84. Grasela TH, Schentag JJ. A clinical pharmacy oriented drug surveillance network. I: Program description. Drug Intell Clin Pharm 1987; 21: 902-8. Barza M, Furie B, Brown AE, Furie BC. Defects in vitamin Kdependent carboxylation associated with moxalactam treatment. J Infect Dis 1986; 153:1166-9. Morris DL, Fabricius PJ, Ambrose NS, Scammell B, Burdon DW, Keighley MR. 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. Ham FM. Hypoprothrombinemia in patients undergoing prolonged intensive care. Med J Aust 1971; 2: 716-8. Schentag JJ, Vari AJ, Winslade NE, et al. Treatment with aztreonam or tobramycin in critical care patients with nosocomial gram-negative pneumonia. Am J Med 1985; 78 (suppl 2A): 34-42. Brown RB, Klar J, Lemeshow S, Teres D, Pastides H, Sand M. Enhanced bleeding with cefoxitin and moxalactam. Statistical analysis within a defined population of 1493 patients. Arch Intern Med 1986; 146: 2159-64. Lipsky JJ, Lewis JC, Novick WJ. Production of hypoprothrombinemia by moxalactam and 1-methyl-5-thiotetrazole in rats. Antimicrob Agents Chemother 1984; 25: 380-1. Mackie IJ, Walshe K, Cohen H, et al. Effects of N-methyl thiotetrazole cephalosporin on haemostasis in patients with reduced serum vitamin K ~concentrations. J Clin Pathol 1986; 39: 1245-9. Weitekamp MR, Caputo GM, AI-Mondhiry HAB, Aber RC. The effects of latamoxef, cefotaxime, and cefoperazone on platelet function and coagulation in normal volunteers. J Antimicrob Chemother 1985; 16: 95-101.
FOCUS
Analysis of Prothrombin Time Prolongation in North American Cefotetan Clinical Trials: Questions and Answers
Neil H. Goldstein, M D , Wilmington, Delaware
Q: What has Stuart's experience been with hypoprothrombinemia associated with cefotetan? A: We undertook a retrospective analysis of prothrombin time prolongation in the North American cefotetan therapeutic clinical trials. All patients enrolled in these trials From the Division of Clinical and Medical Affairs, Stuart Pharmaceuticals, Wilmington, Delaware. Requests for reprints should be addressedto Neil H. Goldstein, MD, 'Division of Clinical and Medical Affairs, Stuart Pharmaceuticals,New Murphy Roadand Concord Pike, Wilmington,Delaware 19897.
44
who had a pretherapy and end or post-therapy prothrombin time were included in this analysis. Table I shows demographics for the cefotetan and comparator drug patients. The types of infections treated are shown for each drug. The cefotetan trials included patients with intraabdominal, gynecologic, skin and soft tissue, and gonococcal infections. Cefoxitin was used in all but the gonococcal trials. Moxalactam was one of our early comparators and only appears in the early intraabdomi-
The American Journal of Surgery
Symposium on the New Cephalosporins
TABLE I
Patients With R e p e a t e d P r o t h r o m b i n Times: Population C h a r a c t e r i s t i c s * Cefotetan (n = 890)
Cefoxitin (n = 138)
Moxalactam (n = 81)
Ceftriaxone (n = 73)
179 (20) 270 (30) 228 (26) 2 ! 3 (24)
42 (30.4) 57 (41.3) 39 (28.3) 0
44 (54) 37 (46) 0 0
0 0 0 73 (100)
Male
459 (52)
62 (45)
25 (31)
61 (84)
Female Age (yr) Range
431 (48)
76 (55)
56 (69)
12 (16)
16-931 35 28
16-84 33.5 28
16-895 39 29.5
17-44 w 25.5 24.5
41 (4)7 77 (9) 31 (3)
18 (13) 13 (9) 3 (2)
5 (6) 5 (6) 8 (10)
0 0 0
Parameter Infection type
Intraabdominal Gynecologic Skin, soft tissue Gonococcal Sex
Mean Median General condition
Poor, critical Alcohol abuse Cancer history Therapy duration (d) Range Mean Median
1-37
2-23
i-12
1
5.4 5
6.3 6
5.8 6
1 1
* Values in parentheses are percentages. 1, n = 879 patients. t n = 76 patients. w n = 72 patients. n = 889 patients.
nal and gynecologic trials. Ceftriaxone was a recent comparator and only appears in the gonococcal trials. The male to female ratios show a preponderance of women in the moxalactam group, most likely due to the proportion of gynecologic infections treated, and a preponderance of men treated for gonorrhea in the ceftriaxone group. The age ranges and mean and median ages for the first three groups are comparable. The ceftriaxone patients were younger. The general condition of the patient as indicated by the investigator showed a slightly higher percentage of patients in poor to critical condition in the cefoxitin group and none in the ceftriaxone group. The rates for alcohol abuse were again similar in the first three groups. The cancer rate was a little higher in the moxalactam group and was lowest in the ceftriaxone group. Not all the can: cers were clearly active at the time of entry into the study. Finally, duration of therapy was also quite similar, except for the shorter therapy in the ceftriaxone group. Despite the differences in types of infections treated, the cefotetan, cefoxitin, and moxalactam patients were fairly similar in their demographics. Ceftriaxone, however, had been used primarily for healthy male outpatients with gonorrhea. Table II shows the pretherapy laboratory values for the different treatment groups: T h e pretherapy creatinine ranges and percentage of patients with creatinine levels greater than 1.5 mg/dl were similar for the first three groups. The protocols discouraged the entering of patients with a creatinine level greater than 2.5 mg/dl. About half the patients in the first three groups had pzetherapy anemia as defined by a hemoglobin level of less than 14 g/dl in men or 12 g/dl in women. There were a
Volume 155 (5A), May 31, 1988
few patients with pretherapy platelet counts under 100,000 cells/mm 3. All the groups also had some patients with pretherapy prothrombin times above 14 seconds. This table, in addition to the previous one, indicates that the cefotetan, cefoxitin, and moxalactam patients were relatively similar in their pretherapy risk factors for coagulopathy. Table III shows the percentage of patients with prothrombin time elevations for each group. An increased prothrombin time was defined as an increase Of more than 1 second in patients who had a pretherapy prothrombin time less than or equal to 14 seconds and a follow-up prothrombin time greater than or equal to 15 seconds at end or post-therapy. It was believed that this definition would be more likely to identify patients with an antibiotic-induced prothrombin time elevation, since these patients all had essentially normal pretherapy prothrombin times. All elevations meeting this definition for the pr Othrombin time increase were included in the analysis regardless of whether the investigator reported the increase as drug-related. The data indicate a 2.5 percent rate of prothrombin time elevation for cefotetan compared with 1.6 percent for cefoxitin, 5.1 percent for moxalactam, and 4.2 percent for ceftriaxone. For the comparators, the total numbers are relatively small. In addition, although the first two tables show similar pretherapy risk profiles for the first three groups, these patient groups were heterogenous. The cefotetan patients, for instance, represent patients treated for several types of infections whose results were compared with those of several different agents. Therefore, although adverse-reaction data can be pooled to provide an overall view and suggest possible trends, a formal statistical anal-
45
Goldstein
T A B L E II
Patients With Repeated PrOthrombin Times: Laboratory Data* Data
Pretherapy creatinine (mg/dl) Range Mean Median Total Pretherapy creatihine ( > ! . 5 mg/dl) Pretherapy aner~ia t Total Pretherapy platelets ( < 100,000 cells/mm 3) Total Pretherapy prothrombin time (>14 s)
Cefotetan (n = 890)
Cefoxiti'n (n = 138)
Moxalactam (n = 81)
Ceftriaxone ( n = 73)
0.3-6.3 1 1 864 40 (5)
0.4-4.6 1.1 i 132 9 (7)
O. 1-2.9 1 0.9 77 6 (8)
0.7-1.5 1.1 1.1 72 0
385 (43) 886 10 (1)
84 (61) 137 0
34 (42)
7 (10) 72 0
813 51 (6)
134 12 (9)
69 3 (4)
2 (3)
2" i3')
* Values in parentheses are percentages. t Anemia defined as a hemoglobin level below 14 g/dl for men and below 12 g/dl for women.
TABLE III
Patients With Increased Prothrombin Time: Antibiotic Groups
Treatment
Cefotetan Cefoxitin Moxalactam Ceftriaxone
Patients With Repeated Prothrombin Times (PT) Patients With PT Total Increase T Number" n % 839 126 78 71
21 2 4 3
2.5 1.6 5.1 4.2
* Patients with a pretherapy prothrombin time of < 14 seconds and a repeated prothrombin time. T Patients with a greater than 1 second increase in prothrombin time, to 15 seconds or more,
ysis is difficult due to the intertrial differences. What is most important, however, is to examine the clinical consequence of the prothrombin time elevations. Each case report form for patients who fulfilled the definition of prothrombin time prolongation shown in Table III was individually examined, and all use of vitamin K was recorded. In addition, if the antibiotic was discontinued prematurely for the prothrombin time elevation or bleeding, this was recorded. Transfusions were included if they were given for prothrombin time elevation or clinical bleeding. Preoperative and immediate postoperative transfusions at the start of antibiotic therapy stated to be for chronic anemia or to replace surgical losses, or subsequent transfusions stated to be for chronic
46
anemia, were not included as required interventions if there was no evidence of clinical bleeding. Bleeding was reported if it was described anywhere in the case report form. Microscopic hematuria alone was not included, since many of the patients had indwelling Foley catheters. This analysis found that the only therapy given the 21 cefotetan patients was vitamin K, which was administered to 3 patients (14 percent). Two of these three patients had prothrombin time elevations of less than 10 seconds. In the third patient, the prothrombin time returned to within normal limits 1 day after receiving vitamin K. All of the cefotetan patients completed their course of antibiotics and none had evidence of clinical bleeding. Three of the four moxalactam patients required some type of intervention. Two received vitamin K, and one of these also had the antibiotic stopped prematurely. The third patient required a premature discontinuation of the antibiotic and transfusions for clinical gastrointestinal bleeding. There was no treatment given for prothrombin time elevations in the cefoxitin or ceftriaxone patients. In conclusion, a retrospective analysis of patients with follow-up prothrombin times indicates similar pretherapy risk factors for the cefotetan, cefoxitin, and moxalactam patients. The ceftriaxone patients were enrolled only in gonococcal trials and Were younger and healthier. Patients with prothrombin time elevations were identified in all the treatment groups, even the relatively healthy ceftriaxone patients. More importantly, however, the only bleeding seen was in a patient given moxalactam. The majority of that group also received therapy, including prematurely stopping the antibiotic and giving vitamin K. The onty therapy given for the cefotetan patients was vitamin K in three patients.
The American Journal of Surgery