Journal of Antimicrobial Chemotherapy (1975) 1 (Suppl.), 37-40
Cephaloridine serum levels after intravenous injection
D. D. Mathews
An antibiotic regime of proven value in the prevention of postoperative wound infection comprises three injections of 1 g of cephaloridine at 6 hourly intervals. The first of these injections is often made intravenously at the onset of surgery. The present work shows the serum levels of cephaloridine that can be expected after an intravenous bolus of 1 g and discusses the implications of the serum level curve in the prevention of bacterial invasion at the time of surgery. Introduction
Postoperative infection is a common and disturbing complication of major abdominal and pelvic surgery. On the assumption that in most instances the infecting organisms are introduced at the time of the operation, attempts have been made to prevent infection occurring by the administration of antibiotics before, during and immediately after surgery. One of the few antibiotic regimes of proven value in this respect comprises the parenteral administration of 3 g of cephaloridine given in divided doses of 1 g at 6 hourly intervals (Polk & Lopez-Mayor, 1969; Evans & Pollock, 1973; Ledger, Sweet & Headington, 1973). The initial injection at about the time of the commencement of surgery is sometimes made intramuscularly and sometimes intravenously. The serum levels of antibiotic to be expected after intramuscular injection are known (Polk & Lopez-Mayor, 1969) but those to be expected after an intravenous bolus of 1 g had not yet been reported. The present work was designed to make good this deficiency. Patients and methods
The study was performed on volunteer patients undergoing either major gynaecological surgery, such as abdominal or vaginal hysterectomy, or minor procedures such as tubal insufflation in which it was particularly desirable that there should be no postoperative infection. Other criteria for inclusion in the study were age between 15 and 50 years, average build, no known allergies, no reason to suspect renal impairment and the presence of peripheral veins suitable for multiple venepuncture. An intravenous bolus of 1 g of cephaloridine in 20 ml of 0-9 % saline, was given at the convenient quarter-hour position on the clock after induction of anaesthesia. Blood samples (5 ml) were then taken by venepuncture into plain glass tubes 15 min, 30 min, 37
Downloaded from http://jac.oxfordjournals.org/ at University of Michigan on July 3, 2015
Department of Obstetrics and Gynaecology All Saints' Hospital, Chatham, Kent, England
38
D. D. Matfaews
1 h, 1 i, 2, 3, 4 and 6 h after injection. Serum was stored at —20°C until collected for cephaloridine assay at Glaxo Laboratories. The results were analysed by using a computer program for a two compartment open model. In all cases, anaesthesia had been induced with methohexitone sodium and continued with nitrous oxide and oxygen supplemented with intravenous injections of a 6 to 1 mixture of pentazocine and droperidol. In cases for major surgery muscular relaxation was induced with succinylcholine and continued with pancuronium bromide after endotracheal intubation. These patients also received up to 500 ml of Dextran 70 by slow intravenous infusion during and after operation. Results Downloaded from http://jac.oxfordjournals.org/ at University of Michigan on July 3, 2015
Of the 10 patients studied, 6 had major and 4 minor operations. The age range was 19 to 40 years (mean 28) and weight 44 to 76 kg (mean 60). Blood urea levels ranged from 23 to 38 mg/100 ml. The mean and standard deviation of the cephaloridine serum levels found at the specified intervals after injection are presented in the Figure.
0
1
2
3 4 Time(h)
5
6
Figure 1. Cephaloridine levels in scrum after a bolus injection of 1 g intravenously
In the computer data analysis the mean time to half initial titre was 34-8 min while the ultimate half life of cephaloridine was found to be 1231 min. Discussion
Commencing prophylactic antibiotic therapy with an intravenous bolus of 1 g of cephaloridine at the beginning of the operation undoubtedly ensures high blood levels of the antibiotic during the operation, so long as the operation is not too long. Cephaloridine, however, is lethal only to dividing organisms and as bacterial multiplication may be delayed for several hours after contamination of the wound, as occurs in vitro, it is possible that a high initial blood level may not be as effective in preventing bacterial invasion at the time of operation as might be supposed. Furthermore, the low antibiotic blood levels that are reached prior to the subsequent intramuscular injection will mean that any haematomata that form at this time will comprise blood with a relatively low
Cephaloridine blood levels
39
Acknowledgements
My thanks are due to Dr Clive Dash and Dr Kay Thompson from Glaxo Laboratories Ltd, and to Mrs C. Field, Glaxo Research Ltd, who carried out the cephaloridine assays, and to my anaesthetist Dr D. S. B. Stephens and the ward and laboratory staff of All Saints' Hospital, Chatham, for their invaluable assistance. References Evans, C. & Pollock, A. V. The reduction of surgical wound infections by prophylactic parenteral cephaloridine. British Journal of Surgery 60: 434-7 (1973). Kirby, W. M. M., de Maine, J. B. & Serrill, W. S. Pharmacokinetics of the cephalosporins in healthy volunteers and uremic patients. Postgraduate Medical Journal {February supplement, 47: 41-6 (1971). Ledger, W. J., Sweet, R. L. & Headington, J. T. Prophylactic cephaloridine in the prevention of postoperative pelvic infections in premenopausal women undergoing vaginal hysterectomy. American Journal of Obstetrics and Gynaecology 115: 766-74 (1973). O'Grady, F., Brown, W. R., Gaya, H. & Mackintosh, I. P. Antibiotic levels on continuous intravenous infusion. Lancet ii: 209 (1971). Polk, H. C. & Lopez-Mayor, J. F. Postoperative wound infection: A prospective study of the determinant factors and prevention. Surgery 66: 97-103 (1969). Discussion Dr R. L. Parsons Can you tell us in what volume, at what pH, and over what period of time this drug was given ? Also, what was the estimated volume of distribution of cephaloridine? Mr D. D. Mathews I cannot answer all those questions. I do not know the pH of the solution. It was dissolved in up to 20 ml and was then injected as rapidly as possible to make it an intravenous bolus injection. Editor's Note As urinary excretion of cephaloridine was not measured, it was not possible with the computer program to estimate the volume of distribution. Kirby, de Maine & Serrill (1971) found the volume of distribution at the steady state to be 161. The pH of a 1 g solution (0-5%) of cephaloridine is approximately 5.
Downloaded from http://jac.oxfordjournals.org/ at University of Michigan on July 3, 2015
cephaloridine concentration and thus less resistance to infection. Certainly many surgeons believe that infection often begins in haematomata that have accumulated after wound closure. It is possible that better clinical results than those already obtained with prophylactic cephaloridine might follow if the initial 1 g were given as an infusion over 6 h rather than as a bolus injection at the commencement of surgery. According to the formula devised by O'Grady, Brown, Gaya & Mackintosh (1971) and using the calculated halflife for cephaloridine of 123-1 min, an infusion of 1 g of cephaloridine in a litre, given over 6 h, would result in the plasma and extracellularfluidconcentration of cephaloridine ultimately stabilizing at about 36 ug/ml, which is an adequate therapeutic level. In practice this is equivalent to an infusion of 2-8 mg/min; 42 drops/min of the solution, assuming a standard drip volume of 15 drops/ml. The somewhat longer half-life of cephaloridine found in this study compared with 112 h estimated by Kirby, de Maine & Serrill (1971) may well be a result of sampling from patients anaesthetized and undergoing minor or major surgical interference.
40
D. D. Mathews
Dr R.L. Parsons Did any of your subjects develop thrombophlebitis? Mr D. D. Mathews No. Dr S. W. B. Newsom When you are thinking of prophylaxis, do you think it better to give an intravenous drug and see it come out into the urine quickly, or give the drug intramuscularly and allow it to act for a longer period ?
Downloaded from http://jac.oxfordjournals.org/ at University of Michigan on July 3, 2015
Mr D. D. Mathews Having looked at the curve of the blood levels, and considering when the haematoma that may cause infection might occur, one is tempted to give a drug which will give a more prolonged action so as to act on the organisms when they start to divide. It may well be that the original intramuscular regime of Polk & Lopez-Mayor (1969) is as good as any, and better than most. I have suggested the infusion regime as a possible alternative.
Cephaloridine serum levels after intravenous injection
D. D. Mathews
An antibiotic regime of proven value in the prevention of postoperative wound infection comprises three injections of 1 g of cephaloridine at 6 hourly intervals. The first of these injections is often made intravenously at the onset of surgery. The present work shows the serum levels of cephaloridine that can be expected after an intravenous bolus of 1 g and discusses the implications of the serum level curve in the prevention of bacterial invasion at the time of surgery. Introduction
Postoperative infection is a common and disturbing complication of major abdominal and pelvic surgery. On the assumption that in most instances the infecting organisms are introduced at the time of the operation, attempts have been made to prevent infection occurring by the administration of antibiotics before, during and immediately after surgery. One of the few antibiotic regimes of proven value in this respect comprises the parenteral administration of 3 g of cephaloridine given in divided doses of 1 g at 6 hourly intervals (Polk & Lopez-Mayor, 1969; Evans & Pollock, 1973; Ledger, Sweet & Headington, 1973). The initial injection at about the time of the commencement of surgery is sometimes made intramuscularly and sometimes intravenously. The serum levels of antibiotic to be expected after intramuscular injection are known (Polk & Lopez-Mayor, 1969) but those to be expected after an intravenous bolus of 1 g had not yet been reported. The present work was designed to make good this deficiency. Patients and methods
The study was performed on volunteer patients undergoing either major gynaecological surgery, such as abdominal or vaginal hysterectomy, or minor procedures such as tubal insufflation in which it was particularly desirable that there should be no postoperative infection. Other criteria for inclusion in the study were age between 15 and 50 years, average build, no known allergies, no reason to suspect renal impairment and the presence of peripheral veins suitable for multiple venepuncture. An intravenous bolus of 1 g of cephaloridine in 20 ml of 0-9 % saline, was given at the convenient quarter-hour position on the clock after induction of anaesthesia. Blood samples (5 ml) were then taken by venepuncture into plain glass tubes 15 min, 30 min, 37
Downloaded from http://jac.oxfordjournals.org/ at University of Michigan on July 3, 2015
Department of Obstetrics and Gynaecology All Saints' Hospital, Chatham, Kent, England
38
D. D. Matfaews
1 h, 1 i, 2, 3, 4 and 6 h after injection. Serum was stored at —20°C until collected for cephaloridine assay at Glaxo Laboratories. The results were analysed by using a computer program for a two compartment open model. In all cases, anaesthesia had been induced with methohexitone sodium and continued with nitrous oxide and oxygen supplemented with intravenous injections of a 6 to 1 mixture of pentazocine and droperidol. In cases for major surgery muscular relaxation was induced with succinylcholine and continued with pancuronium bromide after endotracheal intubation. These patients also received up to 500 ml of Dextran 70 by slow intravenous infusion during and after operation. Results Downloaded from http://jac.oxfordjournals.org/ at University of Michigan on July 3, 2015
Of the 10 patients studied, 6 had major and 4 minor operations. The age range was 19 to 40 years (mean 28) and weight 44 to 76 kg (mean 60). Blood urea levels ranged from 23 to 38 mg/100 ml. The mean and standard deviation of the cephaloridine serum levels found at the specified intervals after injection are presented in the Figure.
0
1
2
3 4 Time(h)
5
6
Figure 1. Cephaloridine levels in scrum after a bolus injection of 1 g intravenously
In the computer data analysis the mean time to half initial titre was 34-8 min while the ultimate half life of cephaloridine was found to be 1231 min. Discussion
Commencing prophylactic antibiotic therapy with an intravenous bolus of 1 g of cephaloridine at the beginning of the operation undoubtedly ensures high blood levels of the antibiotic during the operation, so long as the operation is not too long. Cephaloridine, however, is lethal only to dividing organisms and as bacterial multiplication may be delayed for several hours after contamination of the wound, as occurs in vitro, it is possible that a high initial blood level may not be as effective in preventing bacterial invasion at the time of operation as might be supposed. Furthermore, the low antibiotic blood levels that are reached prior to the subsequent intramuscular injection will mean that any haematomata that form at this time will comprise blood with a relatively low
Cephaloridine blood levels
39
Acknowledgements
My thanks are due to Dr Clive Dash and Dr Kay Thompson from Glaxo Laboratories Ltd, and to Mrs C. Field, Glaxo Research Ltd, who carried out the cephaloridine assays, and to my anaesthetist Dr D. S. B. Stephens and the ward and laboratory staff of All Saints' Hospital, Chatham, for their invaluable assistance. References Evans, C. & Pollock, A. V. The reduction of surgical wound infections by prophylactic parenteral cephaloridine. British Journal of Surgery 60: 434-7 (1973). Kirby, W. M. M., de Maine, J. B. & Serrill, W. S. Pharmacokinetics of the cephalosporins in healthy volunteers and uremic patients. Postgraduate Medical Journal {February supplement, 47: 41-6 (1971). Ledger, W. J., Sweet, R. L. & Headington, J. T. Prophylactic cephaloridine in the prevention of postoperative pelvic infections in premenopausal women undergoing vaginal hysterectomy. American Journal of Obstetrics and Gynaecology 115: 766-74 (1973). O'Grady, F., Brown, W. R., Gaya, H. & Mackintosh, I. P. Antibiotic levels on continuous intravenous infusion. Lancet ii: 209 (1971). Polk, H. C. & Lopez-Mayor, J. F. Postoperative wound infection: A prospective study of the determinant factors and prevention. Surgery 66: 97-103 (1969). Discussion Dr R. L. Parsons Can you tell us in what volume, at what pH, and over what period of time this drug was given ? Also, what was the estimated volume of distribution of cephaloridine? Mr D. D. Mathews I cannot answer all those questions. I do not know the pH of the solution. It was dissolved in up to 20 ml and was then injected as rapidly as possible to make it an intravenous bolus injection. Editor's Note As urinary excretion of cephaloridine was not measured, it was not possible with the computer program to estimate the volume of distribution. Kirby, de Maine & Serrill (1971) found the volume of distribution at the steady state to be 161. The pH of a 1 g solution (0-5%) of cephaloridine is approximately 5.
Downloaded from http://jac.oxfordjournals.org/ at University of Michigan on July 3, 2015
cephaloridine concentration and thus less resistance to infection. Certainly many surgeons believe that infection often begins in haematomata that have accumulated after wound closure. It is possible that better clinical results than those already obtained with prophylactic cephaloridine might follow if the initial 1 g were given as an infusion over 6 h rather than as a bolus injection at the commencement of surgery. According to the formula devised by O'Grady, Brown, Gaya & Mackintosh (1971) and using the calculated halflife for cephaloridine of 123-1 min, an infusion of 1 g of cephaloridine in a litre, given over 6 h, would result in the plasma and extracellularfluidconcentration of cephaloridine ultimately stabilizing at about 36 ug/ml, which is an adequate therapeutic level. In practice this is equivalent to an infusion of 2-8 mg/min; 42 drops/min of the solution, assuming a standard drip volume of 15 drops/ml. The somewhat longer half-life of cephaloridine found in this study compared with 112 h estimated by Kirby, de Maine & Serrill (1971) may well be a result of sampling from patients anaesthetized and undergoing minor or major surgical interference.
40
D. D. Mathews
Dr R.L. Parsons Did any of your subjects develop thrombophlebitis? Mr D. D. Mathews No. Dr S. W. B. Newsom When you are thinking of prophylaxis, do you think it better to give an intravenous drug and see it come out into the urine quickly, or give the drug intramuscularly and allow it to act for a longer period ?
Downloaded from http://jac.oxfordjournals.org/ at University of Michigan on July 3, 2015
Mr D. D. Mathews Having looked at the curve of the blood levels, and considering when the haematoma that may cause infection might occur, one is tempted to give a drug which will give a more prolonged action so as to act on the organisms when they start to divide. It may well be that the original intramuscular regime of Polk & Lopez-Mayor (1969) is as good as any, and better than most. I have suggested the infusion regime as a possible alternative.
