ANTIMaCROBIAL AGENTS AND CHEMOTHERAPY, Apr. 1976, p. 557-560 Copyright C 1976 American Society for Microbiology
Vol. 9, No. 4 Printed in U.S.A.
Peritoneal Transfer of Thiamphenicol During Peritoneal Dialysis K. I. FURMAN,* H. J. KOORNHOF, T. A. KILROE-SMITH, R. LANDLESS, AND R. G. ROBINSON
Departments of Experimental and Clinical Pharmacology and Microbiology,* Uniuersity of the Witwatersrand, and National Research Institute for Occupational Diseases, Johannesburg, South Africa
Received for publication 6 November 1975
The pharmacokinetics of thiamphenicol (TAP) was studied in 17 functionally anephric patients during peritoneal dialysis. Eleven patients were given single intramuscular injections of TAP in doses of 10 to 20 mg/kg of body weight. After this, serial blood samples and outflow dialysate collections were assayed for TAP by gas chromatography. The mean overall elimination rate constant was 0.036 0.007/h, the serum half time was 8.4 h, and the apparent volume of distribution was 71.0% (±14.39%) of the body weight. These parameters were not significantly different from those determined in anephric patients not on dialysis. The mean recovery of the administered TAP doses in the pooled outflow dialysate was 7.7% (±2.76%) over 22 h. In six other patients TAP was added to the inflow dialysate in concentrations of 10 to 20 mg/liter for 22 h. Throughout the dialysis periods, serum TAP levels did not rise above 4 gg/ml in transfer of TAP. ±
Thiamphenicol (TAP) is an analogue of chloramphenicol, in which the p-nitro group on the benzine ring of chloramphenicol is replaced by a methylsulfonyl group. It has a molecular weight of 356.24. Although TAP has a similar antibacterial spectrum to that of chloramphenicol (9), it has a number of important pharmacological differences. TAP is more stable in solution (5). In the body it is not appreciably protein bound and does not undergo significant biotransformation (5). With normal renal function most of an administered dose is excreted unchanged in the urine (3, 7). Also, thus far irreversible aplastic anemia has not been reported with the use of this drug (20). From these known general properties, one would expect this antibiotic to dialyze readily across the peritoneum and be useful for treating peritoneal infections that occur from time to time with peritoneal dialysis. Despite this, a short study by Menz et al. (8) on renal failure patients indicated that the plasma half time of TAP was not shortened by peritoneal dialysis. However, these authors did not measure actual peritoneal transfer of the drug. The purposes of the present studies were to determine the rate and extent of TAP transfer across the peritoneum and to obtain the necessary parameters for calculating dose modifications to patients undergoing peritoneal dialysis.
MATERIALS AND METHODS The method used was based on that described by Atkins et al. (1) for the study of peritoneal transfer of kanamycin. Seventeen informed volunteer patients, 13 males and 4 females aged 30 to 56 years, undergoing maintenance peritoneal dialysis were the subjects of this investigation. All had endogenous creatinine clearance rates of less than 3.0 ml/min between dialyses and urinary volumes of less than 150 ml/24 h while on dilaysis. No patient was clinically septic, none had peritonitis, and none had received any antibiotics in the previous 3 weeks. Peritoneal dialysis was performed by the standard repeated puncture technique with disposable catheters and commercially available dialysate solutions (Baxter, Dianeal, 1.5:2.0 dextrose solution with: Na, 135 meq; K, 3.0 meq; Ca, 3.5 meq; Mg, 1.5 meq; Cl, 101 meq; and lactate, 45 meq/liter). Sixtyminute cycles with 40-min inflow plus dwell times were employed for a total of 22 exchanges, using a 2liter dialysate inflow per exchange. Study I. The first study consisted of TAP removal by peritoneal dialysis after intramuscular administration. TAP-glycinate in doses of approximately 10 mg/ kg of body weight (calculated as TAP base) was given to three patients, 15 mg/kg was given to four patients, and 20 mg/kg was given to four patients, all 1 h before commencement of dialysis. Ten-milliliter samples of venous blood were collected prior to this injection and again at 2, 4, 10, 16, and 22 h after commencement of dialysis. The 3-h period between 557
558
FURMAN ET AL.
the intramuscular TAP injection and the collection of a blood sample after the first 2 h of dialysis was adequate to ensure complete absorption and uniform distribution of the antibiotic for subsequent analysis on the basis of an open model, single compartment kinetic system. Total outflow dialysate collections were made to correspond to the intervals between blood sampling, i.e., serial periods of 2, 2, 6, 6, and 6 h. TAP and creatinine concentrations were determined in each of the blood serum and outflow dialysate samples obtained. TAP assay was by gas chromatography, using the method outlined by Gazzaniga et al. (6), with D(+)-threo-1-(p-methylsulfonyl)2-acetamido-1,3-propane-diol as the internal standard. Preliminary attempts at microbiological assay by gel diffusion and scalar dilution techniques with Pasteurella multicida NTCT 10722 as the test organism proved to be very erratic and were abandoned as unreliable. Creatinine determinations were made by AutoAnalyzer. From the results of the assay, the serum regression equations were calculated by the method of least squares. The basic equation Y = MX + c was used, where Y is log of TAP in micrograms per milliliter, c is log zero-time concentration (CO), M is the overall elimination rate constant (Ke), and X is the time in hours. The serum half times (T12) were derived from the Ke values by the formula: T112 = log 2/Ke. The apparent volume of distribution (AVD) was determined by dividing the administered TAP dose by the CO. This in turn was expressed as a percentage of body weight. The percentage of recovery of each administered TAP dose was calculated from the concentrations and volumes of the outflow dialysate collections. Peritoneal TAP and creatinine clearances were calculated by the formula (D x V)/S where D is the concentration of TAP or creatinine in the outflow dialysate, V is the volume of the outflow dialysate for each collection period in milliliters per minute, and S is the geometric mean of the serum concentrations at the beginning and end of each collection period. Study II. The second study consisted of the transfer of TAP to serum after intraperitoneal administration. TAP was added to each bottle of the inflow dialysate for 22 turnovers in concentrations of 10 mg/liter to one patient, 15 mg/liter to four patients, and 20 mg/liter to one patient. Blood samples were collected in the same manner and at the same intervals as for study I, and the serum assayed for TAP concentrations. The inflow dialysate concentrations were checked by random sampling.
RESULTS Study I. The calculated serum regression equations, CO, T,/2, Ke, and AVD values are listed in Table 1. The mean (+ standard deviation) Ke was 0.036 (±0.007)/h, and the corresponding T1,2 was 8.4 h; the mean AVD was 71.0% (+14.39%) of body weight.
ANTIMICROB. AGENTS CHEMOTHER.
The TAP levels in the outflow dialysate were generally low after all of the administered doses. Concentrations between 5 and 10
Ag/ml
were achieved during the first 16 h of dialysis in one patient (MB) after a TAP dose of 20 mg/kg
of body weight. In all of the other patients, the antibiotic concentrations in the dialysate collections were less than 5 ug/ml throughout the dialysis. The mean recovery of the administered TAP doses in the outflow dialysate was 7.7% (±2.76%) in 22 h (Table 2). It should be noted here that the 22-h dialysis period is equal to two to three times the calculated T1/2 value for TAP, in which period the serum antibiotic concentration would have decayed by more than 75% of the initial peak level. This indicates the presence of a more efficient alternate route of elimination to that of peritoneum. The peritoneal TAP clearances were variable and did not show a constant relationship to creatinine clearances (Table 2). The mean (+standard deviation) peritoneal TAP clearance was 7.7 ml (±2.97 ml)/min, whereas that for creatinine was 14.0 ml (±2.10 ml)/min. Study II. Throughout the dialysis periods, there seemed to be poor peritoneal transfer from the inflow dialysate in the peritoneal cavity to the blood in that low serum levels noted early during the dialyses did not rise progressively, despite continuous TAP supplementation to the inflow dialysate (Table 3). The highest serum level monitored was 4 ug/ml after 16 h in two patients in whom the inflow dialysate TAP concentration was 15 mg/liter (Table 3).
DISCUSSION In subjects with normal renal function, the plasma T1,2 has been estimated to vary between 2.6 and 3.5 h (2, 5, 8). In anuric patients not on dialysis, the mean T112 has been reported to be 9.1 h (2). This value is not significantly different from the determinations of this parameter made on our patients during peritoneal dialysis, which supports the finding by Menz et al. (8) that the plasma decay curve is not appreciably altered by peritoneal dialysis. The enlarged AVD greater than total body water probably reflects early tissue accumulation. This has been shown by McChesney et al. (7) to occur mainly to the liver and kidneys. The liver and biliary system is the most likely alternate route of elimination, which becomes more effective in renal failure. The significance of the early tissue accumulation and the major routes of elimination are apparent in the autoradiographic studies of De Paoli et al. (4). The poor peritoneal transfer of TAP is a property shared by many other antibiotics. Only
VOL. 9, 1976
PERITONEAL TRANSFER OF TAP
559
TABLE 1. Serum TAP concentrations, regression equations, C0, T1,2, and AVD values in 11 patients undergoing peritoneal dialysis after single intramuscular injections of the antibiotic Ptien tient
V
Serum concn at (ha:
TAP dose
(mg)
2
4
Approx 10 mg/kg of body ED 600 14 9 EL 750 19 9 MN 800 10 8
10
16
weight 8 4 8 5
3 3
C0ml)(Agl
T,,2 (h)
weight
Bodeight (kg)
% Body Liters ____
7.7 6.6 8.6
62.6 73.6 83.2
34.4 35.9 65.4
55.0 48.8 78.6
17.0 16.4 15.7 24.0
10.4 6.7 8.8 9.0
68.7 72.0 75.0 78.0
58.8 61.0 70.1 45.9
85.6 84.7 93.5 58.8
31.6 22.8 28.5 31.0
11.4 8.2 6.8 12.6
77.0 55.0 90.0 80.0
47.5 43.9 63.2 51.6
61.7 79.9 70.2 64.5
22
Regression equation"
2 2 2
Y = 1.2415 - 0.0390X Y = 1.3205 - 0.0456X Y = 1.0873 - 0.0349X
17.4 20.9 12.2
4 1 3 4
Y Y Y Y
0.0290X 0.0448X 0.0342X 0.0336X
8 3
Y = 1.4660 - 0.0263X Y = 1.3580 - 0.0368X Y = 1.4554 - 0.0440X Y = 1.5023 - 0.0239X
weight
Approx 15 mg/kg of body weight SR DN BP WR
1,000 1,000 1,100 1,100
16 11 14 18
11 8 9 16
8 7 8 12
5 4 3 6
1.2319 1.2147 1.1609 1.3806
= = = =
-
Approx 20 mg/kg of body weight MB EV AS DM a
1,500 28 1,000 17 1,800 23 1,600 27
22 15 15 23
15 9 10 17
11 6 5 15
8
Hours after onset of dialysis (add 1 h for time lapse after intramuscular injection). log TAP in micrograms per milliliter; X is time in hours.
Y y is
TABLE 2. Peritoneal clearances of TAP (CTA,,) and creatinine (Ccr) - mean values of six collection periods and percentage of recovery of single intramuscular TAP doses in outflow dialysate over 22 h TAP recovery in outflow di-
Peritoneal (ml/ Patient
ED EL MN SR DN BP WR MB EV AS DM
min) CTAP
Ccr
7.2 10.9 10.8 7.3 6.0 12.2 3.3 9.6 8.4 4.2 4.7
12.1 13.6 16.5 13.5 14.0 13.4 13.4 13.8 14.6 17.8 15.9
TAP dose (mg)
600 750 800 1,000 1,000 1,100 1,100 1,500 1,000 1,800 1,600
TAP concn
FV ES ND JV LE DP
(mg/liter) 10 15 15 15 15 20
% of
mg
dose
50 70 52 62 69
8.3 9.8 6.4 6.2
121 48 191 93 70 99
11.0 4.3 12.6 9.3 4.1 6.2
6.2
dialysate
Patient
alysate
of the aminoglycosides, such as gentamicin and tobramycin, tend to dialyze significantly, and even with these the diluting effect of the dialysate usually makes it necessary to supplement the antibiotic to the dialyzing fluid when intraperitoneal activity is required. This can be done effectively with TAP as well. The commericially available TAP-glycinate is rapidly hydrolyzed in the dialysate at body temperature to free TAP independently of enzyme activity (5). One of the major problems with TAP administration is that relatively little substantive insome
TABLE 3. Serum TAP concentrations achieved after the addition of the antibiotic to the inflow dialysis in concentrations of 10, 15, and 20 mg/liter for 22 h Inflow
Serum TAP concn (tg/m1) at (h): 2
4
10
16
22
2 3 2 2 2 1
2 3 3 3 2 2
2 3 3 3 3 2
2 3 4 3 4 2
2 3 4 2 3 3
formation is available to indicate what serum levels might be necessary to treat infections with specific organisms. Recommendations on commercial package inserts have been derived rather empirically and are generally less than that indicated by minimum inhibitory concentrations determined by in vitro studies. This is particularly so far many gram-negative organisms. It has been noted that for many strains of Escherichia coli, Proteus, and Klebsiella species the in vitro minimum inhibitory concentrations are two to ten times that for CAP, and concentrations in excess of 100 ,g/ml may be required (9). Such concentrations are readily achieved in the urine with moderate doses (e.g., 500 mg, 8 h) when treating urinary infections in patients with normal renal function, but the very large doses that would be
560
FURMAN ET AL.
required to maintain such high levels systemically are somewhat impracticable to administer and potentially hazardous. Other organisms, such as Haemophilus influenza and the Neisseria, are extremely sensitive to TAP in concentrations of less than 1 ,ug/ml, and for these TAP may well be one of the antibiotics of choice (5, 9). One of the reasons for the lack of precise information about serum levels is the difficulty many laboratories experience with the microbiological assay methods that have been described for TAP. We have found gas chromatography to be a satisfactory alternative method.
ANTIMICROB. AGENTS CHZMOTHZR.
4.
5. 6.
7.
ACKNOWLEDGMENTS Due acknowledgment is made to Zambon S.p.A., Milan, for assistance and financial support.
8.
LITERATURE CITED 1. Atkins, R. C., C. Mion, C. Despaux, N. Van-Hai, C. Julien, and H. Mion. 1971. Peritoneal transfer of kanamycin and its use in peritoneal dialysis. Kidney Int. 3:391-396. 2. Azzolini, F., A. Gazzaniga, and E. Lodola. 1970. Thiamphenicol excretion in subjects with renal insuf£iciency. Int. J. Clin. Pharmacol. Ther. Toxicol. 4:303-308. 3. Della, C., D. Bella, V. Ferrari, G. Marcia, and L.
9.
10.
Bonanomi. 1968. Chloramphenicol metabolism in the phenobarbital induced rat. Comparison with thiamphenicol. Biochem. Pharmacol. 17:2381-2390. De Paoli, A. M., G. Manzoni, and A. Gazzaniga. 1974. Comparative autoradiographic study of thiamphenicol and chloramphenicol in the rat after oral treatment. Zambon S.p.A., Milan. Ferrari, V. 1968. Thiamphenicol, experimental and clinical basis of a new antibiotic. Zambon S.p.A., Milan. Gazzaniga, A., E. Pezzotti, and A. Cotta Ramusino. 1973. A rapid gas chromatographic method for the determination of thiamphenicol in body fluids and tissues. J. Chromatogr. 81:71-77. McChesney, E. W., R. F. Koss, J. M. Shekosky, and W. H. Deitz. 1960. Metabolism of dextrosulphenidol in several animal species. J. Am. Pharm. Assoc. 49:762766. Menz, H. P., I. Hartmann, R. Ilg, and H. P. von Oldershausen. 1974. On the pharmacokinetics of thiamphenicol. II. Behaviour in renal insufficiency under dialysis conditions. Drug. Res. 24:101-104. Van Beers, D., E. Schoutens, M. P. Vanderlinden, and E. Yourrassowsky. 1975. Comparative in vitro activity of chloramphenicol and thiamphenicol on common aerobic and anaerobic gram-negative bacilli (Salmonella and Shigella excluded). Chemotherapy. 21:7381. Yunis, A. A., D. R. Manyan, and G. K. Arimura. 1973. Comparative effect of chloramphenicol and thiamphenicol on DNA and mitochondrial protein synthesis in mammalian cells. J. Lab. Clin. Med. 81:713718.
Vol. 9, No. 4 Printed in U.S.A.
Peritoneal Transfer of Thiamphenicol During Peritoneal Dialysis K. I. FURMAN,* H. J. KOORNHOF, T. A. KILROE-SMITH, R. LANDLESS, AND R. G. ROBINSON
Departments of Experimental and Clinical Pharmacology and Microbiology,* Uniuersity of the Witwatersrand, and National Research Institute for Occupational Diseases, Johannesburg, South Africa
Received for publication 6 November 1975
The pharmacokinetics of thiamphenicol (TAP) was studied in 17 functionally anephric patients during peritoneal dialysis. Eleven patients were given single intramuscular injections of TAP in doses of 10 to 20 mg/kg of body weight. After this, serial blood samples and outflow dialysate collections were assayed for TAP by gas chromatography. The mean overall elimination rate constant was 0.036 0.007/h, the serum half time was 8.4 h, and the apparent volume of distribution was 71.0% (±14.39%) of the body weight. These parameters were not significantly different from those determined in anephric patients not on dialysis. The mean recovery of the administered TAP doses in the pooled outflow dialysate was 7.7% (±2.76%) over 22 h. In six other patients TAP was added to the inflow dialysate in concentrations of 10 to 20 mg/liter for 22 h. Throughout the dialysis periods, serum TAP levels did not rise above 4 gg/ml in transfer of TAP. ±
Thiamphenicol (TAP) is an analogue of chloramphenicol, in which the p-nitro group on the benzine ring of chloramphenicol is replaced by a methylsulfonyl group. It has a molecular weight of 356.24. Although TAP has a similar antibacterial spectrum to that of chloramphenicol (9), it has a number of important pharmacological differences. TAP is more stable in solution (5). In the body it is not appreciably protein bound and does not undergo significant biotransformation (5). With normal renal function most of an administered dose is excreted unchanged in the urine (3, 7). Also, thus far irreversible aplastic anemia has not been reported with the use of this drug (20). From these known general properties, one would expect this antibiotic to dialyze readily across the peritoneum and be useful for treating peritoneal infections that occur from time to time with peritoneal dialysis. Despite this, a short study by Menz et al. (8) on renal failure patients indicated that the plasma half time of TAP was not shortened by peritoneal dialysis. However, these authors did not measure actual peritoneal transfer of the drug. The purposes of the present studies were to determine the rate and extent of TAP transfer across the peritoneum and to obtain the necessary parameters for calculating dose modifications to patients undergoing peritoneal dialysis.
MATERIALS AND METHODS The method used was based on that described by Atkins et al. (1) for the study of peritoneal transfer of kanamycin. Seventeen informed volunteer patients, 13 males and 4 females aged 30 to 56 years, undergoing maintenance peritoneal dialysis were the subjects of this investigation. All had endogenous creatinine clearance rates of less than 3.0 ml/min between dialyses and urinary volumes of less than 150 ml/24 h while on dilaysis. No patient was clinically septic, none had peritonitis, and none had received any antibiotics in the previous 3 weeks. Peritoneal dialysis was performed by the standard repeated puncture technique with disposable catheters and commercially available dialysate solutions (Baxter, Dianeal, 1.5:2.0 dextrose solution with: Na, 135 meq; K, 3.0 meq; Ca, 3.5 meq; Mg, 1.5 meq; Cl, 101 meq; and lactate, 45 meq/liter). Sixtyminute cycles with 40-min inflow plus dwell times were employed for a total of 22 exchanges, using a 2liter dialysate inflow per exchange. Study I. The first study consisted of TAP removal by peritoneal dialysis after intramuscular administration. TAP-glycinate in doses of approximately 10 mg/ kg of body weight (calculated as TAP base) was given to three patients, 15 mg/kg was given to four patients, and 20 mg/kg was given to four patients, all 1 h before commencement of dialysis. Ten-milliliter samples of venous blood were collected prior to this injection and again at 2, 4, 10, 16, and 22 h after commencement of dialysis. The 3-h period between 557
558
FURMAN ET AL.
the intramuscular TAP injection and the collection of a blood sample after the first 2 h of dialysis was adequate to ensure complete absorption and uniform distribution of the antibiotic for subsequent analysis on the basis of an open model, single compartment kinetic system. Total outflow dialysate collections were made to correspond to the intervals between blood sampling, i.e., serial periods of 2, 2, 6, 6, and 6 h. TAP and creatinine concentrations were determined in each of the blood serum and outflow dialysate samples obtained. TAP assay was by gas chromatography, using the method outlined by Gazzaniga et al. (6), with D(+)-threo-1-(p-methylsulfonyl)2-acetamido-1,3-propane-diol as the internal standard. Preliminary attempts at microbiological assay by gel diffusion and scalar dilution techniques with Pasteurella multicida NTCT 10722 as the test organism proved to be very erratic and were abandoned as unreliable. Creatinine determinations were made by AutoAnalyzer. From the results of the assay, the serum regression equations were calculated by the method of least squares. The basic equation Y = MX + c was used, where Y is log of TAP in micrograms per milliliter, c is log zero-time concentration (CO), M is the overall elimination rate constant (Ke), and X is the time in hours. The serum half times (T12) were derived from the Ke values by the formula: T112 = log 2/Ke. The apparent volume of distribution (AVD) was determined by dividing the administered TAP dose by the CO. This in turn was expressed as a percentage of body weight. The percentage of recovery of each administered TAP dose was calculated from the concentrations and volumes of the outflow dialysate collections. Peritoneal TAP and creatinine clearances were calculated by the formula (D x V)/S where D is the concentration of TAP or creatinine in the outflow dialysate, V is the volume of the outflow dialysate for each collection period in milliliters per minute, and S is the geometric mean of the serum concentrations at the beginning and end of each collection period. Study II. The second study consisted of the transfer of TAP to serum after intraperitoneal administration. TAP was added to each bottle of the inflow dialysate for 22 turnovers in concentrations of 10 mg/liter to one patient, 15 mg/liter to four patients, and 20 mg/liter to one patient. Blood samples were collected in the same manner and at the same intervals as for study I, and the serum assayed for TAP concentrations. The inflow dialysate concentrations were checked by random sampling.
RESULTS Study I. The calculated serum regression equations, CO, T,/2, Ke, and AVD values are listed in Table 1. The mean (+ standard deviation) Ke was 0.036 (±0.007)/h, and the corresponding T1,2 was 8.4 h; the mean AVD was 71.0% (+14.39%) of body weight.
ANTIMICROB. AGENTS CHEMOTHER.
The TAP levels in the outflow dialysate were generally low after all of the administered doses. Concentrations between 5 and 10
Ag/ml
were achieved during the first 16 h of dialysis in one patient (MB) after a TAP dose of 20 mg/kg
of body weight. In all of the other patients, the antibiotic concentrations in the dialysate collections were less than 5 ug/ml throughout the dialysis. The mean recovery of the administered TAP doses in the outflow dialysate was 7.7% (±2.76%) in 22 h (Table 2). It should be noted here that the 22-h dialysis period is equal to two to three times the calculated T1/2 value for TAP, in which period the serum antibiotic concentration would have decayed by more than 75% of the initial peak level. This indicates the presence of a more efficient alternate route of elimination to that of peritoneum. The peritoneal TAP clearances were variable and did not show a constant relationship to creatinine clearances (Table 2). The mean (+standard deviation) peritoneal TAP clearance was 7.7 ml (±2.97 ml)/min, whereas that for creatinine was 14.0 ml (±2.10 ml)/min. Study II. Throughout the dialysis periods, there seemed to be poor peritoneal transfer from the inflow dialysate in the peritoneal cavity to the blood in that low serum levels noted early during the dialyses did not rise progressively, despite continuous TAP supplementation to the inflow dialysate (Table 3). The highest serum level monitored was 4 ug/ml after 16 h in two patients in whom the inflow dialysate TAP concentration was 15 mg/liter (Table 3).
DISCUSSION In subjects with normal renal function, the plasma T1,2 has been estimated to vary between 2.6 and 3.5 h (2, 5, 8). In anuric patients not on dialysis, the mean T112 has been reported to be 9.1 h (2). This value is not significantly different from the determinations of this parameter made on our patients during peritoneal dialysis, which supports the finding by Menz et al. (8) that the plasma decay curve is not appreciably altered by peritoneal dialysis. The enlarged AVD greater than total body water probably reflects early tissue accumulation. This has been shown by McChesney et al. (7) to occur mainly to the liver and kidneys. The liver and biliary system is the most likely alternate route of elimination, which becomes more effective in renal failure. The significance of the early tissue accumulation and the major routes of elimination are apparent in the autoradiographic studies of De Paoli et al. (4). The poor peritoneal transfer of TAP is a property shared by many other antibiotics. Only
VOL. 9, 1976
PERITONEAL TRANSFER OF TAP
559
TABLE 1. Serum TAP concentrations, regression equations, C0, T1,2, and AVD values in 11 patients undergoing peritoneal dialysis after single intramuscular injections of the antibiotic Ptien tient
V
Serum concn at (ha:
TAP dose
(mg)
2
4
Approx 10 mg/kg of body ED 600 14 9 EL 750 19 9 MN 800 10 8
10
16
weight 8 4 8 5
3 3
C0ml)(Agl
T,,2 (h)
weight
Bodeight (kg)
% Body Liters ____
7.7 6.6 8.6
62.6 73.6 83.2
34.4 35.9 65.4
55.0 48.8 78.6
17.0 16.4 15.7 24.0
10.4 6.7 8.8 9.0
68.7 72.0 75.0 78.0
58.8 61.0 70.1 45.9
85.6 84.7 93.5 58.8
31.6 22.8 28.5 31.0
11.4 8.2 6.8 12.6
77.0 55.0 90.0 80.0
47.5 43.9 63.2 51.6
61.7 79.9 70.2 64.5
22
Regression equation"
2 2 2
Y = 1.2415 - 0.0390X Y = 1.3205 - 0.0456X Y = 1.0873 - 0.0349X
17.4 20.9 12.2
4 1 3 4
Y Y Y Y
0.0290X 0.0448X 0.0342X 0.0336X
8 3
Y = 1.4660 - 0.0263X Y = 1.3580 - 0.0368X Y = 1.4554 - 0.0440X Y = 1.5023 - 0.0239X
weight
Approx 15 mg/kg of body weight SR DN BP WR
1,000 1,000 1,100 1,100
16 11 14 18
11 8 9 16
8 7 8 12
5 4 3 6
1.2319 1.2147 1.1609 1.3806
= = = =
-
Approx 20 mg/kg of body weight MB EV AS DM a
1,500 28 1,000 17 1,800 23 1,600 27
22 15 15 23
15 9 10 17
11 6 5 15
8
Hours after onset of dialysis (add 1 h for time lapse after intramuscular injection). log TAP in micrograms per milliliter; X is time in hours.
Y y is
TABLE 2. Peritoneal clearances of TAP (CTA,,) and creatinine (Ccr) - mean values of six collection periods and percentage of recovery of single intramuscular TAP doses in outflow dialysate over 22 h TAP recovery in outflow di-
Peritoneal (ml/ Patient
ED EL MN SR DN BP WR MB EV AS DM
min) CTAP
Ccr
7.2 10.9 10.8 7.3 6.0 12.2 3.3 9.6 8.4 4.2 4.7
12.1 13.6 16.5 13.5 14.0 13.4 13.4 13.8 14.6 17.8 15.9
TAP dose (mg)
600 750 800 1,000 1,000 1,100 1,100 1,500 1,000 1,800 1,600
TAP concn
FV ES ND JV LE DP
(mg/liter) 10 15 15 15 15 20
% of
mg
dose
50 70 52 62 69
8.3 9.8 6.4 6.2
121 48 191 93 70 99
11.0 4.3 12.6 9.3 4.1 6.2
6.2
dialysate
Patient
alysate
of the aminoglycosides, such as gentamicin and tobramycin, tend to dialyze significantly, and even with these the diluting effect of the dialysate usually makes it necessary to supplement the antibiotic to the dialyzing fluid when intraperitoneal activity is required. This can be done effectively with TAP as well. The commericially available TAP-glycinate is rapidly hydrolyzed in the dialysate at body temperature to free TAP independently of enzyme activity (5). One of the major problems with TAP administration is that relatively little substantive insome
TABLE 3. Serum TAP concentrations achieved after the addition of the antibiotic to the inflow dialysis in concentrations of 10, 15, and 20 mg/liter for 22 h Inflow
Serum TAP concn (tg/m1) at (h): 2
4
10
16
22
2 3 2 2 2 1
2 3 3 3 2 2
2 3 3 3 3 2
2 3 4 3 4 2
2 3 4 2 3 3
formation is available to indicate what serum levels might be necessary to treat infections with specific organisms. Recommendations on commercial package inserts have been derived rather empirically and are generally less than that indicated by minimum inhibitory concentrations determined by in vitro studies. This is particularly so far many gram-negative organisms. It has been noted that for many strains of Escherichia coli, Proteus, and Klebsiella species the in vitro minimum inhibitory concentrations are two to ten times that for CAP, and concentrations in excess of 100 ,g/ml may be required (9). Such concentrations are readily achieved in the urine with moderate doses (e.g., 500 mg, 8 h) when treating urinary infections in patients with normal renal function, but the very large doses that would be
560
FURMAN ET AL.
required to maintain such high levels systemically are somewhat impracticable to administer and potentially hazardous. Other organisms, such as Haemophilus influenza and the Neisseria, are extremely sensitive to TAP in concentrations of less than 1 ,ug/ml, and for these TAP may well be one of the antibiotics of choice (5, 9). One of the reasons for the lack of precise information about serum levels is the difficulty many laboratories experience with the microbiological assay methods that have been described for TAP. We have found gas chromatography to be a satisfactory alternative method.
ANTIMICROB. AGENTS CHZMOTHZR.
4.
5. 6.
7.
ACKNOWLEDGMENTS Due acknowledgment is made to Zambon S.p.A., Milan, for assistance and financial support.
8.
LITERATURE CITED 1. Atkins, R. C., C. Mion, C. Despaux, N. Van-Hai, C. Julien, and H. Mion. 1971. Peritoneal transfer of kanamycin and its use in peritoneal dialysis. Kidney Int. 3:391-396. 2. Azzolini, F., A. Gazzaniga, and E. Lodola. 1970. Thiamphenicol excretion in subjects with renal insuf£iciency. Int. J. Clin. Pharmacol. Ther. Toxicol. 4:303-308. 3. Della, C., D. Bella, V. Ferrari, G. Marcia, and L.
9.
10.
Bonanomi. 1968. Chloramphenicol metabolism in the phenobarbital induced rat. Comparison with thiamphenicol. Biochem. Pharmacol. 17:2381-2390. De Paoli, A. M., G. Manzoni, and A. Gazzaniga. 1974. Comparative autoradiographic study of thiamphenicol and chloramphenicol in the rat after oral treatment. Zambon S.p.A., Milan. Ferrari, V. 1968. Thiamphenicol, experimental and clinical basis of a new antibiotic. Zambon S.p.A., Milan. Gazzaniga, A., E. Pezzotti, and A. Cotta Ramusino. 1973. A rapid gas chromatographic method for the determination of thiamphenicol in body fluids and tissues. J. Chromatogr. 81:71-77. McChesney, E. W., R. F. Koss, J. M. Shekosky, and W. H. Deitz. 1960. Metabolism of dextrosulphenidol in several animal species. J. Am. Pharm. Assoc. 49:762766. Menz, H. P., I. Hartmann, R. Ilg, and H. P. von Oldershausen. 1974. On the pharmacokinetics of thiamphenicol. II. Behaviour in renal insufficiency under dialysis conditions. Drug. Res. 24:101-104. Van Beers, D., E. Schoutens, M. P. Vanderlinden, and E. Yourrassowsky. 1975. Comparative in vitro activity of chloramphenicol and thiamphenicol on common aerobic and anaerobic gram-negative bacilli (Salmonella and Shigella excluded). Chemotherapy. 21:7381. Yunis, A. A., D. R. Manyan, and G. K. Arimura. 1973. Comparative effect of chloramphenicol and thiamphenicol on DNA and mitochondrial protein synthesis in mammalian cells. J. Lab. Clin. Med. 81:713718.
