Evaluation of Slow Infusions of Co-Trimoxazole by Using Predictive Pharmacokinetics

Transcription

1 ANTImICROBIAL AGENTS AND CHEmOTHERAPY, Feb. 1980, p /80/ /06$02.00/0 Vol. 17, No. 2 Evaluation of Slow Infusions of Co-Trimoxazole by Using Predictive Pharmacokinetics DENIS J. MORGAN AND KENNETH RAYMOND Victorian College ofpharmacy, Ltd., Parkvile, Victoria, Australia, 3052 Digital computer simulations of plasma concentration-time profiles of single intravenous infsions of trimethoprim (160 mg)/sulfamethoxazole (800 mg) based on data from other workers showed that increasing the infusion period from the hitherto generally recommended 1 to 1.5 h to 6 h did not significantly affect the interval (approximately 10 h and 8.5 h, respectively) during which trimethoprim and sulfamethoxazole plasma concentrations were maintained above their minimum effective plasma concentrations (selected as 0.6 ug/ml and 25 pg/ml, respectively). For the 6-h infusion, the simulated peak plasma concentration of trimethoprim was only approximately 27% less than for the 1-h infusion, and that for sulfamethoxazole was approximately 30% less. The validity ofthese predictions was confirmed by plasma concentration measurements of trimethoprim and sulfamethoxazole in six patients undergoing gynecological surgery, who received co-trimoxazole (160 mg of trimethoprim, 800 mg of sulfamethoxazole) postoperatively by constant-rate intravenous infusion over a 4-h period. It is concluded that infusions of the dose of intravenous co-trimoxazole over periods from 1 to at least 6 h are therapeutically equivalent. Co-trmoxazole, a combination of trimethoprim (TMP) and sulfamethoxazole (SMX), is a broad-spectrum antibacterial agent with bactericidal activity against gram-positive and gramnegative organisms. A parenteral formulation of co-trimoxazole for intravenous infusion is now available, and the drug has been found to be effective in situations where its use was previously precluded due to the fact that only oral dosage forms were available. Such effectiveness has been demonstrated, for example, in the treatment of sepsis in critically ill patients (6) and in the treatment (12) and prophylas (11) of postsurgical infections. The parenteral co-trimoxazole formulation (Bactrim Infusion [Roche Products Pty. Ltd.], or Septrin for Infusion [Wellcome Australasia], containing 80 mg of TMP and 400 mg of SMX per 5-ml ampoule, in 40% propylene glycol, ph about 10) must be well diluted with intravenous infusion solution before use because the aqueous solubility of the trmethoprim component is quite low. A typical dilution is one 5-ml ampoule per 125 ml of an intravenous infusion solution (for example, normal saline). The usual dose of co-trimoxazole infusion is two or three ampoules (10 to 15 ml), diluted appropriately and administred twice daily. The duration of infusions of co-trimoxazole employed in various clinical trials (6, 7, 11, 12) was less than 1.5 h, and the manufacturers recommend that this not be exceeded. However, administration of this relatively large volume of infusion solution may compromise the fluid balance of seriously ill patients, and under these circumstances a slower infusion rate is desirable. Since there are no data in the literature to indicate whether slower infusions of co-trimoxazole are therapeutically effective, the present study utilized pharmacokinetic parameters of TMP and SMX disposition (obtained from 1-h infusions of co-trimoxazole in a previous study) to predict whether effective plasma concentrations of TMP and SMX are attained with infusion periods of up to 6 h. The validity of the predictions was investigated by a subsequent clinical study, involving the measurement of concentrations of TMP and SMX in plasma of patients receiving co-trimoxazole by slow intravenous infusion over 4 h. MATERIALS AND MErHODS Calculation of parameters of TMP and SMX disposition. Plasma concentration-time data for infusion of TMP and SMX were obtained from a study by Wall, Heidrich, Hennes, and Amrein in 1976 (unpublished data on file, Roche Products Pty. Ltd.). In that study, four healthy subjects each received 160 mg of TMP and 800 mg of SMX together in a single intravenous infusion over a 1-h period. Blood samples were collected according to the following schedule: preinjection blank, 10, 20, 30, and 40 min and 1, 1.25, 1.5,2,3,4,5,6,8, 12, and 24 h from the commencement of the infusion. The TMP plasma concentrations of one of the subjects (subject 4 in the present study) were not reported. Estimates of the pharmacokinetic parameters re- 132

2 c2-(1 VOL. 17, 1980 quired to describe the disposition of TMP and SMX were obtained from the plasma concentration-time data using the AUTOAN decision-making program (13). Each set of postinfusion data was fitted by the following general polyexponential equation (14). n c = 2 cse " (1) i-1 where c is the plasma concentration of drug at time t' (postinfusion time); n is the minimum number of exponential terms necessary to describe the plasma concentration-time data; the coefficient c,' is zero-time (i.e., at cessation of infusion) intercept; and the exponent Ai is disposition rate constant. The coefficient c was then corrected to allow for the infusion period so as to correspond to the situation as if the total dose had been given as a bolus intravenous injection (14). Pharmacokinetic smulations. The parameters derived from the data of Wall et al. were used as input for a computer program, INFGH, written in FOR- TRAN and designed to interface with a Tektronix flatbed plotter to simulate plasma concentration-time curves for both TMP and SMX corresponding to intravenous infusions of co-trimoxazole. The simulations were obtained using the following equations (14). During infusion: n C (2) Postinfusion: n Ci c = 2 i (e+\i - 1) eai (3) The coefficient c, is the corrected zero-time intercept, T is the infusion period, and t is the time from the commencement of the infusion. Clinical studies. Our patients (numbered 5 to 10) were six females, age 38 to 55 years, with no clinical or laboratory evidence of renal or hepatic dysfunction. Each patient received two ampoules of co-trimoxazole infusion (Septrin For Infusion), diluted with 500 ml of 5% dextrose and infused immediately at a constant rate over a 4-h period for prophylaxis of postsurgical infection following major gynecological surgery. For all patients but one (patient 10), the intravenous dose of co-trimoxazole was part of the following regimen: two tablets of co-trimoxazole (Septrin, each 80 mg of TMP and 400 mg of SMX) twice daily (usually at 6 a.m. and 6 p.m.) orally on the day before operation. No oral co-trimoxazole was given on the day of operation. The first intravenous infusion of co-trimoxazole was commenced shortly after surgery, which was usually begun at 8 a.m. Infusions of co-trimoxazole were subsequently administered at 12-h intervals for 48 h. Patient 10 received no co-trimoxazole therapy before the first intravenous infusion. Blood samples (10 ml) were collected into heparinized tubes immediately before the commencement of the first infusion and at 2, 4, 6, 8, and 12 h after the commencement of this infusion. Blood samples were taken from a vein contralateral to the infusion site. The plasma was separated from the blood and was stored at -5 C. The concentrations of TMP and SMX in plasma were determined using a high-pressure liquid chromatographic method (2). e~ai') CO-TRIMOXAZOLE INFUSION 133 Elimination half-lives of TMP and SMX were calculated by least-squares linear regression of the terminal log-linear portion of the plasma concentrationtime curves. Utilizing the superposition principle (5) and a knowledge of both the preinfusion plasma drug concentrations and the elimination half-lives, plasma concentration-time curves were calculated to correspond to the situation if no co-trimoxazole had been administered before the first infusion. The use of the superposition principle is appropriate because linear kinetics have been shown to apply for TMP and SMX (9), and the calculations were performed on plasma concentrations determined in the elimination phase of the previously orally administered drugs J5). Data analysis. The plasma concentration-time curves obtained from the simulations and from the clinical studies were compared with those of Wall et al. (which corresponded to 1-h infusions of co-trimoxazole in healthy subjects) using the following criteria: (i) time to attain a selected minimum effective plasma concentration; (ii) peak plasma concentration; and (iii) time during which plasma concentrations were maintained above the selected minimum effective concentration (TEff) (0.6 jig of TMP per ml and 25,ug of SMX per ml). Differences were assessed by the Mann-Whitney U test with the minimum level of significance at P = RESULTS Pharmacokinetic simulations. Table 1 shows the values of the coefficients and exponents obtained from fitting the plasma concentration-time data from the study of Wall et al. to equation (1). The plasma concentration-time curves showed a biexponential decline in all four subjects in the case of SMX and in two subjects in the case of TMP. In subject 3, TMP plasma concentrations showed a monoexponential decline. In all cases, the AUTOAN fits of the individual data sets were good (r > 0.97). The mean plasma elimination half-lives for TMP and SMX obtained from the data of Wall et al. were 9.5 h and 7.8 h, respectively, and these values are in agreement with those from other studies of intravenous co-trmoxazole (TMP, 7.6 h [7] and 11.6 h [4]; SMX, 8.6 h [7]). Using the data from subject 1, Fig. 1 and 2 illustrate typical simulations of plasma concentrations of TMP and SMX, respectively, for a range of infusion rates corresponding to infusion times from 1 to 6 h. For all subjects, respective peak plasma concentrations of TMP and SMX for the 4- and 6-h infusions were significantly less than those for the 1-h infusions. The mean percentage difference of peak plasma concentrations of TMP between the 1-h and 6-h infusions was 26.9%; this value was 30.4% for SMX (Table 2). Similarly, reduction of the infusion rate was associated with a longer period of time before effective plasma concentrations were attained.

3 134 MORGAN AND RAYMOND ANTIMICROB. AGENTS CHEMOTHER. TABLE 1. Pharnacokinetic constants derived from the data of Wall et al. TMP SMX Subject no. C, C2 Al A2 c, C2 A, A2 (jg/ml) (ug/ml) (h-') (h-') (pg/ml) (pg/mi) (h-') (h-') a a _b 4 -b -_ -b a Monoexponential equation. b Data not available. FIG. 1. Typical simulated plasma concentrationtime curves of TMP corresponding to infusion of 160 mg oftmp over 1, 2,4, and 6 h in subject 1. Minimum effective plasma concentration of TMP is taken as 0.6 pg/ml. 0- E sor c 60 a c u 40 E C0 20 lb a to Time (hours) FIG. 2. Typical simulated plasma concentrationtine curves ofsmx corresponding to infusion of 800 mg ofsmx over 1, 2,4, and 6 h in subject 1. Mininum effective plasma concentration ofsmx is taken as 25 pg/ml Table 2 shows that effective plasina concentrations of both TMP and SMX were reached approximately halfway through the infusion period. Also shown in Table 2 is the influence of the duration of co-trimoxazole infusion on the interval (TEfr) during which TMP and SMX plasma concentrations are maintained above their respective minimum effective plasma concentrations. From these simulations, for both TMP and SMX there was no significant difference between the TE:ff values for either the 2-, 4- or 6- h infusions and those of the 1-h infusions. Clinical studies. The findings of the simulation studies indicated that infusion of the recommended dosage of co-trimoxazole over a period of up to 6 h produced effective plasma concentrations of both TMP and SMX. To confirn these findings clinically, serial plasma concentrations of TMP and SMX were measured in six gynecological patients who received co-trimoxazole infusions over 4 h. The mean elimination half-lives obtained with these patients were 9.0 ± 2.7 h (standard deviation) for TMP and 10.3 ± 3.1 h (standard deviation) for SMX. These values are consistent with those from other studies as cited above. The plasma concentration-time curves for TMP and SMX, which resulted from adjusting the measured values to allow for previous oral administration by using the superposition principle, are shown in Fig. 3. For both TMP and SMX, peak plasma concentrations, the time taken to reach the minimum effective plasma concentrations, and the time during which effective plasma concentrations were maintained (TEff; Table 3) were not significantly different from the respective values obtained from the 4- h infusion simulation studies (Table 2). Furthermore, peak plasma concentrations and the time during which effective plasma concentrations were maintained were also not significantly different from the respective values obtained in the 1-h infusion studies of Wall et al. in four healthy volunteers. These findings confirm that the simulated data are reliable and demonstrate that infusions of co-trmoxazole over periods of up to at least 6 h produce therapeutically effective plasma concentrations of TMP and SMX. DISCUSSION Many factors other than the plasma concentration of an antimicrobial drug are important

4 VOL. 17, 1980 TABLE 2. Comparison of simulated plasma concentration-time curves for infusions of co-trimoxazole over various times, using the data of Wall et al.' Duration TMP SMX of infusion Cpkh Tin, TF:ff Cpesk Tmin TMgr (h) (pg/ml) (h) (h) (pg/ml) (h) (h) ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 1.3 a Values indicate mean ± standard deviation. Minimum effective plasma concentrations are taken as 0.6 yg/ ml for TMP and 25 yg/ml for SMX. b Peak simulated plasma concentration. c Time taken to attain the minimum effective concentration. d Time during which effective concentrations are maintained. e *-- Si es %3 E l0 12 Time (hows) FIG. 3. Plasma concentrations of TMP and SMX obtained after infusions of co-trimoxazole over 4 h in six gynecological patients as prophylaxis for postsurgical infections. Plasma concentrations were adjusted to remove the contribution of previously administered co-trimoxazole, using the principle of superposition. Symbols: (0) patient 5; (U) patient 6; (O) patient 7; (A) patient 8; (V) patient 9; (0) patient 10. in determniung the clinical efficacy of the drug at the infection site (10). Nevertheless, Hewitt and McHenry (8) concluded that such measurements may provide valuable information on bioavailability or drug accumulation. It is for this purpose of providing information on the CO-TRIMOXAZOLE INFUSION 135 bioavailability of slow infusions of co-trimoxazole that this study was undertaken, and that measurements of the plasma levels of TMP and SMX have been carried out. Hewitt and Mc- Henry (8) also pointed out that, although comparing the minimal inhibitory concentration of a drug for pathogens in vitro with plasma concentrations of the drug to predict susceptibility appears useful clinically, there is little information on what plasma concentrations of TMP and SMX are required relative to the minimal inhibitory concentration, or how long they should be maintained for therapeutic efficacy. In certain circumstances it has been shown that intermittent high plasma concentrations of an antimicrobial agent are effective, whereas in others, continuous, low but effective concentrations are satisfactory (10). Thus, in the present study, the criteria by which the various rates of co-trimoxazole infusion were evaluated included both a comparison of the peak plasma concentrations achieved and the time during which the plasma concentrations of drug were maintained above a miniimum effective concentration. The data of Wall et al. showed that infusions of co-trimoxazole over 1 h yield plasma concentrations of TMP and SMX above their respective minimum effective concentrations for about 10 h. In the present study, computer simulations, using model-independent pharmacokinetics, predicted that, with infusions of co-trimoxazole over periods of up to 6 h effective plasma concentrations of both TMP and SMX are attained approximately halfway through the infusion period. The delay in the attainment of such effective plasma concentrations may be undesirable with long infusions. This problem would probably not be evident with subsequent doses of the standard twice-daily dosage regimen because some degree of accumulation would be expected to occur after the first and subsequent doses (7). The simulations also predicted that infusions of co-trimoxazole over periods of up to 6 h will

5 136 MORGAN AND RAYMOND result in the maintenance of plasma concentrations above the miniimum effective values for a duration similar to that for the 1-h infusion. Indeed, it appears from the simulations that even with infusions over periods of up to 8 to 12 h (Fig. 4), there is little decrease in the time during which plasma concentrations of either TMP or SMX are above their respective minimum effective values. Eight- to 12-h infusions of co-trimoxazole are of less practical importance because of the greater risk of precipitate formation in the infusion solution at these longer times. The relationship between the duration of infusion and the time during which plasma concentrations are above a given plasma concentration for a drug, whose disposition upon intravenous administration is described by a biexponential equation, is nonlinear and complex. However, the simulations shown in Fig. 4 illustrate that although the time above the given minimum effective concentrations of TMP/SMX is similar for infusion periods of co-trimoxazole up to 8 h, infusion periods greater than 12 h are associated with a rapid decrease in the time above the minimnum effective concentration. The values selected to represent the minimum effective plasma concentrations of TMP and SMX (0.6 Aig/ml and 25 ug/ml, respectively) are consistent with the range of minimum inhibitory concentrations of the majority of susceptible organisms as determined from in vitro susceptibility tests (1, 3). Clearly, the minimum effective plasma concentration will vary with the infecting organism. Nevertheless, inspection of the simulated concentration-time curves (Fig. l and 2) suggests that the findings of this investigation would not have differed markedly had other miniimum effective concentrations been selected. The reliability of the computer predictions was confirmed clinically in patients who had Infusion rime (hours) FIG. 4. Relationship between the time above the minimum effective plasma concentration TEff and the duration of infusion of 160 mg of TMP ( ) and 800 mg of SMX (--) for subject 2. Minimum effective concentration values used were 0.6 pg/ml for TMP and 25 plg/ml for SMX. ANTIMICROB. AGENTS CHEMOTHER. TABLE 3. Summary ofpharmacokinetic parameters of co-trimoxazole infusions in six surgicalpatientsa Drug Drug Cpek T,, TEff (pg/ml) (h) (h) TMP 1.20± ± ±4.7 SMX 54.2 ± ± ± 3.3 aderived from plasma concentrations which were adjusted to remove the contribution of previously administered co-trimoxazole using the principle of superposition. received oral co-trimoxazole the day before surgery, by measuring plama concentrations of TMP and SMX resulting from infusion of cotrimoxazole over a 4-h period commencing shortly after their surgery. In these patients, SMX concentrations above 25 isg/ml appeared about 1 h after the start of the infusion and persisted above this level for about 10 h. For TMP, concentrations of about 0.6 ilg/ml were reached within 1 to 3 h after the start of the infusion and were also above this level for about 10 h. When these measured concentrations were adjusted to account for previous administration of co-trimoxazole, they were in close agreement with the predicted values from the simulation studies (Table 3), which corresponded to single infusions of co-trimoxazole. It is noteworthy that the plasma concentration-time profiles of TMP and SMX obtained for the patient who had received no oral cotrimoxazole before the intravenous infusion (patient 10) were consistent with those obtained for the remaining patients after correction for previously administered co-trimoxazole had been made (Fig. 3). In summary, model-independent pharmacokinetic analysis of literature data led us to predict that increasing the duration of infusion of TMP (160 mg)/smx (800 mg) from 1 to 6 h brought about only a relatively small reduction in peak plasma concentration of each agent (approximately 30%). Furthermore, no clinically significant change was observed in the period during which the plasma concentrations of each agent were maintained above their respective minimum effective plasma concentrations during the usual 12-h dosing interval. These predictions were confirmed clinically in six surgical patients. Consequently, provided attention is given to aspects of the stability of co-trimoxazole infusion solutions, infusion periods greater than the currently recommended 1 to 1.5 h are clinically reliable, based on plasma concentration data. ACKNOWLEDGMENWS We thank D. Byme, M. Gronow, and M. Barnett and the nursing staff of the Royal Women's Hospital, Melbourne, for

6 VOL. 17, 1980 their cooperation, and Roche Products Pty. Ltd. for making the plasma concentration-time data available. Acknowledgment is made to Wellcome Australasia for financial assistance. CO-TRIMOXAZOLE INFUSION 137 LITERATURE CITED 1. Brumfitt, W., J. M. T. Hamilton-Miller, and J. Komidis Trimethoprim-sulfamethoxazole: the present position. J. Infect. Dis. 128(Suppl.):S778-S Bury, R. W., and M. L Mashford Analysis of trimethoprim and sulphamethoxazole in human plasma by high-pressure liquid chromatography. J. Chromatogr. 163: Bushby, S. R. M Trimethoprim-sulfamethoxazole: in vitro microbiological aspects. J. Infect. Dis. 128(Suppl.):S442-S Bushby, S. R. ML, and G. IL Hitchings Trimethoprim, a sulphonamide potentiator. Br. J. Pharmacol. Chemother. 33: Gibaldi, M., and D. Perrier Pharmacokinetics, p Marcel Dekker, Inc., New York. 6. Goodwin, N. M Intravenous Bactrim. A preliminary report. S. Afr. Med. J. 47: Grose, W. E., G. P. Bodey, and T. L Loo Clinical pharmacology of intravenoualy administered trimethoprim-sulfamethoxazole. Antimicrob. Agents Chemother. 15: Hewitt, W. L, and M. C. McHenry Blood level determinations of antimicrobial drugs. Some clinical considerations. Med. Clin. North Am. 62: Kaplan, S. A., R. E. Weinfeld, C. W. Abruzzo, K. McFadden, M. W. Jack, and L Weiisman Pharmacokinetic profile of trimethoprim-sulfamethoxazole in man. J. Infect. Dis. 128(Suppl.):S547-S Kunin, C. M Blood level measurements and antimicrobial agents. Clin. Pharmacol. Ther. 16: Matthews, D. D., H. Ross, and J. Cooper A double-blind trial of single-dose chemoprophylaxis with co-trimozazole during total abdominal hysterectomy. Br. J. Obstet. Gynaecol. 84: Scranowitz, P., and J. Mockwitz Parenterale Verabreichung von Co-trimoxazol bei chirurgischen Patienten. Die Klinikat. 4: Sedman, A. J., and J. G. Wagner AUTOAN: a decision-making pharmacokinetic computer program. Publication Distribution Services, Ann Arbor, Mich. 14. Wagner, J. G Linear pharmacokinetic equations allowing direct calculation of many needed pharmacokinetic parameters from the coefficients and exponents of polyexponential equations which have been fitted to the data. J. Pharmacokinet. Biopharm. 4: Downloaded from on November 30, 2018 by guest