Vancomycin Stability in Heparin and Total Parenteral Nutrition Solutions: Novel Approach to Therapy of Central Venous CatheterRelated Infections JOSEPH D.C. YAO, MD*; CHARLES F. ARKIN, MD†; From the *Division
AND
ADOLF W. KARCHMER, MD*
of Infectious Diseases, Department of Medicine, and †Department of Pathology, New England Deaconess Hospital and Harvard Medical School, Boston, Massachusetts
ABSTRACT. To facilitate therapy of central venous catheterrelated Gram-positive bacterial infection in patients who require total parenteral nutrition (TPN) therapy, we studied the stability of vancomycin in a commonly used TPN solution (VTPN) at final concentrations of 0.5 mg/mL and 1.0 mg/mL and in heparin (100 U/mL in 0.9% NaCl) at 25 μg/mL (V-H). Vancomycin concentrations in V-TPN and V-H after storage at 4°C over 35 and 14 days, respectively, were stable (within 10% of the prestorage vancomycin concentration). After 14 days at 4°C heparin activity in V-H solution was 100 ± 4% of that noted initially. Vancomycin remained stable (100 ± 6% of the original vancomycin concentration) when the previously refrigerated V-TPN was held for an additional 24 hours at 22°C. When the previously refrigerated V-H was held for an
additional 24 hours at 37°C, vancomycin concentrations decreased to 78 ± 9% of the baseline concentrations ( p < .001). The stability of vancomycin in this TPN solution allows the daily dose of vancomycin to be mixed with the solution and then infused over 10 hours. As shown with pharmacokinetic modeling, this form of therapy will achieve serum vancomycin concentrations within the therapeutic range throughout a 24hour period. The relative stability of vancomycin in a heparin line-flush solution allows vancomycin concentration in the lumen of the catheter to be maintained at ≥15 μg/mL during the interval between catheter flushing and the subsequent TPN infusion. A simplified method of administering vancomycin to Journal of patients receiving concurrent TPN is possible. ( Parenteral and Enteral Nutrition 16:268-274, 1992)
pharmacokinetic properties of vancomycin permit its administration, depending on renal function, at intervals of 12 or more hours, thus facilitating therapy particularly when prolonged treatment is to be administered in an outpatient setting. In patients who are stable clinically, attempts to eradicate suspected CVC infection without removing the catheter have gained support recently. 10-13 However, if by Gram-positive bacteria, especially Staphylococcus au- the lumens of both the vein and the catheter are infected, effective therapy without catheter removal may require reus and coagulase-negative staphylococci. Standard not only maintenance of therapeutic concentrations of for catheter-related infection has included retherapy moval of the infected catheter, if necessary placing a new an appropriate antibiotic in serum and tissues, but also Central
catheter (CVC)-related infections are of total parenteral nutrition (TPN) therapy.1-6 In the pathogenesis of these infections, bacteria from the skin commonly traverse the subcutaneous tunnel through which the catheter passes and infect the fibrin-coated outer catheter surface.’ In some instances the lumen of the catheter becomes infected as well.7-9 CVC infections are frequently caused a
venous
common
complication
catheter at an uninfected anatomic site, and the administration of antibiotics intravenously. Long courses of intravenous antibiotic therapy are required when these infections are complicated by septic thrombophlebitis, endocarditis, osteomyelitis, or other deep infections. Vancomycin is often used to treat CVC infections because virtually all Gram-positive organisms causing these infections are susceptible to this drug. In addition, the
Reprint requests: Adolf W. Karchmer, MD, Chief, Division of Infectious Diseases, New England Deaconess Hospital, 185 Pilgrim Rd, Boston, MA 02215. Dr Yao is currently at Division of Infectious Diseases, E5, Calgary General Hospital, 841 Center Ave E., Calgary, Alberta, Canada T2E 0A1.
maintenance of similar concentrations within the lumen of the catheter. When antibiotics are administered by intermittent intravenous infusion followed by flushing of the catheter with a heparin solution, the catheter lumen is devoid of antibiotic for the periods between doses and thus may offer a protected site for persistent infection. Thus an efficient method of maintaining therapeutic concentrations of an antibiotic both systemically and within the catheter lumen might facilitate eradicating a CVC infection without removing the catheter. In patients who develop complicated CVC infections while receiving long-term TPN therapy, an efficient method to administer antibiotic therapy while continuing TPN is desirable. Adding the antibiotic to the TPN solution for simultaneous infusion through the CVC would simplify treatment. Elimination of multiple antibiotic infusions would reduce both the potential for medication error and the frequency of catheter manipulations
268
269 the rate commonly used for TPN (2 liters over 10 to 12 hours per night) could achieve daily vancomycin doses ranging from 1.0 to 2.0 g. V-S solutions served as controls. All solutions were prepared in duplicate and stored in a plastic intravenous bag (Viaflex, Travenol Laboratories, Deerfield. IL) at 4°C for 35 days. As depicted in Figure lA, on days 0, 7, 14, and 35 of storage, each solution was examined visually for the presence of any precipitate and then two 30-mL aliquots were removed.
(events that jeopardize catheter sterility). Addition of the antibiotic to the heparin solution used for flushing the CVC after each infusion of a TPN-antibiotic mixture would result in the exposure of the intralumenal CVC surface to therapeutic concentrations of antibiotic throughout the period between infusions. By mixing an antibiotic with the TPN solution to be infused daily and flushing the CVC with a heparin solution containing the antibiotic, therapeutic concentrations of the antimicrobial could be maintained in serum, tissue, and the catheter lumen throughout the day and yet require no manipulation of the CVC system beyond those needed for standard TPN therapy. To assess the feasibility of a simplified vancomycin regimen that would achieve persistent therapeutic antibiotic concentrations systemically and within the catheter lumen in patients receiving TPN therapy, we examined the stability of vancomycin in a typical home TPN solution and in a heparin flush solution (Hep-Lock, Elkins-Sinn, Inc, Cherry Hill, NJ) using conditions that simulated the clinical setting for patients on home TPN support. TPN solutions are stable for 35 to 40 days. Typically patients receive a 14-day supply of TPN solution and heparin flush; these solutions are then refrigerated and used subsequently. TPN solutions are brought to room temperature and infused over a 10- to 12-hour period. After the TPN solution has been infused, the CVC is flushed with the heparin solution, which remains in the catheter lumen at body temperature for 12 to 14 hours. Thereafter the cycle is repeated. In addition a pharmacokinetic model was developed to predict the serum vancomycin concentrations throughout the day in patients with normal to moderately impaired renal function when treated by administering the daily dose of vancomycin over 10 to 12 hours in the TPN solution.
One aliquot was flash frozen at -70°C immediately, whereas the other was held at 22°C (room temperature) for 24 hours, then reexamined for precipitate and flash frozen at -70°C. All frozen samples were subsequently thawed and analyzed together in triplicate for pH by pHI 70 pH meter (Beckman Instruments, Fullerton, CA, sensitivity of 0.01 pH) and for vancomycin concentration by two methods: (1) agar well diffusion bioassay14 using Bacillus subtilis ATCC 6633 (Bacto subtilis spore suspension ; Difco Laboratories, Inc, Detroit, MI) as the test organism and (2) fluorescence polarization immunoassay (TDx, Abbott Laboratories, North Chicago, IL). The flash freezing and subsequent simultaneous testing of all samples were undertaken to minimize the variations in testing conditions. Preliminary studies with the two assay methods on samples of V-TPN and V-S stored at 70°C for 35 days revealed no significant difference in the concentrations of vancomycin detected immediately after preparation and after storage. For the agar well diffusion bioassay, the linear standard curve was constructed from 6.25, 12.5, 25, 50, and 100 ug of vancomycin per milliliter of distilled water. The sensitivity of the bioassay is 0.2 ,ug/mL, with intrarun coefficients of variation in the range of 3% to 6%.15 V-TPN and V-S samples were diluted 1:50 in distilled water for bioassay. The TDx assay was performed according to the manufacturer’s instruction as described by Schwenzer et al, 16 with the standard curve derived by testing 6.25, 12.5, 25, 50, and 100 ug of vancomycin per milliliter in 0.9% NaCl.
METHODS
Vancomycin-TPN Solution Admixtures A clinical laboratory standard powder of vancomycin hydrochloride (Eli Lilly & Co, Indianapolis, IN) was used in this study. Vancomycin was added to 1-liter aliquots of TPN solution (V-TPN) (Table I) or normal saline (VS) to achieve final vancomycin concentrations of 0.5 mg/ mL and 1.0 mg/mL. If vancomycin is stable in TPN solution at these concentrations, infusion of V-TPN at Composition of the
TABLE I total parenteral nutrition solution
-
FIG. 1. A, Schedule for sampling and testing vancomycin-TPX admixture and vancomycin saline control solutions. B, Schedule for sampling and testing vancomycin-heparin admixtures and vancomycin control and heparin control solutions.
270 The assay has a sensitivity of 0.6 ug/mL, with intrarun coefficients of variation of 1% to 3% .15 V-TPN and V-S samples from solutions with initial vancomycin concentrations of 0.5 mg/mL and 1.0 mg/mL were diluted 1:20 and 1:40, respectively, in 0.9% NaCl for the TDx assay.
Vancomycin-Heparin Flush Solution Admixtures Vancomycin was added to a commercially available heparin flush solution (Hep-Lock; porcine heparin; Elkins-Sinn, Inc, Cherry Hill, NJ) to achieve a final vancomycin concentration of 25 Ag/mL and heparin concentration of 100 U/mL (V-H). This vancomycin concentration was chosen to simulate a peak serum concentration that might be achieved during systemic administration of vancomycin. Solutions of vancomycin at 25 Ag/mL in 0.9% NaCI (V-C) and of heparin (Hep-Lock solution) at 100 U/mL in 0.9% NaCI (H-C) were used as controls. All solutions were prepared in duplicate and stored in 30-mL plastic syringes (Luer-Lok, Becton Dickinson, Rutherford, NJ) at 4°C for 14 days. As indicated in Figure 1B, on days 0, 7, and 14 of storage, each solution was examined visually for the presence of any precipitate. Four 1-mL aliquots were then removed from each solution. One aliquot was flash frozen at -70°C for later determination of vancomycin concentration and one was studied immediately for pH and heparin concentration (see below). The other two aliquots from each solution were incubated at 37°C (normal body temperature) for 24 hours. At the end of the incubation period, these two aliquots were examined for precipitate, and then one aliquot was flash frozen at -70°C and the other was analyzed immediately for pH and heparin concentration. All frozen aliquots were later analyzed together in triplicate for vancomycin concentrations using the bioassay and TDx assay methods. Aliquots were not diluted. The heparin concentration was determined using a colorimetric heparin assay (Coatest Heparin, Helena Laboratories, Beaumont, TX) with a slight modification of the manufacturer’s acid-stopped manual method.17 Because the test samples did not contain human plasma, the standard curve was obtained from testing 0.02, 0.03, 0.04, 0.05, and 0.07 units of heparin (from Hep-Lock) per milliliter of Tris-EDTA buffer with twice the amount of antithrombin III suggested by the manufacturer’s instructions. The assay has a sensitivity of 0.02 U/mL and interrun coefficients of variation of 3% to 6%.17 For heparin assay aliquots were diluted 1:250 in 0.9% NaCl and tested in triplicate. Statistical Analysis
determining stability each admixture was prepared in duplicate and each measurement was performed in triplicate. The resulting six observations for each measurement have been recommended for demonstration of stability of agents in compatibility studies and used stability in parenpreviously in assessing vancomycin teral nutrition solutions. IS, 19 Each vancomycin or heparin concentration and pH value is expressed as the mean ± SD of triplicate determinations. A decrease of from the mean initial vancomycin or heparin >10% In
concentration was considered to represent a significant loss of potency. The paired Student’s t test was used to assess changes in concentrations. The mean vancomycin or heparin concentration at each collection time during storage at 4°C was compared with the respective concentrations immediately after preparation (0 hour) on day 0. The heparin and vancomycin concentrations at each collection point were also compared with the respective concentrations after 24 hours at 22°C (V-TPN, V-S) or 37°C (V-H, H-C, V-C). Degradation of vancomycin and heparin during storage at 4°C was also assessed by linear regression analysis of concentration us time, with p < .05 adopted as the level of significance for negative linear correlation. All the analyses were performed with the Primer of Biostatistics software package. 20
Simulated Pharmacokinetic Model for V-TPN Infusion
Based on a single-compartment model of distribution and first-order elimination kinetics for vancomycin,21 pharmacokinetic parameters can be calculated to determine the daily dosage of vancomycin (mixed in a TPN solution) to achieve commonly accepted therapeutic concentrations in a given patient. Daily dose can be estimated by the following steps: 1) Peak and trough serum vancomycin levels (in micrograms per milliliter) are obtained from the patient at steady state during systemic therapy with conventional intermittent infusion of vancomycin. 2) Serum vancomycin levels (in micrograms per milliliter) vs time of collection (hours) from the end of the
vancomycin infusion are plotted on semi-log graph paper and points are joined with a straight line. 3) From the graph, drug half-life (t~,2) (in hours) is determined as the length of time for serum drug level to decrease by one half. 4) The straight line is extrapolated to both the y and x axes to determine, respectively, the instantaneous peak drug concentration (Cp°) (in micrograms per milliliter) at the end of dose infusion and the residual drug concentration (Cpr) (in micrograms per milliliter) just before the start of next dose infusion. 5) Volume of distribution (Vd) (in liters) and elimination rate constant (Kd) (in hours) for vancomycin are calculated by:
where AT is the interval between doses hours.
6) Daily vancomycin dose (mg) by:
(Cp°
to
Cpr)
to be mixed in
in
TPN
solution is determined
where
Cpmax, t;n,
and Vi are,
vancomycin level (eg, of V-TPN infusion (eg, 10 serum
respectively, desirable peak 25 to 40 ,ug/mL), duration to 12
hours), and dosing
271
interval (eg, 24 or 48 hours). 7) Serum vancomycin level (Cp’ ) at any time ( t’ ) after discontinuation of a V-TPN infusion is predicted from
Vancomycin-Heparin Admixtures No precipitate was found in the ~’-H mixtures or vancomycin (25 ~g/mL) and heparin (100 C; jmL) controls (V-C and H-C, respectively) during the 14-day
Cp’ = Cp ° - Kd t’ . To illustrate the potential clinical application of infusat 4°C or after 24 hours at 37°C. The baseline ing the entire daily dose of vancomycin over 10 hours in storage pH values (time 0 hour on day 0) of these solutions were 2 liters of V-TPN, predicted serum vancomycin concentrations were calculated, using the previously noted 5.87 ± 0.02, 5.18 ± 0.01, and 5.99 ± 0.04, respectively. methods, for a patient with normal renal function (pa- The pH of V-H, V-C, and H-C increased 0.12 ± 0.02, tient 1) and one with moderate renal insufficiency (pa- 0.42 ± 0.05, and 1.05 ± 0.15, respectively, during storage tient 2). Subsequently patient 2, a 75-year-old woman at 4°C. stability of vancomycin when mixed with heparin dependent on long-term TPN support, received nightly is The indicated in Table III. At a concentration of 25 pg/ 10-hour V-TPN infusions for treatment of CVC-associchange) during ated S epidermidis septicemia. During this treatment of mL, the vancomycin was stable ( infection. NVe have eradicated bacteremic CVC infection caused eradicate CVC infection it may not always be necessary to remove the involved catheter.10-13 Thus in patientsby coagulase-negative staphylococci from two patients V’ancomycin pharmacokinetic parameters in two patients receiving intermittent systemic uancomycin (based on first-order elimination
*
>
.
,
274
patient 2) who required chronic TPN therapy (unpublished data). Their treatment, which was administered for 4 weeks, utilized a 10-hour V-TPN infusion (2.0 liters) daily, followed by a 2.0-mL V-H flush (one of whom
was
of the central catheter. The Hickman catheter was not removed from either patient. Both remained free of infection throughout the following 6 months. The stability of vancomycin in these commonly used TPN and heparin flush solutions can simplify the administration of vancomycin to patients receiving TPN in the hospital or in an outpatient setting. Pending further information on the optimal vancomycin concentration for use in the catheter flush portion of treatment, this simplified approach must be used cautiously and within the established clinical guidelines for the treatment of catheter-related infection. ACKNOWLEDGMENTS
11.
12.
13.
14.
15.
16.
We thank Ruth Colman for secretarial assistance. 17.
REFERENCES 18. 1.
2.
Ryan JA, Abel RM, Abbot WM, Hoplins CC, Chesney TM, Colley R, Phillips K, Fischer JE: Catheter complications in total parenteral nutrition. A prospective study of 200 consecutive patients. N Engl J Med 290:757-761, 1974 Ladefoged K, Efsen F, Krogh-Christoffersen J, Jarnum S: Longterm parenteral nutrition. II. Catheter-related complications. Scand J Gastroenterol 16:913-919, 1981
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Snydman DR, Murray SA, Kornfeld ST, Majka JA, Ellis CA: Total parenteral nutrition-related infections: Prospective epidemiologic study using semi-quantitative methods. Am J Med 73:695-699,
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1982
OJ, Sim AJW: A comparison of tunnelled and nontunnelled subclavian vein catheters: Prospective study of complications during parenteral feeding. Clin Nutr 2:51-54, 1983 Rannem T, Ladefoged K, Tvede M, Lorentzen JE, Jarnum S: Catheter-related septicaemia in patients receiving home parenteral nutrition. Scand J Gastroenterol 21:455-460, 1986 Maki DG: Infections associated with intravascular lines. IN Current Clinical Topics in Infectious Diseases, vol 3, Remington JS, Swartz MN (eds). McGraw-Hill Book Co, New York, 1982, pp 309363 Cooper GL, Hopkins CC: Rapid diagnosis of intravascular catheterassociated infection by direct gram staining of catheter segments. N Engl J Med 312:1142-1147, 1985 Tenney JH, Moody MR, Newman KA, Schimpff SS, Wade JC, Costerton JW, Reed WP: Adherent micro-organisms on lumenal surfaces of long-term intravenous catheters: Importance of Staphylococcus epidermidis in patients with cancer. Arch Intern Med 146:1949-1954, 1986 Russell PB, Kline J, Yoder MC, Polin RA: Staphylococcal adherence to polyvinyl chloride and heparin-bonded polyurethane catheters is species dependent and enhanced by fibronectin. J Clin Microbiol 25:1083-1087, 1987 Olson TA, Fischer GW, Lupo MC, Garcia VF, Maybee DA, Keiser
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J, Hartman KR: Antimicrobial therapy of Broviac catheter infections in pediatric hematology oncology patients. J Pediatr Surg 22:839-842, 1987 Benezra D, Keihn TE, Gold JWM, Brown AE, Turnbull ADM, Armstrong D: Prospective study of infections in indwelling central venous catheters using quantitative blood cultures. Am J Med 85:495-498, 1988 Flynn PM, Shenep JL, Stokes DC, Barrett FD: In situ management of confirmed central venous catheter-related bacteremia. Pediatr Infect Dis J 6:729-734, 1987 Hartman GE, Shochat SJ: Management of septic complications associated with Silastic catheters in childhood malignancy. Pediatr Infect Dis J 6:1042-1047, 1987 Anhalt JP: Assays for antimicrobial agents in body fluids. IN Manual of Clinical Microbiology, 4th ed, Lennette EH, Balows A, Hausler WJ Jr, Shadomy HJ (eds). American Society for Microbiology, Washington, DC, 1985, pp 1009-1014 Pfaller MA, Krogstad DJ, Granich GG, Murray PR: Laboratory evaluation of five assay methods for vancomycin: Bioassay, highpressure liquid chromatography, fluorescence polarization immunoassay, radioimmunoassay, and fluorescence immunoassay. J Clin Microbiol 20:311-316, 1984 Schwenzer KS, Wang CHJ, Anhalt JP: Automated fluorescence polarization immunoassay for monitoring vancomycin. Ther Drug Monit 5:341-345, 1983 Teien AN, Lie M: Evaluation of an amidolytic heparin assay method: increased sensitivity by adding purified antithrombin III. Thromb Res 10:399-410, 1977 Trissel LA: Avoiding common flaws in stability and compatibility studies of injectable drugs. Am J Hosp Pharm 40:1159-1160, 1983 Schilling CG, Watson DM, McCoy HG, Uden DL: Stability and delivery of vancomycin hydrochloride when admixed in a total parenteral nutrition solution. JPEN 13:63-64, 1989 Glantz SA: Primer of Biostatistics: The Program. McGraw-Hill, New York, 1988 Winter ME: Basic Clinical Pharmacokinetics. Applied Therapeutics, Vancouver, WA, 1988 Fox AS, Boyer KM, Sweeney HM: Antibiotic stability in a pediatric parenteral alimentation solution. J Pediatr 112:813-817, 1988 Nahata MC: Stability of vancomycin hydrochloride in total parenteral nutrient solutions. Am J Hosp Pharm 46:2055-2057, 1989 Barg NL, Supena RB, Fekety R: Persistent staphylococcal bacteremia in an intravenous drug abuser. Antimicrob Agents Chemother 29:209-211, 1986 Henrickson KJ, Powell KR, Schwartz CL: A dilute solution of vancomycin and heparin retains antibacterial and anticoagulant activities. J Infect Dis 157:600-601, 1988 Trissel LA: Handbook on Injectable Drugs. American Society of Hospital Pharmacists, Bethesda, MD, 1990, pp 369-370 Cooper GL, Given DB: Vancomycin: a comprehensive review of 30 years of clinical experience. Park Row Publishers, San Diego, CA, 1986 Messing B, Peitra-Cohen S, Debure A, Beliah M, Bernier JJ: Antibiotic-lock technique: A new approach to optimal therapy for catheter-related sepsis in home-parenteral nutrition patients. JPEN 12:185-189, 1988 Gaillard JL, Merlino R, Pajot N, Goulet O, Fauchere JL, Ricour C, Vernon M: Conventional and nonconventional modes of vancomycin administration to decontaminate the internal surface of catheters colonized with coagulase-negative staphylococci. JPEN
14:593-597, 1990
RC, Holmes CJ: Effect of vancomycin hydrochloride on Staphylococcus epidermidis biofilm associated with silicone elastomer. Antimicrob Agents Chemother 31:889-894, 1987
30. Evans
AND
ADOLF W. KARCHMER, MD*
of Infectious Diseases, Department of Medicine, and †Department of Pathology, New England Deaconess Hospital and Harvard Medical School, Boston, Massachusetts
ABSTRACT. To facilitate therapy of central venous catheterrelated Gram-positive bacterial infection in patients who require total parenteral nutrition (TPN) therapy, we studied the stability of vancomycin in a commonly used TPN solution (VTPN) at final concentrations of 0.5 mg/mL and 1.0 mg/mL and in heparin (100 U/mL in 0.9% NaCl) at 25 μg/mL (V-H). Vancomycin concentrations in V-TPN and V-H after storage at 4°C over 35 and 14 days, respectively, were stable (within 10% of the prestorage vancomycin concentration). After 14 days at 4°C heparin activity in V-H solution was 100 ± 4% of that noted initially. Vancomycin remained stable (100 ± 6% of the original vancomycin concentration) when the previously refrigerated V-TPN was held for an additional 24 hours at 22°C. When the previously refrigerated V-H was held for an
additional 24 hours at 37°C, vancomycin concentrations decreased to 78 ± 9% of the baseline concentrations ( p < .001). The stability of vancomycin in this TPN solution allows the daily dose of vancomycin to be mixed with the solution and then infused over 10 hours. As shown with pharmacokinetic modeling, this form of therapy will achieve serum vancomycin concentrations within the therapeutic range throughout a 24hour period. The relative stability of vancomycin in a heparin line-flush solution allows vancomycin concentration in the lumen of the catheter to be maintained at ≥15 μg/mL during the interval between catheter flushing and the subsequent TPN infusion. A simplified method of administering vancomycin to Journal of patients receiving concurrent TPN is possible. ( Parenteral and Enteral Nutrition 16:268-274, 1992)
pharmacokinetic properties of vancomycin permit its administration, depending on renal function, at intervals of 12 or more hours, thus facilitating therapy particularly when prolonged treatment is to be administered in an outpatient setting. In patients who are stable clinically, attempts to eradicate suspected CVC infection without removing the catheter have gained support recently. 10-13 However, if by Gram-positive bacteria, especially Staphylococcus au- the lumens of both the vein and the catheter are infected, effective therapy without catheter removal may require reus and coagulase-negative staphylococci. Standard not only maintenance of therapeutic concentrations of for catheter-related infection has included retherapy moval of the infected catheter, if necessary placing a new an appropriate antibiotic in serum and tissues, but also Central
catheter (CVC)-related infections are of total parenteral nutrition (TPN) therapy.1-6 In the pathogenesis of these infections, bacteria from the skin commonly traverse the subcutaneous tunnel through which the catheter passes and infect the fibrin-coated outer catheter surface.’ In some instances the lumen of the catheter becomes infected as well.7-9 CVC infections are frequently caused a
venous
common
complication
catheter at an uninfected anatomic site, and the administration of antibiotics intravenously. Long courses of intravenous antibiotic therapy are required when these infections are complicated by septic thrombophlebitis, endocarditis, osteomyelitis, or other deep infections. Vancomycin is often used to treat CVC infections because virtually all Gram-positive organisms causing these infections are susceptible to this drug. In addition, the
Reprint requests: Adolf W. Karchmer, MD, Chief, Division of Infectious Diseases, New England Deaconess Hospital, 185 Pilgrim Rd, Boston, MA 02215. Dr Yao is currently at Division of Infectious Diseases, E5, Calgary General Hospital, 841 Center Ave E., Calgary, Alberta, Canada T2E 0A1.
maintenance of similar concentrations within the lumen of the catheter. When antibiotics are administered by intermittent intravenous infusion followed by flushing of the catheter with a heparin solution, the catheter lumen is devoid of antibiotic for the periods between doses and thus may offer a protected site for persistent infection. Thus an efficient method of maintaining therapeutic concentrations of an antibiotic both systemically and within the catheter lumen might facilitate eradicating a CVC infection without removing the catheter. In patients who develop complicated CVC infections while receiving long-term TPN therapy, an efficient method to administer antibiotic therapy while continuing TPN is desirable. Adding the antibiotic to the TPN solution for simultaneous infusion through the CVC would simplify treatment. Elimination of multiple antibiotic infusions would reduce both the potential for medication error and the frequency of catheter manipulations
268
269 the rate commonly used for TPN (2 liters over 10 to 12 hours per night) could achieve daily vancomycin doses ranging from 1.0 to 2.0 g. V-S solutions served as controls. All solutions were prepared in duplicate and stored in a plastic intravenous bag (Viaflex, Travenol Laboratories, Deerfield. IL) at 4°C for 35 days. As depicted in Figure lA, on days 0, 7, 14, and 35 of storage, each solution was examined visually for the presence of any precipitate and then two 30-mL aliquots were removed.
(events that jeopardize catheter sterility). Addition of the antibiotic to the heparin solution used for flushing the CVC after each infusion of a TPN-antibiotic mixture would result in the exposure of the intralumenal CVC surface to therapeutic concentrations of antibiotic throughout the period between infusions. By mixing an antibiotic with the TPN solution to be infused daily and flushing the CVC with a heparin solution containing the antibiotic, therapeutic concentrations of the antimicrobial could be maintained in serum, tissue, and the catheter lumen throughout the day and yet require no manipulation of the CVC system beyond those needed for standard TPN therapy. To assess the feasibility of a simplified vancomycin regimen that would achieve persistent therapeutic antibiotic concentrations systemically and within the catheter lumen in patients receiving TPN therapy, we examined the stability of vancomycin in a typical home TPN solution and in a heparin flush solution (Hep-Lock, Elkins-Sinn, Inc, Cherry Hill, NJ) using conditions that simulated the clinical setting for patients on home TPN support. TPN solutions are stable for 35 to 40 days. Typically patients receive a 14-day supply of TPN solution and heparin flush; these solutions are then refrigerated and used subsequently. TPN solutions are brought to room temperature and infused over a 10- to 12-hour period. After the TPN solution has been infused, the CVC is flushed with the heparin solution, which remains in the catheter lumen at body temperature for 12 to 14 hours. Thereafter the cycle is repeated. In addition a pharmacokinetic model was developed to predict the serum vancomycin concentrations throughout the day in patients with normal to moderately impaired renal function when treated by administering the daily dose of vancomycin over 10 to 12 hours in the TPN solution.
One aliquot was flash frozen at -70°C immediately, whereas the other was held at 22°C (room temperature) for 24 hours, then reexamined for precipitate and flash frozen at -70°C. All frozen samples were subsequently thawed and analyzed together in triplicate for pH by pHI 70 pH meter (Beckman Instruments, Fullerton, CA, sensitivity of 0.01 pH) and for vancomycin concentration by two methods: (1) agar well diffusion bioassay14 using Bacillus subtilis ATCC 6633 (Bacto subtilis spore suspension ; Difco Laboratories, Inc, Detroit, MI) as the test organism and (2) fluorescence polarization immunoassay (TDx, Abbott Laboratories, North Chicago, IL). The flash freezing and subsequent simultaneous testing of all samples were undertaken to minimize the variations in testing conditions. Preliminary studies with the two assay methods on samples of V-TPN and V-S stored at 70°C for 35 days revealed no significant difference in the concentrations of vancomycin detected immediately after preparation and after storage. For the agar well diffusion bioassay, the linear standard curve was constructed from 6.25, 12.5, 25, 50, and 100 ug of vancomycin per milliliter of distilled water. The sensitivity of the bioassay is 0.2 ,ug/mL, with intrarun coefficients of variation in the range of 3% to 6%.15 V-TPN and V-S samples were diluted 1:50 in distilled water for bioassay. The TDx assay was performed according to the manufacturer’s instruction as described by Schwenzer et al, 16 with the standard curve derived by testing 6.25, 12.5, 25, 50, and 100 ug of vancomycin per milliliter in 0.9% NaCl.
METHODS
Vancomycin-TPN Solution Admixtures A clinical laboratory standard powder of vancomycin hydrochloride (Eli Lilly & Co, Indianapolis, IN) was used in this study. Vancomycin was added to 1-liter aliquots of TPN solution (V-TPN) (Table I) or normal saline (VS) to achieve final vancomycin concentrations of 0.5 mg/ mL and 1.0 mg/mL. If vancomycin is stable in TPN solution at these concentrations, infusion of V-TPN at Composition of the
TABLE I total parenteral nutrition solution
-
FIG. 1. A, Schedule for sampling and testing vancomycin-TPX admixture and vancomycin saline control solutions. B, Schedule for sampling and testing vancomycin-heparin admixtures and vancomycin control and heparin control solutions.
270 The assay has a sensitivity of 0.6 ug/mL, with intrarun coefficients of variation of 1% to 3% .15 V-TPN and V-S samples from solutions with initial vancomycin concentrations of 0.5 mg/mL and 1.0 mg/mL were diluted 1:20 and 1:40, respectively, in 0.9% NaCl for the TDx assay.
Vancomycin-Heparin Flush Solution Admixtures Vancomycin was added to a commercially available heparin flush solution (Hep-Lock; porcine heparin; Elkins-Sinn, Inc, Cherry Hill, NJ) to achieve a final vancomycin concentration of 25 Ag/mL and heparin concentration of 100 U/mL (V-H). This vancomycin concentration was chosen to simulate a peak serum concentration that might be achieved during systemic administration of vancomycin. Solutions of vancomycin at 25 Ag/mL in 0.9% NaCI (V-C) and of heparin (Hep-Lock solution) at 100 U/mL in 0.9% NaCI (H-C) were used as controls. All solutions were prepared in duplicate and stored in 30-mL plastic syringes (Luer-Lok, Becton Dickinson, Rutherford, NJ) at 4°C for 14 days. As indicated in Figure 1B, on days 0, 7, and 14 of storage, each solution was examined visually for the presence of any precipitate. Four 1-mL aliquots were then removed from each solution. One aliquot was flash frozen at -70°C for later determination of vancomycin concentration and one was studied immediately for pH and heparin concentration (see below). The other two aliquots from each solution were incubated at 37°C (normal body temperature) for 24 hours. At the end of the incubation period, these two aliquots were examined for precipitate, and then one aliquot was flash frozen at -70°C and the other was analyzed immediately for pH and heparin concentration. All frozen aliquots were later analyzed together in triplicate for vancomycin concentrations using the bioassay and TDx assay methods. Aliquots were not diluted. The heparin concentration was determined using a colorimetric heparin assay (Coatest Heparin, Helena Laboratories, Beaumont, TX) with a slight modification of the manufacturer’s acid-stopped manual method.17 Because the test samples did not contain human plasma, the standard curve was obtained from testing 0.02, 0.03, 0.04, 0.05, and 0.07 units of heparin (from Hep-Lock) per milliliter of Tris-EDTA buffer with twice the amount of antithrombin III suggested by the manufacturer’s instructions. The assay has a sensitivity of 0.02 U/mL and interrun coefficients of variation of 3% to 6%.17 For heparin assay aliquots were diluted 1:250 in 0.9% NaCl and tested in triplicate. Statistical Analysis
determining stability each admixture was prepared in duplicate and each measurement was performed in triplicate. The resulting six observations for each measurement have been recommended for demonstration of stability of agents in compatibility studies and used stability in parenpreviously in assessing vancomycin teral nutrition solutions. IS, 19 Each vancomycin or heparin concentration and pH value is expressed as the mean ± SD of triplicate determinations. A decrease of from the mean initial vancomycin or heparin >10% In
concentration was considered to represent a significant loss of potency. The paired Student’s t test was used to assess changes in concentrations. The mean vancomycin or heparin concentration at each collection time during storage at 4°C was compared with the respective concentrations immediately after preparation (0 hour) on day 0. The heparin and vancomycin concentrations at each collection point were also compared with the respective concentrations after 24 hours at 22°C (V-TPN, V-S) or 37°C (V-H, H-C, V-C). Degradation of vancomycin and heparin during storage at 4°C was also assessed by linear regression analysis of concentration us time, with p < .05 adopted as the level of significance for negative linear correlation. All the analyses were performed with the Primer of Biostatistics software package. 20
Simulated Pharmacokinetic Model for V-TPN Infusion
Based on a single-compartment model of distribution and first-order elimination kinetics for vancomycin,21 pharmacokinetic parameters can be calculated to determine the daily dosage of vancomycin (mixed in a TPN solution) to achieve commonly accepted therapeutic concentrations in a given patient. Daily dose can be estimated by the following steps: 1) Peak and trough serum vancomycin levels (in micrograms per milliliter) are obtained from the patient at steady state during systemic therapy with conventional intermittent infusion of vancomycin. 2) Serum vancomycin levels (in micrograms per milliliter) vs time of collection (hours) from the end of the
vancomycin infusion are plotted on semi-log graph paper and points are joined with a straight line. 3) From the graph, drug half-life (t~,2) (in hours) is determined as the length of time for serum drug level to decrease by one half. 4) The straight line is extrapolated to both the y and x axes to determine, respectively, the instantaneous peak drug concentration (Cp°) (in micrograms per milliliter) at the end of dose infusion and the residual drug concentration (Cpr) (in micrograms per milliliter) just before the start of next dose infusion. 5) Volume of distribution (Vd) (in liters) and elimination rate constant (Kd) (in hours) for vancomycin are calculated by:
where AT is the interval between doses hours.
6) Daily vancomycin dose (mg) by:
(Cp°
to
Cpr)
to be mixed in
in
TPN
solution is determined
where
Cpmax, t;n,
and Vi are,
vancomycin level (eg, of V-TPN infusion (eg, 10 serum
respectively, desirable peak 25 to 40 ,ug/mL), duration to 12
hours), and dosing
271
interval (eg, 24 or 48 hours). 7) Serum vancomycin level (Cp’ ) at any time ( t’ ) after discontinuation of a V-TPN infusion is predicted from
Vancomycin-Heparin Admixtures No precipitate was found in the ~’-H mixtures or vancomycin (25 ~g/mL) and heparin (100 C; jmL) controls (V-C and H-C, respectively) during the 14-day
Cp’ = Cp ° - Kd t’ . To illustrate the potential clinical application of infusat 4°C or after 24 hours at 37°C. The baseline ing the entire daily dose of vancomycin over 10 hours in storage pH values (time 0 hour on day 0) of these solutions were 2 liters of V-TPN, predicted serum vancomycin concentrations were calculated, using the previously noted 5.87 ± 0.02, 5.18 ± 0.01, and 5.99 ± 0.04, respectively. methods, for a patient with normal renal function (pa- The pH of V-H, V-C, and H-C increased 0.12 ± 0.02, tient 1) and one with moderate renal insufficiency (pa- 0.42 ± 0.05, and 1.05 ± 0.15, respectively, during storage tient 2). Subsequently patient 2, a 75-year-old woman at 4°C. stability of vancomycin when mixed with heparin dependent on long-term TPN support, received nightly is The indicated in Table III. At a concentration of 25 pg/ 10-hour V-TPN infusions for treatment of CVC-associchange) during ated S epidermidis septicemia. During this treatment of mL, the vancomycin was stable ( infection. NVe have eradicated bacteremic CVC infection caused eradicate CVC infection it may not always be necessary to remove the involved catheter.10-13 Thus in patientsby coagulase-negative staphylococci from two patients V’ancomycin pharmacokinetic parameters in two patients receiving intermittent systemic uancomycin (based on first-order elimination
*
>
.
,
274
patient 2) who required chronic TPN therapy (unpublished data). Their treatment, which was administered for 4 weeks, utilized a 10-hour V-TPN infusion (2.0 liters) daily, followed by a 2.0-mL V-H flush (one of whom
was
of the central catheter. The Hickman catheter was not removed from either patient. Both remained free of infection throughout the following 6 months. The stability of vancomycin in these commonly used TPN and heparin flush solutions can simplify the administration of vancomycin to patients receiving TPN in the hospital or in an outpatient setting. Pending further information on the optimal vancomycin concentration for use in the catheter flush portion of treatment, this simplified approach must be used cautiously and within the established clinical guidelines for the treatment of catheter-related infection. ACKNOWLEDGMENTS
11.
12.
13.
14.
15.
16.
We thank Ruth Colman for secretarial assistance. 17.
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30. Evans
