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Comparison of vancomycin pharmacodynamics (1 g every 12 or 24 h) against methicillin-resistant staphylococci
International Journal of Antimicrobial Agents 15 (2000) 25 – 30 www.ischemo.org
Original article
Comparison of vancomycin pharmacodynamics (1 g every 12 or 24 h) against methicillin-resistant staphylococci Melinda K. Lacy a,* , Pamela R. Tessier b, David P. Nicolau b,c,d, Charles H. Nightingale b,c, Richard Quintiliani b,c a
Department of Pharmacy Practice, School of Pharmacy, The Uni6ersity of Kansas Medical Center, 3901 Rainbow Boule6ard, Kansas City, KS 66160 -7231, USA b Department of Pharmacy Research, Hartford Hospital, Hartford, CT 06102, USA c Office of Research, Hartford Hospital, Hartford, CT 06102, USA d Di6ision of Infectious Diseases, Hartford Hospital, Hartford, CT 06102, USA Received 22 December 1999; accepted 13 January 2000
Abstract This study compared the duration of serum bactericidal activity for vancomycin, 1 g every 12 or 24 h at steady state, against methicillin-resistant Staphylococcus aureus (MRSA) and coagulase-negative staphylococci (MR-CNS). All four test isolates were susceptible to vancomycin with minimal inhibitory concentration (MIC) values of either 2 or 4 mg/l. Serum bactericidal titres (SBTs) were run in duplicate and serum bactericidal activity (SBA) was defined as the time points at which all subject SBTs were greater than or equal to 1:2. For the every 12-h regimen, SBA was 10 – 12 h. With the every 24-h regimen, the duration of SBA was 10–16 h for MRSA and 8–10 h for MR-CNS. The pharmacodynamic data suggest that for those with good renal function a Q12h dosing interval is most appropriate for MR-CNS or staphylococcal isolates with MICs of 4. © 2000 Elsevier Science B.V. and International Society of Chemotherapy. All rights reserved. Keywords: Vancomycin; Pharmacodynamics; Bactericidal; Methicillin-resistant Staphylococcus aureus; Coagulase-negative staphylococci; Methicillin-resistant Staphylococcus epidermidis
1. Introduction Vancomycin has been used clinically for over 40 years against Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis and other Gram-positive bacteria [1]. Pharmacokinetically it has a long elimination half-life of 5 – 11 h for patients with normal renal function [2] and demonstrates a postantibiotic effect against staphylococci lasting between 1 and 6 h [3 – 6]. Pharmacodyamically vancomycin has been shown to exhibit time-dependent bactericidal activity in both in vitro and animal studies [7 – 9]. Previous studies
* Corresponding author. Tel.: +1-913-5885314; fax: + 1-9135882355. E-mail address: [email protected] (M.K. Lacy)
with vancomycin and b-lactams have shown that these antibiotics have maximal rates of bactericidal activity at levels between two and four times above the minimal inhibitory concentration (MIC) of susceptible bacteria [6]. However, it is common clinical practice to maintain vancomycin trough levels up to ten times or more than the MICs of susceptible pathogens, that typically have MIC values of less than or equal to 2 mg/l. No published studies have evaluated vancomycin efficacy at serum concentrations below accepted trough values or situations where serum concentrations fall below MIC values during a dosing interval. Therefore, current vancomycin reference ranges used in clinical practice are based upon achieving serum concentrations above the MIC of susceptible pathogens for 100% of the dosing interval using observations from clinical practice, retrospective analyses and anecdotal reports.
0924-8579/00/$20 © 2000 Elsevier Science B.V. and International Society of Chemotherapy. All rights reserved. PII: S 0 9 2 4 - 8 5 7 9 ( 0 0 ) 0 0 1 2 1 - 7
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M.K. Lacy et al. / International Journal of Antimicrobial Agents 15 (2000) 25–30
To investigate the duration of vancomycin serum bactericidal activity (SBA) against methicillin-resistant S. aureus and coagulase-negative staphylococcal isolates we evaluated two commonly employed vancomycin dosing regimens in healthy subjects. The duration of time that serum concentrations remained above pathogen MIC values was also determined. (This work was presented at the 1998 Annual Meeting of the American College of Clinical Pharmacy, Cincinnati, Ohio, 8– 11 November 1998 [10]).
2. Materials and methods
2.1. Study design This was a prospective, randomized, multidose, openlabel, two-period crossover study separated by a 4- or 6-day washout period. The protocol and informed consent were reviewed and approved by the institutional review board prior to study initiation.
2.2. Subjects Healthy volunteers 18 years of age or older underwent a screening physical examination and a medical history was obtained to rule out the possibility of renal, hepatic, cardiovascular, endocrine, neurological or other disease and antibiotic hypersensitivities. Blood chemistry, haematology and urinalysis were performed for each subject prior to enrolment. Female volunteers were screened by a direct latex agglutination test to confirm each subject was not pregnant. Exclusion criteria included the following: history of hypersensitivity to vancomycin, substance abuse, diabetes mellitus, acute illness within 7 days prior to study entry, any concomitant medication other than vitamins or birth control pills, any anti-infective medication within 2 weeks prior to study entry, pregnancy or any detected abnormal laboratory values (e.g. serum creatinine \2.0 mg/dl, liver transaminases less than twice the upper limit of normal values). Eligible subjects were enrolled after written informed consent was obtained. Post-study laboratory evaluations were performed on all subjects at the completion of the study.
2.3. Study antibiotic and administration Subjects were randomly assigned to receive intravenous vancomycin (Abbott Laboratories, North Chicago, IL, lot 10 716Z7, or Vancocin, Eli Lilly & Company, Indianapolis, IN, lot 9MW33M) 1 g every 12 h× four doses, and vancomycin 1 g every 24 h× three doses. These multidose regimens were selected in order to test the activity of vancomycin at steady-state against the study isolates. The ADD-Vantage vial sys-
tem was used to prepare all vancomycin infusions and doses were diluted in 250 ml of 5% dextrose USP (Abbott Laboratories, North Chicago, IL, lot 13-246JT) less than 3 h prior to infusion. Vancomycin was infused via a peripheral catheter over 60–90 min.
2.4. Study periods Study periods were either 3 or 4 days in length and were conducted in an institutional clinical research center. Subjects were not allowed to consume any caffeine or alcohol-containing beverages during the study. Food and all beverages except water were withheld at least 2 h before and for 2 h after administration of the last dose but otherwise were permitted ad libitum.
2.5. Sampling Venous blood samples were obtained from a catheter placed in the arm contralateral to that used for drug administration. Predose samples were obtained on the first day of each study period before drug administration. Blood samples (10 ml) were collected from each subject at time 0, 2, 4, 6, 8, 10 and 12 h from the start of infusion on the last dose. For the every 24-h regimen, samples were also drawn at the 16-, 18-, 20-, 22and 24-h time points. At each sample collection, the first 3 ml of blood from the sampling catheter was discarded. After collection of the blood sample the site was flushed with 3 ml of normal saline and heparinized with 1 ml of 100 units/ml to maintain site patency. Collected samples were allowed to clot at room temperature for 30 min. Following refrigerated centrifugation (4°C, 1000 × g for 10 min), the serum samples were aliquoted into two portions: one portion to be used for assay of drug concentration and the second portion to be used for determination of bactericidal activity. All serum samples were stored at − 80°C until analyzed.
2.6. Bacterial isolates Four methicillin-resistant staphylococcal isolates were selected for evaluation: two clinical isolates of methicillin-resistant S. aureus (MRSA 32 and MRSA 34) from the Hartford Hospital Department of Microbiology and two isolates of coagulase-negative staphylococci from the American Type Culture Collection (Manassas, VA), methicillin-resistant S. epidermidis (MRSE 51625) and methicillin-resistant Staphylococcus hominis (MRSH 51624). The MICs were determined in duplicate for the four test organisms by the microdilution method according to National Committee for Clinical Laboratory Standards (NCCLS) guidelines using cation-adjusted Mueller Hinton broth (CAMHB, Becton Dickinson, Cockeysville, MD) as the growth medium [11]. Addi-
M.K. Lacy et al. / International Journal of Antimicrobial Agents 15 (2000) 25–30
tionally, the coagulase-negative staphylococci (MRCNS) isolates were also tested using haemophilus test medium (HTM, Becton Dickinson, Cockeysville, MD), as this medium was used for the serum bactericidal titre (SBT) determinations and to insure that the HTM did not affect the microbiological activity of vancomycin against the test isolates. All study isolates were susceptible to vancomycin with MIC values of either 2 or 4 mg/l. The MICs were the same whether tested in HTM or CAMHB prior to and throughout the SBT testing.
27
Lotus Development Corporation). The selected intervals for inclusion in the elimination rate analysis were hours 4–12 for the every 12-h regimen and for hours 8–16 for the every 24-h regimen. These ranges were linear based upon examination of all log concentration versus time plots. A half-life was determined for each subject using a standard pharmacokinetic equation (ln 2/Ke). Duration of time that serum concentrations exceeded the MIC of each organism were calculated using the elimination rate constant for each subject and known MIC values for each study isolate.
2.7. Serum bactericidal acti6ity Duplicate SBTs were determined by NCCLS methodology for each subject at selected time points to determine the duration of activity for each regimen [12]. CAMHB was used as the diluent for the MRSA isolates and based upon preliminary studies, HTM for the MR-CNS isolates. The SBT endpoint was determined as the highest dilution that killed 99.9% of the test isolate. All SBT results were combined and used in the final analysis for comparison. The definition of SBA used in this study was the time point after dosing at which all subjects’ SBTs were greater than or equal to 1:2.
2.8. Analytical methods Selected serum samples from the elimination phase were assayed for vancomycin concentration using the Abbott FLxTDx System (Abbott Laboratories) at our institution. Samples were stored at − 80°C until analyzed.
2.9. Data analysis The observed duration and percentage of the dosing interval that SBA was noted for each regimen and organism combination was recorded. The elimination rate of vancomycin was calculated from the slope of the regression line for the final dose in each study period (Freelance Graphics for Windows, Release 2.1, 1994,
Table 1 Mean (9 S.D.) demographic data for study subjects and resultant vancomycin pharmacokinetic parameters Age Weight Gender Ke T1/2 Cmin a
25.5 94.5 years 74.1 99.6 kg 9 male, 3 female 1 g Q12h: 0.15990.02 h−1; 1 g Q24h: 0.14290.03 h−1 1g Q12h: 4.4 9 0.6 h; 1 g Q24h: 5.191.0 h 1 g Q12h: 5.791.6 mg/ml; 1 g Q24h: 0.8 9 0.4 mg/mla
Calculated value since actual concentrations were below assay limit of detection.
3. Results
3.1. Subjects Fifteen subjects were enrolled and 12 subjects completed both study periods as indicated in Table 1. Three subjects were withdrawn for the following reasons. One subject developed a generalized body rash within 24 h of the first dose, the second experienced nausea and vomiting and intense facial flushing during the infusion of the first dose, and the third experienced vasovagal syncope upon placement of the first intravenous catheter prior to any study antibiotic administration. All of the withdrawn subjects fully recovered without further incident.
3.2. Antibiotic administration Of the 12 subjects that completed the study, ten experienced mild-to-moderate infusion-related facial flushing and/or pruritus of the head, neck and upper chest areas during the first study period. The infusion times of subsequent doses were extended from 60 to 90 min, however, the majority of subjects still experienced infusion-related effects. A different manufacturer of vancomycin was used for the second study period (Abbott Laboratories) and less intense reactions were subjectively reported with the change in manufacturers and with each successive dose. All infusion-related reactions rapidly subsided within a couple of hours after drug administration. One subject was given 25 mg of diphenhydramine prior to each dose due to intense facial flushing and pruritus that was not accompanied by any measurable hypotension.
3.3. Susceptibility testing Individual MIC values for the study isolates are shown in Table 2. All isolates were fully susceptible to vancomycin with a range of MIC values of either 2 or 4 mg/l.
M.K. Lacy et al. / International Journal of Antimicrobial Agents 15 (2000) 25–30
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Table 2 Susceptibility profiles of study isolates, duration of bactericidal activity and duration of serum concentrations above the MIC Organism
MRSA 34 MRSA 32 MRSH 51624 MRSE 51625 a b
VAN MICa (mg/l)
2 4 2 4
Duration of measurable SBAb (h)
Duration serum concentrations\MIC (h)
1g Q12h
1 g Q24h
1g Q12h
1 g Q24h
12 10 12 10
16 10 10 8
12 12 12 12
18 13 18 13
Vancomycin MIC values. Serum bactericidal activity.
3.4. Pharmacokinetic 6alues Mean pharmacokinetic values are shown in Table 1. All serum concentrations were normalized to 70 kg and resultant values were similar to previously published ranges for vancomycin in healthy volunteers [13].
3.5. Serum bactericidal acti6ity Measurable bactericidal activity was maintained throughout greater than 80% of the dosing interval for the MRSA and MR-CNS isolates for the 1-g Q12h regimen. Serum concentrations remained above the MIC of all study isolates for 100% of the dosing interval for the Q12h regimen. For the 1-g Q24h regimen, bactericidal activity was observed for more than 66% of the dosing interval for only the MRSA isolate with an MIC value of 2 mg/l. Against MRSE, MRSH, and the MRSA isolate with an MIC of 4 mg/l, bactericidal activity was maintained for less than 50%. Vancomycin serum concentrations exceeded the MIC for 75% of the dosing interval when the MIC was 2 mg/l and for 54% when the MIC was 4 mg/l during the Q24h regimen. Table 2 summarizes the duration of bactericidal activity and the duration of time that serum concentrations exceeded the test isolates’ MIC values for each dosing regimen.
The majority of staphylococcal isolates have vancomycin MIC values of 2 mg/l or less with a susceptibility breakpoint of less than or equal to 4 mg/l. We chose to evaluate the duration of bactericidal activity for MRSA and MR-CNS at the upper range of susceptibility using isolates with MICs of 2 or 4 mg/l. Since healthy subjects with excellent renal function were selected, this study considered the most conservative situation regarding the duration of activity with standard dosing regimens. In this study, the Q12h interval provided for optimal bactericidal activity against all of the study isolates as shown in Fig. 1. However, it was interesting to note that for the Q24h regimen, activity was observed for 67% of the dosing interval for the MRSA isolate with an MIC of 2. This appears to suggest that a once daily interval might be successful against MRSA as long as the MIC was less than 2, especially when the long PAE against staphylococci is considered. However, this would obviously need to be verified in future clinical trials and certainly would not be applicable to the coagulase-negative isolates based upon our results. Neither would a once-daily interval be recommended for the management of endocarditis, meningitis or other serious infections in patients with good renal function. As expected, measurable bactericidal activity was observed for the entire dosing interval for the every
4. Discussion Despite more than 40 years of clinical use and a plethora of in vitro data demonstrating the time-dependent pharmacodynamic bactericidal characteristics of vancomycin [7–9], few clinical studies associating serum levels with bactericidal activity can be found. Current trough ranges fall between 5 and 15 mg/l. The vancomycin reference ranges used in clinical practice are based primarily on retrospective studies and anecdotal reports [14]. While vancomycin doses are often modified based upon information provided by serum drug concentrations, this practice is declining, especially in those with good renal function [15 – 17].
Fig. 1. Duration of vancomycin serum bactericidal activity (SBT ] 1:2) at steady-state as a percentage of the dosing interval.
M.K. Lacy et al. / International Journal of Antimicrobial Agents 15 (2000) 25–30
12-h dosing regimen with MIC values of 2. Slightly less activity was noted for the isolates with MIC values of 4 mg/l. Bactericidal activity was observed for less than 50% of the dosing interval for MR-CNS for the once daily dosing regimen regardless of MIC. The duration of the dosing interval that serum concentrations exceeded the study isolate MIC values was similar to the duration of measurable bactericidal activity (Table 2). The differences may be explained by the initial 1:2 serum dilution that that is made when conducting the SBT test. Furthermore, the two types of data differ since serum concentration data are continuous and SBA data are not. The optimal duration of time in a dosing interval that vancomycin bactericidal activity is required for successful clinical outcomes is unknown. It has been suggested that vancomycin serum levels of 2 mg/ml should protect against the emergence of resistant staphylococci [18]. Unsurprisingly, positive therapeutic outcomes have been reported when bactericidal activity lasted throughout the entire dosing interval or when serum concentrations were within established trough reference ranges, thereby guaranteeing 100% time above the MIC throughout a dosing interval [17,19,20]. Clinical and in vivo data for other antibiotics with time-dependent pharmacodynamics (penicillins, cephalosporins, carbapenems) suggest that antibiotic concentrations do not need to remain above MIC values throughout the entire dosing interval in order to achieve a positive outcome [21,22]. This has been demonstrated in animal models of infection for S. aureus when cephalosporins were used [23,24]. In one study maximal efficacy was noted with only 40% time above the MIC for cefotaxime and ceftriaxone — less than that required for Gram-negative bacteria or streptococci [23]. For cefazolin, maximal efficacy was achieved when concentrations exceeded the MIC for 55% of the treatment interval with 20% indicated as a minimal level for bactericidal activity [24]. Once again, this was less than the greater than 60% of the interval required for Escherichia coli in the same study. These differences were directly attributed to the prolonged PAE for cephalosporins against staphylococci [23]. In the present study, infusion-related effects or red man syndrome was observed in a majority of the subjects. These effects are mediated by histamine release with the administration of a vancomycin dose [25,26] and are more frequently noted in healthy volunteers than in acutely-ill patients [27]. In retrospect, our use of two different vancomycin manufacturers was probably unnecessary given the fact that these wellknow effects are commonly reported in healthy volunteers. However, the use of a different manufacturer for each study period is not thought to have influenced our study results or conclusions. In considering future vancomycin studies involving healthy volunteers, 2-h infu-
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sion times should be employed to minimize the frequency and severity of histamine-induced infusionrelated reactions [26].
5. Conclusion In conclusion, the vancomycin pharmacodynamic data from this study suggests that a Q12h dosing interval is most appropriate in those with good renal function when a coagulase-negative staphylococcus is suspected and for MRSA when MICs approach the susceptibility breakpoint. It remains to be seen whether a once-daily interval would be effective when treating MRSA infections or other highly susceptible pathogens when MIC values are less than or equal to 2 mg/l, but our bactericidal data suggests that it may be feasible. However, this would need to be carefully evaluated in further studies using pathogens with lower MICs and should not be employed in the treatment of serious infections. In cases of known MR-CNS infections or when the MIC is unknown, vancomycin serum concentrations should be maintained within the current trough ranges to ensure that concentrations remain above the susceptibility breakpoint.
Acknowledgements Supported by a research grant from Hartford Hospital, Hartford, Connecticut. We also thank Christina Turley for her technical assistance.
References [1] Fekety R. Vancomycin and teicoplanin. In: Mandell GLBJ, Dolin R, editors. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases, vol. 1. New York: Churchill Livingstone, 1995:346. [2] Krogstad DJ, Moellering RC, Greenblatt DJ. Single-dose kinetics of intravenous vancomycin. J Clin Pharmacol 1980;20:197– 201. [3] McDonald PJ, Craig WA, Kunin CM. Persistent effect of antibiotics on staphylococcus aureus after exposure for limited periods of time. J Infect Dis 1977;135:217 – 23. [4] Bundtzen RW. Postantibiotic suppression of bacterial growth. Rev Infect Dis 1981;3:28 – 37. [5] Cooper MA, Jin Y-F, Ashby JP, Andrews JM, Wise R. In-vitro comparison of the postantibiotic effect of vancomycin and teicoplanin. J Antimicrob Chemother 1990;26:203 – 7. [6] Ebert SC, Craig WA. Pharmacodynamic properties of antibiotics: application to drug monitoring and dosage regimen design. Infect Control Hosp Epidemiol 1990;11:319 – 26. [7] Ackerman BH, Vannier AM, Eudy EB. Analysis of vancomycin time-kill studies with Staphylococcus species by using a curve stripping program to describe the relationship between concentration and pharmacodynamic response. Antimicrob Agents Chemother 1992;36:1766 – 9.
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[8] Lowdin E, Odenholt I, Cars O. In vitro studies of pharmacodynamic properties of vancomycin against Staphylococcus aureus and Staphylococcus epidermidis. Antimicrob Agents Chemother 1998;42:2739 – 44. [9] Duffull SB, Begg EJ, Chambers ST, Barclay ML. Efficacies of different vancomycin dosing regimens against Staphylococcus aureus determined with a dynamic in vitro model. Antimicrob Agents Chemother 1994;38:2480–2. [10] Lacy MK, Tessier PR, Nicolau DP, Nightingale CH, Quintiliani R. Comparison of vancomycin pharmacodynamics (1 gram every 12 or 24 hours) against methicillin-resistant taphylococcus isolates [Abstract 63]. Pharmacotherapy 1998;18:1148. [11] National Committee for Clinical and Laboratory Standards. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. Approved standard M7-A4. Wayne, PA, 1997. [12] National Committee for Clinical and Laboratory Standards. Methodology for the serum bactericidal test. Tentative guideline M21-T, Wayne, PA, 1992. [13] Klepser ME, Patel KB, Nicolau DP, Quintiliani R, Nightingale CH. Comparison of bactericidal activities of intermittent and continuous infusion dosing of vancomycin against methicillin-resistant Staphylococcus aureus and Enterococcus faecalis. Pharmacotherapy 1998;18:1069–74. [14] Zimmermann AE, Katona BG, Plaisance KI. Association of vancomycin serum concentrations with outcomes in patients with gram-positive bacteremia. Pharmacotherapy 1995;15:85 – 91. [15] Edwards DJ, Pancorbo S. Routine monitoring of serum vancomycin concentrations: waiting for proof of its value. Clin Pharm 1987;6:652 – 4. [16] Freeman CD, Quintiliani R, Nightingale CH. Vancomycin therapeutic drug monitoring: is it necessary? Ann Pharmacother 1993;27:652 – 4. [17] Karam CM, McKinnon PS, Neuhauser MM, Rybak MJ. Outcome assessment of minimizing vancomycin monitoring and dosing adjustments. Pharmacotherapy 1999;19:257–66.
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[18] Griffith RS. Introduction to vancomycin. Rev Infect Dis 1981;3:S200 – 4. [19] James JK, Palmer SM, Levine DP, Rybak MJ. Comparison of conventional dosing versus continuous-infusion vancomycin therapy for patients with suspected or documented gram-positive infections. Antimicrob Agents Chemother 1996;40:696 –700. [20] Rybak MJ, Cappelletty DM, Ruffing MJ et al. Influence of vancomycin (V) serum concentrations on the outcome of patients being treated for gram-positive infections. Abstracts of the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy. Toronto, Ontario, Canada, 29 September 1997. [21] Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis 1998;26:1 – 12. [22] Craig WA, Andes D. Pharmacokinetics and pharmacodynamics of antibiotics in otitis media. Pediatr Infect Dis J 1996;15:255–9. [23] Craig WA. Interrelationship between pharmacokinetics and pharmacodynamics in determining dosage regimens for broadspectrum cephalosporins. Diagn Microbiol Infect Dis 1995;22:89 – 96. [24] Vogelman B, Gudmundsson S, Leggett J, Turnidge J, Ebert S, Craig WA. Correlation of antimicrobial pharmacokinetic parameters with therapeutic efficacy in an animal model. J Infect Dis 1988;158:831 – 47. [25] Sahai J, Healy DP, Shelton MJ, Miller JS, Ruberg SJ, Polk R. Comparison of vancomycin- and teicoplanin-induced histamine release and ‘red man syndrome’. Antimicrob Agents Chemother 1990;34:765 – 9. [26] Healy DP, Sahai JV, Fuller SH, Polk RE. Vancomycin-induced histamine release and ‘red man syndrome’: a comparison of 1and 2-hour infusions. Antimicrob Agents Chemother 1990;34:550 – 4. [27] Rybak MJ, Bailey EM, Warbasse LH. Absence of ‘red man syndrome’ in patients being treated with vancomycin or highdose teicoplanin. Antimicrob Agents Chemother 1992;36:1204– 7.
Original article
Comparison of vancomycin pharmacodynamics (1 g every 12 or 24 h) against methicillin-resistant staphylococci Melinda K. Lacy a,* , Pamela R. Tessier b, David P. Nicolau b,c,d, Charles H. Nightingale b,c, Richard Quintiliani b,c a
Department of Pharmacy Practice, School of Pharmacy, The Uni6ersity of Kansas Medical Center, 3901 Rainbow Boule6ard, Kansas City, KS 66160 -7231, USA b Department of Pharmacy Research, Hartford Hospital, Hartford, CT 06102, USA c Office of Research, Hartford Hospital, Hartford, CT 06102, USA d Di6ision of Infectious Diseases, Hartford Hospital, Hartford, CT 06102, USA Received 22 December 1999; accepted 13 January 2000
Abstract This study compared the duration of serum bactericidal activity for vancomycin, 1 g every 12 or 24 h at steady state, against methicillin-resistant Staphylococcus aureus (MRSA) and coagulase-negative staphylococci (MR-CNS). All four test isolates were susceptible to vancomycin with minimal inhibitory concentration (MIC) values of either 2 or 4 mg/l. Serum bactericidal titres (SBTs) were run in duplicate and serum bactericidal activity (SBA) was defined as the time points at which all subject SBTs were greater than or equal to 1:2. For the every 12-h regimen, SBA was 10 – 12 h. With the every 24-h regimen, the duration of SBA was 10–16 h for MRSA and 8–10 h for MR-CNS. The pharmacodynamic data suggest that for those with good renal function a Q12h dosing interval is most appropriate for MR-CNS or staphylococcal isolates with MICs of 4. © 2000 Elsevier Science B.V. and International Society of Chemotherapy. All rights reserved. Keywords: Vancomycin; Pharmacodynamics; Bactericidal; Methicillin-resistant Staphylococcus aureus; Coagulase-negative staphylococci; Methicillin-resistant Staphylococcus epidermidis
1. Introduction Vancomycin has been used clinically for over 40 years against Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis and other Gram-positive bacteria [1]. Pharmacokinetically it has a long elimination half-life of 5 – 11 h for patients with normal renal function [2] and demonstrates a postantibiotic effect against staphylococci lasting between 1 and 6 h [3 – 6]. Pharmacodyamically vancomycin has been shown to exhibit time-dependent bactericidal activity in both in vitro and animal studies [7 – 9]. Previous studies
* Corresponding author. Tel.: +1-913-5885314; fax: + 1-9135882355. E-mail address: [email protected] (M.K. Lacy)
with vancomycin and b-lactams have shown that these antibiotics have maximal rates of bactericidal activity at levels between two and four times above the minimal inhibitory concentration (MIC) of susceptible bacteria [6]. However, it is common clinical practice to maintain vancomycin trough levels up to ten times or more than the MICs of susceptible pathogens, that typically have MIC values of less than or equal to 2 mg/l. No published studies have evaluated vancomycin efficacy at serum concentrations below accepted trough values or situations where serum concentrations fall below MIC values during a dosing interval. Therefore, current vancomycin reference ranges used in clinical practice are based upon achieving serum concentrations above the MIC of susceptible pathogens for 100% of the dosing interval using observations from clinical practice, retrospective analyses and anecdotal reports.
0924-8579/00/$20 © 2000 Elsevier Science B.V. and International Society of Chemotherapy. All rights reserved. PII: S 0 9 2 4 - 8 5 7 9 ( 0 0 ) 0 0 1 2 1 - 7
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M.K. Lacy et al. / International Journal of Antimicrobial Agents 15 (2000) 25–30
To investigate the duration of vancomycin serum bactericidal activity (SBA) against methicillin-resistant S. aureus and coagulase-negative staphylococcal isolates we evaluated two commonly employed vancomycin dosing regimens in healthy subjects. The duration of time that serum concentrations remained above pathogen MIC values was also determined. (This work was presented at the 1998 Annual Meeting of the American College of Clinical Pharmacy, Cincinnati, Ohio, 8– 11 November 1998 [10]).
2. Materials and methods
2.1. Study design This was a prospective, randomized, multidose, openlabel, two-period crossover study separated by a 4- or 6-day washout period. The protocol and informed consent were reviewed and approved by the institutional review board prior to study initiation.
2.2. Subjects Healthy volunteers 18 years of age or older underwent a screening physical examination and a medical history was obtained to rule out the possibility of renal, hepatic, cardiovascular, endocrine, neurological or other disease and antibiotic hypersensitivities. Blood chemistry, haematology and urinalysis were performed for each subject prior to enrolment. Female volunteers were screened by a direct latex agglutination test to confirm each subject was not pregnant. Exclusion criteria included the following: history of hypersensitivity to vancomycin, substance abuse, diabetes mellitus, acute illness within 7 days prior to study entry, any concomitant medication other than vitamins or birth control pills, any anti-infective medication within 2 weeks prior to study entry, pregnancy or any detected abnormal laboratory values (e.g. serum creatinine \2.0 mg/dl, liver transaminases less than twice the upper limit of normal values). Eligible subjects were enrolled after written informed consent was obtained. Post-study laboratory evaluations were performed on all subjects at the completion of the study.
2.3. Study antibiotic and administration Subjects were randomly assigned to receive intravenous vancomycin (Abbott Laboratories, North Chicago, IL, lot 10 716Z7, or Vancocin, Eli Lilly & Company, Indianapolis, IN, lot 9MW33M) 1 g every 12 h× four doses, and vancomycin 1 g every 24 h× three doses. These multidose regimens were selected in order to test the activity of vancomycin at steady-state against the study isolates. The ADD-Vantage vial sys-
tem was used to prepare all vancomycin infusions and doses were diluted in 250 ml of 5% dextrose USP (Abbott Laboratories, North Chicago, IL, lot 13-246JT) less than 3 h prior to infusion. Vancomycin was infused via a peripheral catheter over 60–90 min.
2.4. Study periods Study periods were either 3 or 4 days in length and were conducted in an institutional clinical research center. Subjects were not allowed to consume any caffeine or alcohol-containing beverages during the study. Food and all beverages except water were withheld at least 2 h before and for 2 h after administration of the last dose but otherwise were permitted ad libitum.
2.5. Sampling Venous blood samples were obtained from a catheter placed in the arm contralateral to that used for drug administration. Predose samples were obtained on the first day of each study period before drug administration. Blood samples (10 ml) were collected from each subject at time 0, 2, 4, 6, 8, 10 and 12 h from the start of infusion on the last dose. For the every 24-h regimen, samples were also drawn at the 16-, 18-, 20-, 22and 24-h time points. At each sample collection, the first 3 ml of blood from the sampling catheter was discarded. After collection of the blood sample the site was flushed with 3 ml of normal saline and heparinized with 1 ml of 100 units/ml to maintain site patency. Collected samples were allowed to clot at room temperature for 30 min. Following refrigerated centrifugation (4°C, 1000 × g for 10 min), the serum samples were aliquoted into two portions: one portion to be used for assay of drug concentration and the second portion to be used for determination of bactericidal activity. All serum samples were stored at − 80°C until analyzed.
2.6. Bacterial isolates Four methicillin-resistant staphylococcal isolates were selected for evaluation: two clinical isolates of methicillin-resistant S. aureus (MRSA 32 and MRSA 34) from the Hartford Hospital Department of Microbiology and two isolates of coagulase-negative staphylococci from the American Type Culture Collection (Manassas, VA), methicillin-resistant S. epidermidis (MRSE 51625) and methicillin-resistant Staphylococcus hominis (MRSH 51624). The MICs were determined in duplicate for the four test organisms by the microdilution method according to National Committee for Clinical Laboratory Standards (NCCLS) guidelines using cation-adjusted Mueller Hinton broth (CAMHB, Becton Dickinson, Cockeysville, MD) as the growth medium [11]. Addi-
M.K. Lacy et al. / International Journal of Antimicrobial Agents 15 (2000) 25–30
tionally, the coagulase-negative staphylococci (MRCNS) isolates were also tested using haemophilus test medium (HTM, Becton Dickinson, Cockeysville, MD), as this medium was used for the serum bactericidal titre (SBT) determinations and to insure that the HTM did not affect the microbiological activity of vancomycin against the test isolates. All study isolates were susceptible to vancomycin with MIC values of either 2 or 4 mg/l. The MICs were the same whether tested in HTM or CAMHB prior to and throughout the SBT testing.
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Lotus Development Corporation). The selected intervals for inclusion in the elimination rate analysis were hours 4–12 for the every 12-h regimen and for hours 8–16 for the every 24-h regimen. These ranges were linear based upon examination of all log concentration versus time plots. A half-life was determined for each subject using a standard pharmacokinetic equation (ln 2/Ke). Duration of time that serum concentrations exceeded the MIC of each organism were calculated using the elimination rate constant for each subject and known MIC values for each study isolate.
2.7. Serum bactericidal acti6ity Duplicate SBTs were determined by NCCLS methodology for each subject at selected time points to determine the duration of activity for each regimen [12]. CAMHB was used as the diluent for the MRSA isolates and based upon preliminary studies, HTM for the MR-CNS isolates. The SBT endpoint was determined as the highest dilution that killed 99.9% of the test isolate. All SBT results were combined and used in the final analysis for comparison. The definition of SBA used in this study was the time point after dosing at which all subjects’ SBTs were greater than or equal to 1:2.
2.8. Analytical methods Selected serum samples from the elimination phase were assayed for vancomycin concentration using the Abbott FLxTDx System (Abbott Laboratories) at our institution. Samples were stored at − 80°C until analyzed.
2.9. Data analysis The observed duration and percentage of the dosing interval that SBA was noted for each regimen and organism combination was recorded. The elimination rate of vancomycin was calculated from the slope of the regression line for the final dose in each study period (Freelance Graphics for Windows, Release 2.1, 1994,
Table 1 Mean (9 S.D.) demographic data for study subjects and resultant vancomycin pharmacokinetic parameters Age Weight Gender Ke T1/2 Cmin a
25.5 94.5 years 74.1 99.6 kg 9 male, 3 female 1 g Q12h: 0.15990.02 h−1; 1 g Q24h: 0.14290.03 h−1 1g Q12h: 4.4 9 0.6 h; 1 g Q24h: 5.191.0 h 1 g Q12h: 5.791.6 mg/ml; 1 g Q24h: 0.8 9 0.4 mg/mla
Calculated value since actual concentrations were below assay limit of detection.
3. Results
3.1. Subjects Fifteen subjects were enrolled and 12 subjects completed both study periods as indicated in Table 1. Three subjects were withdrawn for the following reasons. One subject developed a generalized body rash within 24 h of the first dose, the second experienced nausea and vomiting and intense facial flushing during the infusion of the first dose, and the third experienced vasovagal syncope upon placement of the first intravenous catheter prior to any study antibiotic administration. All of the withdrawn subjects fully recovered without further incident.
3.2. Antibiotic administration Of the 12 subjects that completed the study, ten experienced mild-to-moderate infusion-related facial flushing and/or pruritus of the head, neck and upper chest areas during the first study period. The infusion times of subsequent doses were extended from 60 to 90 min, however, the majority of subjects still experienced infusion-related effects. A different manufacturer of vancomycin was used for the second study period (Abbott Laboratories) and less intense reactions were subjectively reported with the change in manufacturers and with each successive dose. All infusion-related reactions rapidly subsided within a couple of hours after drug administration. One subject was given 25 mg of diphenhydramine prior to each dose due to intense facial flushing and pruritus that was not accompanied by any measurable hypotension.
3.3. Susceptibility testing Individual MIC values for the study isolates are shown in Table 2. All isolates were fully susceptible to vancomycin with a range of MIC values of either 2 or 4 mg/l.
M.K. Lacy et al. / International Journal of Antimicrobial Agents 15 (2000) 25–30
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Table 2 Susceptibility profiles of study isolates, duration of bactericidal activity and duration of serum concentrations above the MIC Organism
MRSA 34 MRSA 32 MRSH 51624 MRSE 51625 a b
VAN MICa (mg/l)
2 4 2 4
Duration of measurable SBAb (h)
Duration serum concentrations\MIC (h)
1g Q12h
1 g Q24h
1g Q12h
1 g Q24h
12 10 12 10
16 10 10 8
12 12 12 12
18 13 18 13
Vancomycin MIC values. Serum bactericidal activity.
3.4. Pharmacokinetic 6alues Mean pharmacokinetic values are shown in Table 1. All serum concentrations were normalized to 70 kg and resultant values were similar to previously published ranges for vancomycin in healthy volunteers [13].
3.5. Serum bactericidal acti6ity Measurable bactericidal activity was maintained throughout greater than 80% of the dosing interval for the MRSA and MR-CNS isolates for the 1-g Q12h regimen. Serum concentrations remained above the MIC of all study isolates for 100% of the dosing interval for the Q12h regimen. For the 1-g Q24h regimen, bactericidal activity was observed for more than 66% of the dosing interval for only the MRSA isolate with an MIC value of 2 mg/l. Against MRSE, MRSH, and the MRSA isolate with an MIC of 4 mg/l, bactericidal activity was maintained for less than 50%. Vancomycin serum concentrations exceeded the MIC for 75% of the dosing interval when the MIC was 2 mg/l and for 54% when the MIC was 4 mg/l during the Q24h regimen. Table 2 summarizes the duration of bactericidal activity and the duration of time that serum concentrations exceeded the test isolates’ MIC values for each dosing regimen.
The majority of staphylococcal isolates have vancomycin MIC values of 2 mg/l or less with a susceptibility breakpoint of less than or equal to 4 mg/l. We chose to evaluate the duration of bactericidal activity for MRSA and MR-CNS at the upper range of susceptibility using isolates with MICs of 2 or 4 mg/l. Since healthy subjects with excellent renal function were selected, this study considered the most conservative situation regarding the duration of activity with standard dosing regimens. In this study, the Q12h interval provided for optimal bactericidal activity against all of the study isolates as shown in Fig. 1. However, it was interesting to note that for the Q24h regimen, activity was observed for 67% of the dosing interval for the MRSA isolate with an MIC of 2. This appears to suggest that a once daily interval might be successful against MRSA as long as the MIC was less than 2, especially when the long PAE against staphylococci is considered. However, this would obviously need to be verified in future clinical trials and certainly would not be applicable to the coagulase-negative isolates based upon our results. Neither would a once-daily interval be recommended for the management of endocarditis, meningitis or other serious infections in patients with good renal function. As expected, measurable bactericidal activity was observed for the entire dosing interval for the every
4. Discussion Despite more than 40 years of clinical use and a plethora of in vitro data demonstrating the time-dependent pharmacodynamic bactericidal characteristics of vancomycin [7–9], few clinical studies associating serum levels with bactericidal activity can be found. Current trough ranges fall between 5 and 15 mg/l. The vancomycin reference ranges used in clinical practice are based primarily on retrospective studies and anecdotal reports [14]. While vancomycin doses are often modified based upon information provided by serum drug concentrations, this practice is declining, especially in those with good renal function [15 – 17].
Fig. 1. Duration of vancomycin serum bactericidal activity (SBT ] 1:2) at steady-state as a percentage of the dosing interval.
M.K. Lacy et al. / International Journal of Antimicrobial Agents 15 (2000) 25–30
12-h dosing regimen with MIC values of 2. Slightly less activity was noted for the isolates with MIC values of 4 mg/l. Bactericidal activity was observed for less than 50% of the dosing interval for MR-CNS for the once daily dosing regimen regardless of MIC. The duration of the dosing interval that serum concentrations exceeded the study isolate MIC values was similar to the duration of measurable bactericidal activity (Table 2). The differences may be explained by the initial 1:2 serum dilution that that is made when conducting the SBT test. Furthermore, the two types of data differ since serum concentration data are continuous and SBA data are not. The optimal duration of time in a dosing interval that vancomycin bactericidal activity is required for successful clinical outcomes is unknown. It has been suggested that vancomycin serum levels of 2 mg/ml should protect against the emergence of resistant staphylococci [18]. Unsurprisingly, positive therapeutic outcomes have been reported when bactericidal activity lasted throughout the entire dosing interval or when serum concentrations were within established trough reference ranges, thereby guaranteeing 100% time above the MIC throughout a dosing interval [17,19,20]. Clinical and in vivo data for other antibiotics with time-dependent pharmacodynamics (penicillins, cephalosporins, carbapenems) suggest that antibiotic concentrations do not need to remain above MIC values throughout the entire dosing interval in order to achieve a positive outcome [21,22]. This has been demonstrated in animal models of infection for S. aureus when cephalosporins were used [23,24]. In one study maximal efficacy was noted with only 40% time above the MIC for cefotaxime and ceftriaxone — less than that required for Gram-negative bacteria or streptococci [23]. For cefazolin, maximal efficacy was achieved when concentrations exceeded the MIC for 55% of the treatment interval with 20% indicated as a minimal level for bactericidal activity [24]. Once again, this was less than the greater than 60% of the interval required for Escherichia coli in the same study. These differences were directly attributed to the prolonged PAE for cephalosporins against staphylococci [23]. In the present study, infusion-related effects or red man syndrome was observed in a majority of the subjects. These effects are mediated by histamine release with the administration of a vancomycin dose [25,26] and are more frequently noted in healthy volunteers than in acutely-ill patients [27]. In retrospect, our use of two different vancomycin manufacturers was probably unnecessary given the fact that these wellknow effects are commonly reported in healthy volunteers. However, the use of a different manufacturer for each study period is not thought to have influenced our study results or conclusions. In considering future vancomycin studies involving healthy volunteers, 2-h infu-
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sion times should be employed to minimize the frequency and severity of histamine-induced infusionrelated reactions [26].
5. Conclusion In conclusion, the vancomycin pharmacodynamic data from this study suggests that a Q12h dosing interval is most appropriate in those with good renal function when a coagulase-negative staphylococcus is suspected and for MRSA when MICs approach the susceptibility breakpoint. It remains to be seen whether a once-daily interval would be effective when treating MRSA infections or other highly susceptible pathogens when MIC values are less than or equal to 2 mg/l, but our bactericidal data suggests that it may be feasible. However, this would need to be carefully evaluated in further studies using pathogens with lower MICs and should not be employed in the treatment of serious infections. In cases of known MR-CNS infections or when the MIC is unknown, vancomycin serum concentrations should be maintained within the current trough ranges to ensure that concentrations remain above the susceptibility breakpoint.
Acknowledgements Supported by a research grant from Hartford Hospital, Hartford, Connecticut. We also thank Christina Turley for her technical assistance.
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