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High Dose Vancomycin for Osteomyelitis: Continuous vs. Intermittent Infusion

Background: Previous research has shown that high elevated serum concentrations of vancomycin are needed to effectively treat MRSA osteomyelitis without promoting further emergence of glycopeptide resistance.

Objective: The objective was to determine which therapy for gram-positive cocci osteomyelitis-intermittent vancomycin infusion (IVI) or continuous vancomycin infusion (CVI)- is more efficacious, easier to adjust, and safer.

Methods: This was a 36-month, consecutive (non-random), prospective, parallel, non-blinded, experimental trial. This was a multi-center study as patients were selected from five teaching or affiliated hospitals in France. Patients were considered eligible for enrollment into the study if they had the following: bone biopsy-proven osteomyelitis requiring vancomycin for greater than four weeks, bone biopsy culture positive for methacillin resistant staphylococcus aureas (MRSA) or methacillin resistant strains of coagulase negative staphylococcus (MRCNS), or a case of simultaneous staphylococcus infection and b-lactam allergy. Patients were excluded from the study if they had the following: a serum creatinine level greater than 300 mmol/L, concomitant treatment with other nephrotoxic drugs, previous treatment with vancomycin, or if patients were pregnant. There were two treatment groups, 21 patients were non-randomly assigned to the intermittent vancomycin infusion (IVI) group and 23 were non-randomly assigned to the continuous vancomycin infusion (CVI) group. Both groups received vancomycin (Vancocyn® by Lilly) which was diluted with normal saline solution and infused by an automatic volumetric device using 60 mL syringes. Also, both groups received an initial loading dose of 20 mg/kg over 60 minutes. Thereafter, the doses in both groups were adjusted according to serum creatinine level. The dosing regimen for those in the IVI group was 20 mg/kg over 60 minutes every 12 hours and 40 mg/kg over 24 hours for those in the CVI group. The targeted peak and trough concentrations were <50 mg/L and 20-25 mg/L, respectively. Once steady-state was reached, patients were discharged and treatment and surveillance were continued at home by visiting nurses.

Results: The three primary outcome measures in this study were pharmacokinetics, safety, and efficacy. Although the mean daily dosing for both the IVI and CVI were no different, the mean trough vancomycin concentration in the IVI group was lower than the mean plateau concentration in the CVI group, 21.7 + 9.3 vs. 26.0 + 6.1 mg/L, respectively (P < 0.0001). There was less variability of serum concentration in the CVI group than in the IVI group, 5.6 vs. 7.9, respectively (P = 0.001). Also statistically significant was the difference between groups in terms of the number of patients with a serum inhibitor quotient (serum antibiotic level/MIC) alternatively > or < 10, IVI-12, 70.6% vs. CVI-5, 25.0% (P = 0.04). For the safety outcome measure, adverse drug reactions responsible for discontinuation of the study occurred more frequently in the IVI group with 9 occurrences (42.9%) vs. 2 occurrences (8.7%) in the CVI group (P = 0.03). Surprisingly however, a Kaplan-Meier analysis showed that 57.1% of patients in the IVI group had developed no adverse drug reactions by week six in comparison to the 94.7% of patients that had developed at least one ADR by week six in the CVI group (P = 0.005). Since there were fewer occurrences in the CVI group overall (2 vs. 9 in the IVI group), perhaps it took less time for them to appear making 94.7% sound falsely high. Nevertheless, when a survival multiple regression analysis using Cox’s proportional hazard model was performed later, the only factors deemed responsible for the discontinuation of treatment were IVI (RR = 5.9, P = 0.03) and osteomyelitis of the foot (RR = 5.2, P = 0.01). Serum creatinine concentrations increased to a greater degree in the IVI group when compared to the CVI group (P = 0.02). In terms of efficacy measures, more patients in the CVI group finished the study as planned, 18, 78.3% vs. 9, 42.9% in the IVI group. The mean treatment duration in weeks was much longer in the CVI group than the IVI group, 14.4 + 8.4 vs. 9.4 + 12.2, respectively.

Strengths: The study was able to accomplish its objective. Most likely, no bias was introduced by the sponsor of the study since Baxter infusion pumps were used in both groups. The study did use a lot of statistical tests appropriately; for example, where they mention that bias could have been introduced due to the variability in surgical debridement techniques, they performed a multiple regression analysis to adjust for confounding factors in the occurrence of adverse drug reactions. Also, authors were forthcoming in owning their weaknesses in the study. The study did list the specific adverse drug reactions.

Weaknesses: There were a far greater number of weaknesses in this study relative to strengths. A very small number of patients actually participated in this study none of which were randomized. Neither the patients nor researchers were blinded. Long-term efficacy was difficult to assess because only 27 patients were left after one year of follow-up. Also, bias could have been introduced due to the variability in surgical debridement techniques and there was no compliance data compiled. Nurses administered the study medications at home and error could have been introduced here as well. There was no time period given for excluding those that had taken vancomycin previously and other antibiotics were used as 14 patients received concomitant rifampin (9 in the IVI group and 5 in CVI group) and 6 received concomitant ciprofloxacin (2 in the IVI group and 4 in CVI group).

Conclusion: Continuous vancomycin infusion offers another option in which to give long term glycopeptide therapy. It may be as effective as intermittent vancomycin infusion and based on the results presented in this study, it may offer several advantages when administered to the appropriate patient. The authors state that the continuous vancomycin infusion may decrease overall cost and increase patient compliance; however, the later may be debatable since the treatment duration with the continuous infusion was much longer than with the intermittent infusion and patients would be required to be hooked up to it continuously. It is also difficult to assess if the pharmacokinetic results are in fact comparable since a plateau measurement is not exactly the same as a true trough. It may be advantageous to maintain a more stable treatment course with continuous infusion versus intermittent since having to do less dosing manipulations would certainly decrease variability in success rates. Because so few patients were available for long-term assessment after one year, it is difficult to say with certainty that continuous vancomycin infusion yields better long-term outcomes. Better designed studies are needed to determine the usefulness of continuous vancomycin infusion and its place in the treatment of osteomyelitis.

Journal Citation: Vuagnat A, Stern R, Lotthe A, Schuhmacher H, Duong M, Hoffmeyer P, et al. High dose vancomycin for osteomyelitis: continuous vs. intermittent infusion. J Clin Phar Ther. 2004 Aug; 29(4): 351-7.

Karen E. Baird, Pharm.D. Candidate