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Comparison of intermittent versus continuous-infusion vancomycin for treating severe patients in intensive care units

Abstract

Purpose

The aim of this study was to compare pharmacokinetic characteristics between intermittent infusion and continuous infusion of vancomycin for critically ill patients admitted to intensive care units.

Methods

Intermittent therapy was administered for 60 minutes and prescribed as a loading dose of 30 mg/kg and continued with 15 mg/kg q12 h. Continuous infusion was prescribed as a loading dose of 30 mg/kg followed by 30 mg/kg on constant infusion pump. Blood samples from vancomycin intermittent infusion group were collected 1 h before third dose, 1 h, 8 h and 24 h after third dose infusion. Blood samples from vancomycin continuous infusion group were collected 1 h after loading dose, 12 h, 24 h, 36 h, and 48 h after continuous infusion initiation.

Results

Median serum concentration of continuous infusion group at 24-hour was 23.59 µg/mL [14.52–28.97], while of intermittent infusion group at 23-hour was 12.30 µg/mL [7.27–18.12] and on 25-hour was 17.58 µg/mL [12.5–22.5]. Medians AUC24–48h were 357.2 mg.h/L and 530.2 mg.h/L for intermittent infusion and continuous infusion groups, respectively (p = 0.559).

Conclusion

Vancomycin CI reached steady state earlier, which guaranteed therapeutic levels from the first day and made it possible to manage therapeutic drug monitoring faster.

Keywords
Pharmacokinetics; Vancomycin; Infusion; Intensive care unit

Patients admitted to intensive care unit (ICU) are under risk for infections by methicillin-resistant Staphylococcus aureus (MRSA) strains11 Koulenti D, Tsigou E, Rello J. Nosocomial pneumonia in 27 ICUs in Europe: perspectives from the EU-VAP/CAP study. Eur J Clin Microbiol Infect Dis. 2017;36:1999-2006.,22 Rello J, Molano D, Villabon M, et al. Differences in hospital- and ventilator-associated pneumonia due to Staphylococcus aureus (methicillin-susceptible and methicillin-resistant) between Europe and Latin America: a comparison of the EUVAP and LATINVAP study cohorts. Med Intensiva. 2013;37:241-247. and vancomycin continues to be an important therapeutic option for Gram-positive infections.33 Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52:e18-e55. This glycopolypeptide inhibits the second stage of cell-wall synthesis of Gram-positive bacteria44 Cunha BA. Vancomycin. Med Clin North Am. 1995;79:817-831. and because of its area under the curve (AUC) dependent pharmacodynamics, it does not require a high peak level to be effective.55 Rybak MJ, Le J, Lodise TP, et al. Executive Summary: Therapeutic monitoring of vancomycin for serious methicillin-resistant Staphylococcus aureus infections: a revised consensus guideline and review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists. Pharmacotherapy. 2020;40:363-367. Moreover, vancomycin usage is growing due to increasing incidence of MRSA infections which is related to high mortality rate. Therefore, vancomycin still has a major role in the treatment of these infections.66 Sogawa K, Watanabe M, Ishige T, et al. Rapid discrimination between methicillin-sensitive and methicillin-resistant Staphylococcus aureus using MALDI-TOF mass spectrometry. Biocontrol Sci. 2017;22:163-169.

Once it is eliminated through glomerular filtration, therapeutic drug monitoring (TDM) is needed to avoid the well-known vancomycin nephrotoxicity as a result of drug accumulation in the presence of renal impairment. Recently, Infectious Diseases Society of American (IDSA) changed recommendations to vancomycin TDM protocol. Previously, treatment recommendation was based on trough serum concentrations and aimed between (i) 15–25 µg/mL for severe infections caused by the MRSA, such as bacteremia, endocarditis, pneumonia, or (ii) 10–15 µg/mL to non-severe infections.77 Rybak MJ, Lomaestro BM, Rotschafer JC, et al. Therapeutic monitoring of vancomycin in adults summary of consensus recommendations from the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Pharmacotherapy. 2009;29:1275-1279. Nevertheless, IDSA updated recommendations which no longer support vancomycin treatment based only on trough levels and emphasizes the importance of Bayesian software programs to individually fit serum levels of patient's pharmacokinetics to achieve a ratio ≥400 between AUC and minimum inhibitory concentration (MIC).55 Rybak MJ, Le J, Lodise TP, et al. Executive Summary: Therapeutic monitoring of vancomycin for serious methicillin-resistant Staphylococcus aureus infections: a revised consensus guideline and review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists. Pharmacotherapy. 2020;40:363-367.,88 Cristallini S, Hites M, Kabtouri H, et al. New regimen for continuous infusion of vancomycin in critically ill patients. Antimicrob Agents Chemother. 2016;60:4750-4756. Serum target levels of the drug may be achieved with continuous infusion (CI) or intermittent infusion (II). Values above and below these concentrations are considered inadequate and need adjustment. CI reaches target serum levels faster than II, with lower daily doses and fewer adverse reactions.99 Hao JJ, Chen H, Zhou JX. Continuous versus intermittent infusion of vancomycin in adult patients: a systematic review and meta-analysis. Int J Antimicrob Agents. 2016;47:28-35. Moreover, CI is convenient for dosage adjustment since it can be done by modifying infusion speed, and not by changing dose interval, as it is the case with II.1010 Bissell BD, Riggi G, Morrison C. Evaluation of continuous infusion vancomycin administration in a critically ill trauma population. J Intensive Care Med. 2018;:. However, there are no reports in the literature showing difference in patient's outcomes between both types of administration.1111 Downes KJ. Continuous-infusion vancomycin-teaching an old dog new tricks?. J Pediatric Infect Dis Soc. 2018;7:e128-e130.,1212 Farber BF, Moellering RC. Retrospective study of the toxicity of preparations of vancomycin from 1974 to 1981. Antimicrob Agents Chemother. 1983;23:138-141.

There are several pharmacodynamic (PD) parameters to be considered when prescribing vancomycin, including trough serum bactericidal titers, AUC and MIC. Moise-Broder et al. described an AUC24h/MIC ratio > 350–400 related to better clinical and bacteriological outcomes on patients with pneumonia by Staphylococcus aureus.1313 Moise-Broder PA, Forrest A, Birmingham MC, Schentag JJ. Pharmacodynamics of vancomycin and other antimicrobials in patients with Staphylococcus aureus lower respiratory tract infections. Clin Pharmacokinet. 2004;43:925-942. However, this PD target is usually extrapolated to other site of infections, which must be used cautiously. Besides it, AUC:MIC > 400 with MRSA MIC above 1.5–2.0 µg/mL is rarely achieved.1414 Mohr JF, Murray BE. Point: Vancomycin is not obsolete for the treatment of infection caused by methicillin-resistant Staphylococcus aureus. Clin Infect Dis. 2007;44:1536-1542.

The aim of this study was to compare pharmacokinetic characteristics between II and CI vancomycin therapy for critically ill patients admitted to intensive care units. This study was approved by the ethical committee at PUCPR (number 75526017.0.0000.0020). Informed authorization was obtained from all patients.

This was an observational prospective study performed from January 2018 to July 2019, comparing pharmacokinetic/pharmacodynamic parameters and clinical data of patients with suspected or documented Gram-positive infections receiving vancomycin conventional dose (intermittent infusion) or continuous infusion. Treatment regimens were prescribed at the discretion of the medical assistant team. Vancomycin blood concentrations were collected as described below.

Inclusion criteria were patients admitted to Intensive Care Unit of Hospital Universitario Cajuru (Curitiba, Paraná, Brazil) for whom vancomycin was prescribed for presumed or documented Gram-positive infections. Exclusion criteria were (i) history of hypersensitivity to vancomycin, (ii) life expectancy ≤ 48 h, (iii) renal dysfunction (serum creatinine ≥ 2.5 mg/dl or estimated creatinine clearance ≤ 40 mL/min), (iv) age < 18 years or an inability to obtain informed consent. Demographic data, including age, sex, weight, height, and infectious diagnosis, were collected upon enrollment in the study. Serum creatinine was measured, and creatinine clearance was estimated on each day of the study. Patients were followed up until ending vancomycin treatment. Acute Kidney Injury Network classification (AKIN) was used to evaluate renal toxicity from both CI and II vancomycin groups.

All patients received vancomycin (ABL, Cosmópolis, Brazil) reconstituted according manufacture’ s guidelines. Intermittent therapy was administered for 60 minutes and prescribed as a loading dose of 30 mg/kg and continued with 15 mg/kg q12 h. Continuous infusion was prescribed as a loading dose of 30 mg/kg followed by 30 mg/kg on constant infusion pump. Blood samples from vancomycin intermittent infusion group were collected 1 h before third dose, 1 h, 8 h and 24 h after third dose infusion. Blood samples from vancomycin continuous infusion group were collected 1 h after loading dose, 12 h, 24 h, 36 h and 48 h after continuous infusion initiation, as previous published studies.1515 Sima M, Bakhouche H, Hartinger J, Cikankova T, Slanar O. Therapeutic drug monitoring of antibiotic agents: evaluation of predictive performance. Eur J Hosp Pharm. 2019;26:85-88. All samples were measured by Siemens Dimension Xpand Plus® HM clinical analyzer (Siemens, Munich, Germany).

Twenty-three patients were enrolled in this study, 11 on CI group (63% male) and 12 on II group (76% male). Clinical characteristics were similar between CI and II group (Table 1). Most frequent sites of infection were lungs (n = 12) and central nervous system (CNS) (n = 4), followed by skin/soft tissue (n = 3) and abdominal (n = 2).

Table 1
Pharmacokinetic characteristics of vancomycin therapy.

Blood samples from II group were collected 23 h after first dose (H23) and 1 (H25), 8 (H32) and 24 h (H48) after third infusion. Median serum vancomycin concentrations were 12.30, 17.58, 14.56 and 19.10 µg/mL, respectively. Blood samples from CI group were collected 1 h after loading dose (H1) and 12 (H12), 24 (H24), 36 (H36) and 48 h (H48) after CI started. Median serum vancomycin concentrations were 23.91, 19.68, 23.59, 21.53 and 18.28 µg/mL, respectively (Table 1). II and CI vancomycin AUC2448h were calculated (Table 2). Medians [IQR] AUC24–48h were 357.2 mg.h/L [150.1–564.3] and 530.2 mg.h/L [108–958.4] from II and CI groups, respectively (p = 0.559) (Fig. 1).

Fig. 1
Serum level of vancomycin in critically ill patients treated with continuous (n = 11) and intermittent (n = 13) infusion of intravenous vancomycin.

Table 2
Clinical characteristics of patients treated with continuous and intermittent infusion of intravenous vancomycin.

Median serum concentration of CI group at 24-hour was 23.59 µg/mL [14.52–28.97], while of II group at 23-hour was 12.30 µg/mL [7.27–18.12] and at 25-hour was 17.58 µg/mL [12.5–22.5]. Thus, median serum concentrations of II group one hour after vancomycin third dose were lower than those of CI group at 24-hour, and steady state was reached faster on CI group. However, there were no significant differences on vancomycin serum levels between both infusion groups at 48-hours [CI 18.28 µg/mL (10.6–27.125) vs. II 19.10 µg/mL (10.25–20.5).

In this study, pharmacokinetic parameters of II versus CI vancomycin therapy for critical ill patients admitted to intensive care units were assessed. Moreover, serum level curves of 11 CI patients and 12 II patients were compared. The median serum concentrations on II group one hour after vancomycin third dose were lower than those of CI group at 24-hour and steady state was probably reached faster on CI group. However, there were no significant differences on vancomycin serum levels between both infusion groups at 48-hours, since at this time steady state had already been reached on both groups.

Difference between first 24-hour vancomycin concentrations (II vs. CI) is important when considering treating severe ICU patients. Critical patients with renal failure may be spared from toxicity due more predictable vancomycin AUC and benefitted from CI premature steady state attainment when compared with II. Nevertheless, patients’ outcomes did not differ between infusion regimens.1515 Sima M, Bakhouche H, Hartinger J, Cikankova T, Slanar O. Therapeutic drug monitoring of antibiotic agents: evaluation of predictive performance. Eur J Hosp Pharm. 2019;26:85-88.1717 Cataldo MA, Tacconelli E, Grilli E, Pea F, Petrosillo N. Continuous versus intermittent infusion of vancomycin for the treatment of Gram-positive infections: systematic review and meta-analysis. J Antimicrob Chemother. 2012;67:17-24. Cataldo et al. 2011 compared both infusion regimens and found similar mortality rates (CI vs. II), however, with minor renal impairment rate to CI group. There has been concern about vancomycin nephrotoxicity since its approval and when used concomitantly with other drugs potentially nephrotoxic drugs, such as aminoglycosides, amphotericin, and acyclovir. Additionally, the combination of vancomycin and piperacillin-tazobactam can result in augmented nephrotoxicity compared to vancomycin alone.1818 Filippone EJ, Kraft WK, Farber JL. The nephrotoxicity of vancomycin. Clin Pharmacol Ther. 2017;102:459-469.2020 Meaney CJ, Hynicka LM, Tsoukleris MG. Vancomycin-associated nephrotoxicity in adult medicine patients: incidence, outcomes, and risk factors. Pharmacotherapy. 2014;34:653-661. Toxicities during vancomycin therapy with concomitant aminoglycosides are shown in Table 2.

Divergence on Pk target concentration of vancomycin CI is presented on literature. Cristallini et al. considered values from 20 to 30 µg/mL while Sin et al. proposed 15–25 µg/mL.88 Cristallini S, Hites M, Kabtouri H, et al. New regimen for continuous infusion of vancomycin in critically ill patients. Antimicrob Agents Chemother. 2016;60:4750-4756.,2121 Sin JH, Newman K, Elshaboury RH, Yeh DD, de Moya MA, Lin H. Prospective evaluation of a continuous infusion vancomycin dosing nomogram in critically ill patients undergoing continuous venovenous haemofiltration. J Antimicrob Chemother. 2018;73:199-203. The target concentration according our hospital TDM protocol was 15–25 µg/mL. Middle-income regions may not afford the new IDSA recommendations of Bayesian software programs to guide vancomycin treatment. However, given the importance to optimize TDM, CI may be a cheaper option once it does not require expensive softwares, but only two measures within 24 h to establish the AUC in a given patient.

This study has several limitations. Few patients were included and patients with renal failure were excluded. However, there is a lack of data on vancomycin CI administration and its pharmacokinetic parameters, which are essentials to real effectiveness and sparing patients from toxicities.

Vancomycin CI reached steady state earlier, which guaranteed therapeutic levels from the first day and made it possible to manage therapeutic drug monitoring faster. This practice may reduce nephrotoxicity risk and assure both treatment efficacy and safety.

  • Financial support
    None.

References

  • 1
    Koulenti D, Tsigou E, Rello J. Nosocomial pneumonia in 27 ICUs in Europe: perspectives from the EU-VAP/CAP study. Eur J Clin Microbiol Infect Dis. 2017;36:1999-2006.
  • 2
    Rello J, Molano D, Villabon M, et al. Differences in hospital- and ventilator-associated pneumonia due to Staphylococcus aureus (methicillin-susceptible and methicillin-resistant) between Europe and Latin America: a comparison of the EUVAP and LATINVAP study cohorts. Med Intensiva. 2013;37:241-247.
  • 3
    Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52:e18-e55.
  • 4
    Cunha BA. Vancomycin. Med Clin North Am. 1995;79:817-831.
  • 5
    Rybak MJ, Le J, Lodise TP, et al. Executive Summary: Therapeutic monitoring of vancomycin for serious methicillin-resistant Staphylococcus aureus infections: a revised consensus guideline and review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists. Pharmacotherapy. 2020;40:363-367.
  • 6
    Sogawa K, Watanabe M, Ishige T, et al. Rapid discrimination between methicillin-sensitive and methicillin-resistant Staphylococcus aureus using MALDI-TOF mass spectrometry. Biocontrol Sci. 2017;22:163-169.
  • 7
    Rybak MJ, Lomaestro BM, Rotschafer JC, et al. Therapeutic monitoring of vancomycin in adults summary of consensus recommendations from the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Pharmacotherapy. 2009;29:1275-1279.
  • 8
    Cristallini S, Hites M, Kabtouri H, et al. New regimen for continuous infusion of vancomycin in critically ill patients. Antimicrob Agents Chemother. 2016;60:4750-4756.
  • 9
    Hao JJ, Chen H, Zhou JX. Continuous versus intermittent infusion of vancomycin in adult patients: a systematic review and meta-analysis. Int J Antimicrob Agents. 2016;47:28-35.
  • 10
    Bissell BD, Riggi G, Morrison C. Evaluation of continuous infusion vancomycin administration in a critically ill trauma population. J Intensive Care Med. 2018;:.
  • 11
    Downes KJ. Continuous-infusion vancomycin-teaching an old dog new tricks?. J Pediatric Infect Dis Soc. 2018;7:e128-e130.
  • 12
    Farber BF, Moellering RC. Retrospective study of the toxicity of preparations of vancomycin from 1974 to 1981. Antimicrob Agents Chemother. 1983;23:138-141.
  • 13
    Moise-Broder PA, Forrest A, Birmingham MC, Schentag JJ. Pharmacodynamics of vancomycin and other antimicrobials in patients with Staphylococcus aureus lower respiratory tract infections. Clin Pharmacokinet. 2004;43:925-942.
  • 14
    Mohr JF, Murray BE. Point: Vancomycin is not obsolete for the treatment of infection caused by methicillin-resistant Staphylococcus aureus Clin Infect Dis. 2007;44:1536-1542.
  • 15
    Sima M, Bakhouche H, Hartinger J, Cikankova T, Slanar O. Therapeutic drug monitoring of antibiotic agents: evaluation of predictive performance. Eur J Hosp Pharm. 2019;26:85-88.
  • 16
    Saugel B, Nowack MC, Hapfelmeier A, et al. Continuous intravenous administration of vancomycin in medical intensive care unit patients. J Crit Care. 2013;28:9-13.
  • 17
    Cataldo MA, Tacconelli E, Grilli E, Pea F, Petrosillo N. Continuous versus intermittent infusion of vancomycin for the treatment of Gram-positive infections: systematic review and meta-analysis. J Antimicrob Chemother. 2012;67:17-24.
  • 18
    Filippone EJ, Kraft WK, Farber JL. The nephrotoxicity of vancomycin. Clin Pharmacol Ther. 2017;102:459-469.
  • 19
    Lodise TP, Lomaestro B, Graves J, Drusano GL. Larger vancomycin doses (at least four grams per day) are associated with an increased incidence of nephrotoxicity. Antimicrob Agents Chemother. 2008;52:1330-1336.
  • 20
    Meaney CJ, Hynicka LM, Tsoukleris MG. Vancomycin-associated nephrotoxicity in adult medicine patients: incidence, outcomes, and risk factors. Pharmacotherapy. 2014;34:653-661.
  • 21
    Sin JH, Newman K, Elshaboury RH, Yeh DD, de Moya MA, Lin H. Prospective evaluation of a continuous infusion vancomycin dosing nomogram in critically ill patients undergoing continuous venovenous haemofiltration. J Antimicrob Chemother. 2018;73:199-203.

Publication Dates

  • Publication in this collection
    02 Oct 2020
  • Date of issue
    Jul-Aug 2020

History

  • Received
    4 Mar 2020
  • Accepted
    1 July 2020
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