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Thérapie 2014 Novembre-Décembre; 69 (6): 529–530 DOI: 10.2515/therapie/2014204
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© 2014 Société Française de Pharmacologie et de Thérapeutique
Vancomycin Therapeutic Drug Monitoring in Cerebrospinal Fluid Imen Aouinti1,2, Rim Charfi1,2, Sameh Trabelsi1,2, Emna Gaïes1,2, Issam Salouage1,2, Nadia Jebabli1, Hanène El Jebari1, Mohamed Lakhal1,2 and Anis Klouz1,2 1 Service de pharmacologie clinique, Centre national de pharmacovigilance, Tunis, Tunisie 2 Université de Tunis El Manar, Faculté de médecine, Tunis, Tunisie Text received May 19th, 2014; accepted September 1st, 2014 This case has been declared to National Pharmacovigilance Centre of Tunis (Tunisia) on March 9th, 2012
Abstract – Vancomycin penetrates poorly through the blood-brain barrier. Determination of vancomycin concentration in plasma is recommended. In contrast, its determination in cerebrospinal fluid (CSF) is rarely performed. We report the case of a 74-year-old man with post traumatic meningitis with vancomycin concentration measured in CSF. Keywords: therapeutic drug monitoring; vancomycin; cerebrospinal fluid; meningitis Résumé – Suivi thérapeutique pharmacologique de la vancomycine dans le liquide céphalorachidien. La vancomycine pénètre mal la barrière hémato-méningée. Le dosage de la concentration plasmatique de vancomycine est recommandé. Toutefois, il est rarement effectué dans le liquide céphalo-rachidien (LCR). Nous rapportons le cas d’un homme âgé de 74 ans ayant une méningite post-traumatique chez lequel le dosage de la vancomycine dans le LCR a été déterminé. Mots clés : suivi thérapeutique pharmacologique ; vancomycine ; liquide céphalorachidien ; méningite Abbreviations: see end of article.
1. Introduction Vancomycin is a glycopeptide antibiotic administered to treat staphylococcal and streptococcal infections in hospitalized patients. Due to its narrow therapeutic range, monitoring of its plasma concentrations is widely recommended in order to optimize vancomycin efficacy and to minimize toxicity or adverse drug reactions.[1] Vancomycin therapeutic range varies from 20 to 25 µg/mL in case of administration by continuous infusion.[2] Vancomycin therapeutic drug monitoring (TDM) in cerebrospinal fluid (CSF) is less commonly performed. Vancomycin therapeutic range in CSF varies from 4 to 5 µg/mL.[3] We report the case of a patient with post traumatic meningitis to emphasize the interest of vancomycin monitoring in CSF.
2. Case report A 74-year old man with no previous medical history was hospitalized in March 2012 in intensive care unit for posttraumatic meningitis associated with hydrocephalus. Renal function was normal. CSF bacteriological study and hemoculture were negative. A first-line treatment with vancomycin 4.5 g per day by continuous intravenous infusion, imipenem 3 g per day, aciclovir 2.25 g per day and rifampicin 600 mg three times a day was started associated with an external ventricular drainage. On day 7, vancomycin concentrations were determined concomitantly in plasma and CSF by fluorescence polarization immunoassay on the automate AXSYM from Abbott Laboratories. Vancomycin plasma concentration was subtherapeutic (33.92 µg/mL). Value in CSF was 12.07 µg/mL (35.6% of plasmatic concentration). Few days later, the patient was transferred to neurology department for one week and then readmitted in intensive care unit because of respiratory troubles. The patient was sedated with fentanyl and midazolam. Carbamazepin and phenobarbital were added. Doses of vancomycin and rifampicin were adjusted respectively to 4 g per day by continuous intravenous infusion and 600 mg four times a day. A second determination of vancomycin plasma concentration was performed on day 19 and was subtherapeutic (35 µg/mL). Vancomycin concentration in CSF was not performed. The patient suffered from renal insufficiency (creatinine clearance level: 8 mL/min) leading to a daily dialysis. Dose of vancomycin was reduced to 750 mg per day. No clinical improvement was observed despite efficient vancomycin concentrations. Thus, etiological investigations were performed. Brain magnetic resonance imaging showed an aspect suggesting meningeal tuberculosis. A brain biopsy confirmed the diagnosis with a granulomatosis with caseum necrosis.
Article publié par EDP Sciences
530
Aouinti et al.
Vancomycin was stopped and a combined antituberculous treatment (rifampicin 600 mg per day, isoniazid 300 mg per day, pyrazinamide 1 600 mg per day and ethambutol 1 100 mg per day) was started on day 26.
3. Discussion Determination of vancomycin plasmatic concentrations is recommended because of: • a narrow therapeutic range: thus a little change in its plasmatic concentration may lead to vancomycin inefficacy or toxicity; • an inter and intra individual variability meaning that the same dose administered in different patients or in the same patient at different periods, may result in different plasma vancomycin concentrations; • vancomycin is a time dependent antibiotic. Thus, maintaining an adequate tough concentration is essential for its antibacterial activity.[4] Therapeutic range of vancomycin plasmatic concentrations varies from 20 to 25 µg/mL when administered by continuous infusion.[1] In the present case, determination of vancomycin CSF concentrations was also performed. We would like to discuss the interest of such measurments of vancomycin. Blood-brain barrier (BBB) is a functional barrier that excludes serum components from neuronal tissue, maintaining homeostasis within the central nervous system. It is well known that the capacity of an antibiotic to reach the infected compartment depends on its physicochemical properties (molecular weight, lipophilicity), its power to bind to proteins. In the present case, it also depends on the BBB permeability. In fact, BBB permeability is modulated by inflammation (such as meningitis) and active transporters.[5,6] Antibiotics are not known to be metabolized in the CSF. Their concentrations and half-lives in CSF depend on the balance between drug penetration and elimination through the BBB. The transport of hydrophilic drugs (like vancomycin) depends on the opening of tight junctions. They penetrate poorly through the BBB. Their CSF peak concentrations are delayed, and their CSF half lives extended. In case of inflammation of the BBB, their CSF penetration is significantly increased.[5] Vancomycin CSF concentration can reach 10 to 20% of its plasma concentration so it varies between 4 and 5 µg/mL.[3] In the present case, vancomycin CSF concentration was about 35.6% of plasmatic concentration (12.07 µg/mL), suggesting vancomycin penetration through the BBB. This result allowed clinicians to reevaluate the diagnosis. Further etiological investigations lead to the diagnosis of tuberculous meningoencephalitis.
© Société Française de Pharmacologie et de Thérapeutique
Therefore, determination of vancomycin concentration in CSF is useful to evaluate vancomycin penetration through the BBB and to ensure effective concentrations. Thus, we could suggest not sustained low plasma concentration of vancomycin could allow CSF penetration better than high plasma levels. Thus, the estimation of CSF penetration by measuring the ratio of the area under the concentration curve (AUC) is probably better than that based on single simultaneous measurements of CSF and serum antibiotic concentrations which can be misleading because of delayed CSF penetration.[7]
4. Conclusion This case report underlines the interest of vancomycin concentration measurment in CSF in case of meningitis. In fact, it is useful especially in case of treatment failure in order to evaluate vancomycin BBB penetration allowing optimizing treatment. Conflict of interests. None. Abbreviations. AUC: area under the concentration curve; BBB: blood-brain barrier; CSF: cerebrospinal fluid; TDM: therapeutic drug monitoring.
References 1.
Kang JS, Lee MH. Overview of therapeutic drug monitoring. Korean J Intern Med 2009; 24: 1-10
2.
Lacarelle B, Baltasat A, Bouquet S, et al. Suivi thérapeutique de la vancomycine. In : Marquet P. Suivi thérapeutique pharmacologique pour l’adaptation de posologie des médicaments. Paris: Elsevier 2004: 75-83
3.
Domart Y, Veyssier P. Vancomycine, teicoplanine. In: Bryskier A., Ed. Antibiotiques, agents antibactériens et antifongiques. Paris: Ellipses 1999: 929-46
4.
Billaud EM, Mainardi JL. Faut-il encore doser les glycopeptides ? Revue Française des Laboratoires 2004; 365: 35-8
5.
Lutsar I, McCracken GH Jr, Friedland IR. Antibiotic pharmacodynamics in cerebrospinal fluid. Clin Infect Dis 1998; 27(5): 1117-27
6.
Van Bambeke F, Tulkens PM. Pharmacodynamie des antibiotiques dans le LCR : principes et conséquences (facteurs prédictifs d’efficacité). Médecine et maladies infectieuses 2009; 39: 483-92
7.
Auvergnat JC, Le Net R, Massip P, et al. Pharmacocinétique comparée de différents antibiotiques dans le LCR en fonction du mode d’administration intra-veineux. Médecine et maladies infectieuses 1976: 125-33
Correspondence and offprints: Rim Charfi, Service de pharmacologie clinique, Centre national de pharmacovigilance, 9 avenue Dr Zouheïr Essafi, 1006 Tunis, Tunisie. E-mail: [email protected]
Thérapie 2014 Novembre-Décembre; 69 (6)
À LA
Thérapie 2014 Novembre-Décembre; 69 (6): 529–530 DOI: 10.2515/therapie/2014204
RÉDACTION
© 2014 Société Française de Pharmacologie et de Thérapeutique
Vancomycin Therapeutic Drug Monitoring in Cerebrospinal Fluid Imen Aouinti1,2, Rim Charfi1,2, Sameh Trabelsi1,2, Emna Gaïes1,2, Issam Salouage1,2, Nadia Jebabli1, Hanène El Jebari1, Mohamed Lakhal1,2 and Anis Klouz1,2 1 Service de pharmacologie clinique, Centre national de pharmacovigilance, Tunis, Tunisie 2 Université de Tunis El Manar, Faculté de médecine, Tunis, Tunisie Text received May 19th, 2014; accepted September 1st, 2014 This case has been declared to National Pharmacovigilance Centre of Tunis (Tunisia) on March 9th, 2012
Abstract – Vancomycin penetrates poorly through the blood-brain barrier. Determination of vancomycin concentration in plasma is recommended. In contrast, its determination in cerebrospinal fluid (CSF) is rarely performed. We report the case of a 74-year-old man with post traumatic meningitis with vancomycin concentration measured in CSF. Keywords: therapeutic drug monitoring; vancomycin; cerebrospinal fluid; meningitis Résumé – Suivi thérapeutique pharmacologique de la vancomycine dans le liquide céphalorachidien. La vancomycine pénètre mal la barrière hémato-méningée. Le dosage de la concentration plasmatique de vancomycine est recommandé. Toutefois, il est rarement effectué dans le liquide céphalo-rachidien (LCR). Nous rapportons le cas d’un homme âgé de 74 ans ayant une méningite post-traumatique chez lequel le dosage de la vancomycine dans le LCR a été déterminé. Mots clés : suivi thérapeutique pharmacologique ; vancomycine ; liquide céphalorachidien ; méningite Abbreviations: see end of article.
1. Introduction Vancomycin is a glycopeptide antibiotic administered to treat staphylococcal and streptococcal infections in hospitalized patients. Due to its narrow therapeutic range, monitoring of its plasma concentrations is widely recommended in order to optimize vancomycin efficacy and to minimize toxicity or adverse drug reactions.[1] Vancomycin therapeutic range varies from 20 to 25 µg/mL in case of administration by continuous infusion.[2] Vancomycin therapeutic drug monitoring (TDM) in cerebrospinal fluid (CSF) is less commonly performed. Vancomycin therapeutic range in CSF varies from 4 to 5 µg/mL.[3] We report the case of a patient with post traumatic meningitis to emphasize the interest of vancomycin monitoring in CSF.
2. Case report A 74-year old man with no previous medical history was hospitalized in March 2012 in intensive care unit for posttraumatic meningitis associated with hydrocephalus. Renal function was normal. CSF bacteriological study and hemoculture were negative. A first-line treatment with vancomycin 4.5 g per day by continuous intravenous infusion, imipenem 3 g per day, aciclovir 2.25 g per day and rifampicin 600 mg three times a day was started associated with an external ventricular drainage. On day 7, vancomycin concentrations were determined concomitantly in plasma and CSF by fluorescence polarization immunoassay on the automate AXSYM from Abbott Laboratories. Vancomycin plasma concentration was subtherapeutic (33.92 µg/mL). Value in CSF was 12.07 µg/mL (35.6% of plasmatic concentration). Few days later, the patient was transferred to neurology department for one week and then readmitted in intensive care unit because of respiratory troubles. The patient was sedated with fentanyl and midazolam. Carbamazepin and phenobarbital were added. Doses of vancomycin and rifampicin were adjusted respectively to 4 g per day by continuous intravenous infusion and 600 mg four times a day. A second determination of vancomycin plasma concentration was performed on day 19 and was subtherapeutic (35 µg/mL). Vancomycin concentration in CSF was not performed. The patient suffered from renal insufficiency (creatinine clearance level: 8 mL/min) leading to a daily dialysis. Dose of vancomycin was reduced to 750 mg per day. No clinical improvement was observed despite efficient vancomycin concentrations. Thus, etiological investigations were performed. Brain magnetic resonance imaging showed an aspect suggesting meningeal tuberculosis. A brain biopsy confirmed the diagnosis with a granulomatosis with caseum necrosis.
Article publié par EDP Sciences
530
Aouinti et al.
Vancomycin was stopped and a combined antituberculous treatment (rifampicin 600 mg per day, isoniazid 300 mg per day, pyrazinamide 1 600 mg per day and ethambutol 1 100 mg per day) was started on day 26.
3. Discussion Determination of vancomycin plasmatic concentrations is recommended because of: • a narrow therapeutic range: thus a little change in its plasmatic concentration may lead to vancomycin inefficacy or toxicity; • an inter and intra individual variability meaning that the same dose administered in different patients or in the same patient at different periods, may result in different plasma vancomycin concentrations; • vancomycin is a time dependent antibiotic. Thus, maintaining an adequate tough concentration is essential for its antibacterial activity.[4] Therapeutic range of vancomycin plasmatic concentrations varies from 20 to 25 µg/mL when administered by continuous infusion.[1] In the present case, determination of vancomycin CSF concentrations was also performed. We would like to discuss the interest of such measurments of vancomycin. Blood-brain barrier (BBB) is a functional barrier that excludes serum components from neuronal tissue, maintaining homeostasis within the central nervous system. It is well known that the capacity of an antibiotic to reach the infected compartment depends on its physicochemical properties (molecular weight, lipophilicity), its power to bind to proteins. In the present case, it also depends on the BBB permeability. In fact, BBB permeability is modulated by inflammation (such as meningitis) and active transporters.[5,6] Antibiotics are not known to be metabolized in the CSF. Their concentrations and half-lives in CSF depend on the balance between drug penetration and elimination through the BBB. The transport of hydrophilic drugs (like vancomycin) depends on the opening of tight junctions. They penetrate poorly through the BBB. Their CSF peak concentrations are delayed, and their CSF half lives extended. In case of inflammation of the BBB, their CSF penetration is significantly increased.[5] Vancomycin CSF concentration can reach 10 to 20% of its plasma concentration so it varies between 4 and 5 µg/mL.[3] In the present case, vancomycin CSF concentration was about 35.6% of plasmatic concentration (12.07 µg/mL), suggesting vancomycin penetration through the BBB. This result allowed clinicians to reevaluate the diagnosis. Further etiological investigations lead to the diagnosis of tuberculous meningoencephalitis.
© Société Française de Pharmacologie et de Thérapeutique
Therefore, determination of vancomycin concentration in CSF is useful to evaluate vancomycin penetration through the BBB and to ensure effective concentrations. Thus, we could suggest not sustained low plasma concentration of vancomycin could allow CSF penetration better than high plasma levels. Thus, the estimation of CSF penetration by measuring the ratio of the area under the concentration curve (AUC) is probably better than that based on single simultaneous measurements of CSF and serum antibiotic concentrations which can be misleading because of delayed CSF penetration.[7]
4. Conclusion This case report underlines the interest of vancomycin concentration measurment in CSF in case of meningitis. In fact, it is useful especially in case of treatment failure in order to evaluate vancomycin BBB penetration allowing optimizing treatment. Conflict of interests. None. Abbreviations. AUC: area under the concentration curve; BBB: blood-brain barrier; CSF: cerebrospinal fluid; TDM: therapeutic drug monitoring.
References 1.
Kang JS, Lee MH. Overview of therapeutic drug monitoring. Korean J Intern Med 2009; 24: 1-10
2.
Lacarelle B, Baltasat A, Bouquet S, et al. Suivi thérapeutique de la vancomycine. In : Marquet P. Suivi thérapeutique pharmacologique pour l’adaptation de posologie des médicaments. Paris: Elsevier 2004: 75-83
3.
Domart Y, Veyssier P. Vancomycine, teicoplanine. In: Bryskier A., Ed. Antibiotiques, agents antibactériens et antifongiques. Paris: Ellipses 1999: 929-46
4.
Billaud EM, Mainardi JL. Faut-il encore doser les glycopeptides ? Revue Française des Laboratoires 2004; 365: 35-8
5.
Lutsar I, McCracken GH Jr, Friedland IR. Antibiotic pharmacodynamics in cerebrospinal fluid. Clin Infect Dis 1998; 27(5): 1117-27
6.
Van Bambeke F, Tulkens PM. Pharmacodynamie des antibiotiques dans le LCR : principes et conséquences (facteurs prédictifs d’efficacité). Médecine et maladies infectieuses 2009; 39: 483-92
7.
Auvergnat JC, Le Net R, Massip P, et al. Pharmacocinétique comparée de différents antibiotiques dans le LCR en fonction du mode d’administration intra-veineux. Médecine et maladies infectieuses 1976: 125-33
Correspondence and offprints: Rim Charfi, Service de pharmacologie clinique, Centre national de pharmacovigilance, 9 avenue Dr Zouheïr Essafi, 1006 Tunis, Tunisie. E-mail: [email protected]
Thérapie 2014 Novembre-Décembre; 69 (6)
