Scandinavian Journal of Infectious Diseases, 2014; 46: 69–72


Cerebrospinal fluid penetration of tigecycline

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CARLO PALLOTTO1, MAURIZIO FIORIO1, ANTONIO D’AVOLIO2, ALESSIO SGRELLI1, FRANCO BALDELLI1, GIOVANNI DI PERRI2 & GIUSEPPE VITTORIO DE SOCIO1 From the 1Infectious Diseases Clinic, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, “Santa Maria della Misericordia” Hospital, Perugia, and 2Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy

Abstract We report, in a clinical setting, the tigecycline concentration and area under the concentration–time curve (AUC) – both in blood and in cerebrospinal fluid (CSF) – of a patient with a ventriculo-atrial shunt infection. Tigecycline weakly penetrates CSF the CSF-to-serum concentration ratio was 0.079 and CSF-to-serum AUC0–12 ratio was 0.067.

Keywords: Tigecycline, CSF, pharmacokinetics

Introduction Tigecycline is a synthetic derivate of minocycline and belongs to the glycylcycline class of antibiotics. Tigecycline has an expanded broad-spectrum activity against Gram-positive and Gram-negative bacteria, including multidrug-resistant strains (vancomycinresistant enterococci, methicillin-resistant staphylococci, and Acinetobacter baumannii) [1]. Due to its scarce bioavailability after oral administration, the drug is usually administered as a 30–60-min intravenous (IV) infusion [2]. The halflife of tigecycline ranges between 16 and 67 h [1–3]. The drug is mainly excreted unchanged in the faeces and its dosage does not need adjustment in the case of renal failure [2]. Tigecycline is rapidly distributed into the tissues and becomes concentrated primarily in the bile and in the bowel [3,4] and, to a lesser extent, in the lungs [3]. Data regarding the ability of tigecycline to penetrate bone tissue are conflicting, especially between the murine model [5] and the human model [3]. Furthermore, easily comparable data on the ability of the drug to penetrate the central nervous system are lacking [3,4,6]. We report the pharmacokinetic data acquired from CSF and serum samples collected at steady-state

through an external ventricular drainage (EVD) from a patient with hydrocephalus treated with tigecycline.

Case report A 31-y-old woman affected by systemic lupus erythematosus (SLE) with hydrocephalus was admitted to our unit in March 2012 because of fever and chills. The patient had been diagnosed with SLE in 2007 and after an initial positive response to steroids and immunosuppressive therapy, her condition had started to worsen in March 2010. In fact, in March 2011, she was diagnosed with hydrocephalus, and a ventriculo-peritoneal shunt (VPS) needed to be placed. The VPS was replaced several times because of infections and obstructions, and in January 2012 a ventriculo-atrial shunt (VAS) was placed. When the patient came to our attention with fever and chills, she was still on therapy with methylprednisolone 16 mg/day. Microbiological tests, which comprised blood culture and CSF culture acquired through lumbar puncture and VAS, showed the presence of multidrug-resistant Enterococcus faecium with sensitivity only to linezolid and tigecycline. Based on the above-mentioned results, the patient was initially treated with IV linezolid 600 mg every

Correspondence: C. Pallotto, Clinica di Malattie Infettive, Università degli Studi di Perugia, Ospedale “Santa Maria della Misericordia”, piazzale Menghini, 1 – 06129 Perugia, Italy. Tel: ⫹ 39 075 5784379. Fax: ⫹ 39 075 5784346. E-mail: [email protected] (Received 3 July 2013 ; accepted 12 August 2013) ISSN 0036-5548 print/ISSN 1651-1980 online © 2014 Informa Healthcare DOI: 10.3109/00365548.2013.837957

C. Pallotto et al.

12 h, and tigecycline 100 mg IV as a loading dose, followed by 50 mg IV every 12 h thereafter. After 9 days of therapy, the E. faecium still grew from blood samples and the fever was still present. The VAS was removed and replaced with an EVD. E. faecium was also isolated from VAS culture. Blood cultures became negative after 14 days of treatment, but the CSF samples acquired on the same day proved positive for Nocardia farcinica; therefore, trimethoprim–sulfamethoxazole 400/80 mg IV was introduced every 6 h, followed by amoxicillin– clavulanate IV 1750/250 mg every 8 h. On day 38, linezolid administration was stopped because of haematological toxicity. Although all of the CSF samples acquired after 23 days of therapy had negative results both for E. faecium and N. farcinica, after such a prolonged incubation, the patient’s condition deteriorated progressively due to neurological worsening. The patient underwent further neurosurgery to replace the EVD, but no clinical improvement was registered, and eventually, after 75 days of hospitalization, she died.

Materials and methods Due to both the scarce pharmacokinetic and pharmacodynamic information on the CSF penetration of tigecycline, and the unclear clinical response of the patient, CSF samples, together with blood samples, were collected from the patient after her informed consent was obtained on day 38 of tigecycline treatment. Samples were collected before the expected administration of tigecycline (t0) and 3, 8, and 12 h after the beginning of the drug infusion (times t1, t2, and t3, respectively). In order to avoid a worsening of the patient’s nausea and vomiting, the overall time of the drug infusion was 2 h instead of the usual 1-h time interval. The blood and CSF samples acquired through the EVD were kept at ⫺ 80°C until analysis. The drug serum and CSF concentrations were evaluated using two validated methods: ultra performance liquid chromatography–photodiode array (UPLC-PDA) and UPLC–mass/mass spectrometry (UPLC-MS/ MS), respectively. The serum and CSF areas under the concentration– time curve of a 12-h interval (AUC0–12) – corresponding to the time interval between each drug administration – were calculated using non-compartmental analysis with Kinetica software (v. 5.0), and the AUC of a 24-h time interval (AUC0–24) and the AUC of time zero to infinity (AUC0–∞) were estimated.

Microbial identification was obtained using a validated and automated system (BD Phoenix Automated Microbiology System). E. faecium susceptibility to tigecycline and the corresponding minimum inhibitory concentration (MIC) threshold were determined by epsilometer test (Etest) method and were interpreted in accordance with the European Committee on Antimicrobial Susceptibility Testing guidelines [7].

Results The trough concentration of tigecycline (before the following expected administration, t0) was 49 ng/ml in serum and 5.2 ng/ml in the CSF at steady-state. At 1 h after the end of the infusion, the drug serum concentration was 203 ng/ml and the CSF concentration was 13.4 ng/ml (Figure 1). The average ratio of CSF-to-serum concentration was 0.079 (0.059–0.106 interval). The serum AUC0–12 was 1361.5 h*ng/ml and the CSF AUC0–12 was 91.6 h*ng/ml. The ratio between CSF and serum AUC0–12 was 0.067 (6.7%). The serum AUC0–24 was 2723 h*ng/ml and the CSF AUC0–24 was 183.2 h*ng/ml. In an interval from time zero to infinity, the serum and CSF AUCs were 3167.6 h*ng/ml and 227.38 h*ng/ml, respectively. Biochemical analysis of the CSF sample taken at t0 showed no pathological findings (glucose 60 mg/ dl, proteins 13 mg/dl, 1 cell/mm3). The E. faecium MIC threshold for tigecycline was equal to 190 ng/ml.

225 Serum

200 concentration (ng/ml)

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175 150 125 100 75 50 25




time (h)



Figure 1. Serum (red line) and cerebrospinal fluid (green line) concentration–time curve of tigecycline at steady-state (day 38 of therapy). Samples were collected before the expected administration of tigecycline (t0) and 3, 8, and 12 h after the beginning of the drug infusion (times t1, t2, and t3, respectively). The overall time of the drug infusion was 2 h.

CSF penetration of tigecycline

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Discussion The number of infections caused by multidrugresistant bacteria is growing dramatically. Tigecycline has demonstrated activity against most of these bacterial strains, with the exception of Pseudomonas spp. [1]. Therefore, it is becoming increasingly important to understand the pharmacokinetic and pharmacodynamic profile of tigecycline in order to eradicate these difficult-to-treat infections; this is also important when particular tissues are affected, such as bone tissue and the central nervous system. Data on the CSF penetration of tigecycline are still scarce, and only a few studies have evaluated the diffusion of tigecycline in the CSF using the ratio between the serum and the CSF concentration. Moreover, due to the great heterogeneity of these studies, the results are difficult to compare. We believe that our study is the first to approach this issue from a practical clinical point of view. The data we have acquired show, on average, a low CSF concentration of the drug equal to 7.9% of the serum concentration (5.9–10.6% interval). If we compare the values for the CSF and serum AUC0–12, the results are no different (CSF-to-serum AUC0–12 ratio equals to 6.7%). Even the values for AUC0–24 and the AUC0–∞ are lower than those described in the literature [1–3,6] (Table I). There may be different explanations for the heterogeneity of these results; explanations that lie in the ‘real-life’ limitations of clinical trials. First of all, it is known that the serum concentration of tigecycline tends to reduce rapidly, soon after the infusion, as the drug distributes rapidly into the tissues [4]. The studies on pharmacokinetics that we analysed [1–4,6] mainly focused on a 30–60-min infusion of the drug and its serum concentration, which was measured through blood samples acquired 1 h after the infusion. Instead, in our case, the infusion took 2 h in order to minimize the patient’s nausea; this slower infusion might have influenced the data on the peak concentration of the drug. In addition to this, as observed by Ray et al. [6], the drug, after spreading through the nervous system tissues, can accumulate in polymorphonuclear cells, causing a fast decrease in its peak concentration.


Secondly, it is also known that if the dosage of tigecycline is increased, the drug serum concentration and the drug AUC will increase proportionately [4]. Since we administered 50 mg tigecycline every 12 h, instead of administering the amount of 100 mg as used by Rodvold et al. [3], the values we obtained cannot be perfectly compared. According to the literature, tigecycline barely penetrates the blood–brain barrier [4], even in cases of meningeal inflammation [6]. Our data (serum and CSF concentrations and AUCs) do not appear to diverge from this. Rodvold et al. [3] were the first to describe the CSF penetration of tigecycline through the CSFto-serum AUC0–24 ratio, which was equal to 0.11. The conditions for the evaluation, though, could be described as ‘experimental’. Patients were healthy adults who were only administered a single 100-mg dose of tigecycline IV. Our data show a lower ratio (CSF-to-serum AUC0–24 ratio equal to 0.067), possibly because of the lower dosage administered (tigecycline 50 mg every 12 h at steady-state). Also comparing the AUC0–∞, the result matches the values of all the remaining ratios, and is equal to 7.2%. Despite the CSF concentration of tigecycline being below the MIC threshold (190 ng/ml) of the isolated E. faecium, the microbiological tests run from day 14 of therapy were all negative for E. faecium. Also Ray et al. [6], in a patient affected by Acinetobacter baumannii cerebritis, and Dandache et al. [8], in a case of meningitis due to multidrugresistant Klebsiella pneumoniae, had already observed the microbiological efficacy of a CSF tigecycline concentration below the MIC threshold of the corresponding etiologic agent. As mentioned above, tigecycline distributes rapidly into the tissues and concentrates inside polymorphonuclear cells [6]. Therefore, it could be useful to consider the tissue concentration of tigecycline for predicting its efficacy instead of the fluid concentration. Finally, the ratio, as the plasma concentration of tigecycline, may be influenced by the pharmacogenetics of the patient (transporters, metabolizing enzymes, etc.).

Table I. Serum and CSF trough and peak concentration and serum and CSF AUC0–24: comparison with literature data. Serum concentration (ng/ml) Author Present work Rodvold et al. 2006 [3] Ray et al. 2010 [6]

Trough 49 62 129

CSF concentration (ng/ml)

AUC0–24 (ng*h/ml)

CSF/serum ratio









203 306 259

5.2 25 39

13.4 15 48

0.106 0.242 0.302

0.066 0.049 0.185

2723 4180 //

183.2 460 //

0.067 0.11 //

CSF, cerebrospinal fluid; AUC, area under the concentration–time curve.

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C. Pallotto et al.

In conclusion, given the actual theoretical framework on the pharmacokinetic and pharmacodynamic profile of tigecycline, and in compliance with the above-mentioned studies, the clinical outcome of severe infections of the central nervous system treated with tigecycline cannot be fully predicted and the reasons are yet to be determined. Since the number of infections caused by multidrug-resistant bacteria with preserved in vitro sensitivity to tigecycline is increasing, further clinical and pharmacological studies including larger numbers of patients should be carried out in order to draw conclusions on the potential use of tigecycline for the treatment of infections of the central nervous system. Declaration of interest: No conflict of interest.

References [1] Pankey GA. Tigecycline. J Antimicrob Chemother 2005; 56:470–80.

[2] Meagher AK, Ambrose PG, Grasela TH, Ellis-Grosse EJ. The pharmacokinetic and pharmacodynamic profile of tigecycline. Clin Infect Dis 2005;41(Suppl 5):S333–40. [3] Rodvold KA, Gotfried MH, Cwik M, Korth-Bradley JM, Dukart G, Ellis-Grosse EJ. Serum, tissue and body fluid concentrations of tigecycline after a single 100 mg dose. J Antimicrob Chemother 2006;58:1221–9. [4] Muralidharan G, Micalizzi M, Speth J, Raible D, Troy S. Pharmacokinetics of tigecycline after single and multiple doses in healthy subjects. Antimicrob Agents Chemother 2005; 49:220–9. [5] Tombs NL. Tissue distribution of GAR-936, a broad-spectrum antibiotic, in male rats. Abstract 413. Programs and Abstracts of the Thirty-ninth Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, 1999. Washington, DC: American Society of Microbiology; 1999. p. 302. [6] Ray L, Levasseur K, Nicolau DP, Scheetz MH. Cerebral spinal fluid penetration of tigecycline in a patient with Acinetobacter baumannii cerebritis. Ann Pharmacother 2010;44:582–6. [7] European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for interpretation of MICs and zone diameters. Version 2.0, 1 January 2012 to 31 December 2012; 2012. Available at: (accessed 10 December 2012). [8] Dandache P, Nicolau DP, Sakoulas G. Tigecycline for the treatment of multidrug-resistant Klebsiella pneumoniae meningitis. Infect Dis Clin Pract 2009;17:66–8.

Cerebrospinal fluid penetration of tigecycline.

We report, in a clinical setting, the tigecycline concentration and area under the concentration-time curve (AUC) - both in blood and in cerebrospinal...
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