Intrathecal tigecycline is a safe and effective treatment for central nervous system infections
Article information
Abstract
Both the safety and effectiveness of intrathecal tigecycline (TGC) for treatment of infections of the central nervous system (CNS) are discussed using the clinical findings from a study of a recent patient who came to our attention, along with a literature review. Although penetration into the CNS is low (approximately 11%), intraventricular TGC could help treat patients with severe post-neurosurgical CNS infections. The use of multiple routes of TGC administration appears to be encouraging and should be considered in managing life-threatening intraventricular infections.
Introduction
Tigecycline (TGC) is a glycylcycline antibiotic widely employed for systemic (intravenous) treatment of skin-skin structures and intraabdominal infections caused by susceptible gram-positive and gram-negative bacteria. Experiences with infections of the central nervous system (CNS) are limited [1], while those encompassing intrathecal administration are even rare. Combined intravenous and intrathecal treatment has been used in a few cases of CNS infections due to multi-resistant, gram-negative pathogens [2–19].
The report was approved by the Institutional Review Board of Azienda Ospedaliera di Cosenza, Cosenza, Italy and written informed consent was obtained from the patient for publication of this case report.
Case Report
After a subarachnoid hemorrhage, a 51-year-old male received external ventricular drainage (EVD) after a ventriculoperitoneal shunt became infected by Staphylococcus aureus, leading to a clinical picture of CNS infection (ventriculitis). A baseline computed tomography (CT) scan of his head revealed endovascular treatment of embolization at the apex of the basilar artery using a simple coiling technique, with evidence of metal coils at the level of the interpeduncular cistern, which generated artifacts. The scan also revealed the presence of a cerebral spinal fluid (CSF) shunt catheter with right transfrontal and extreme proximal access in the anterior recesses of the third ventricle, with thickening and inhomogeneity of the frontoparietal subgaleal soft tissues delimiting the shunt catheter, a ventricular system of dimensions within the limits, and midline structures on axis.
The S. aureus strain proved to be resistant to beta-lactams, macrolides, and clindamycin but fully susceptible to glycopeptides and TGC (minimum inhibitory concentration, <0.12 μg/mL).
Together with full-dose intravenous teicoplanin, TGC was administered by both intravenous (full dose) and intraventricular (IVT) routes, the latter at 1 mg twice daily, followed by 5 mg twice daily in a 0.9% saline solution (at a final concentration of 1 mg/mL), maintaining a closed IVT shunt for 2 hours.
Recommended antimicrobial therapy has included the use of 400 mg of teicoplanin in sodium chloride 0.9% intravenous solution 100 mL injection every 12 hours for 3 days, then 400 mg/day plus 100 mg of TGC in sodium chloride 0.9% intravenous solution of 250 mL as a loading dose, followed by 50 mg in sodium chloride 0.9% intravenous solution 100 mL every 12 hours. To enhance antimicrobial activity, use of the IVT route followed a recommended protocol. First, on the second day of therapy, the dose of intravenous TGC was reduced to 49 mg in sodium chloride 0.9% intravenous solution 100 mL every 12 hours, and 1 mg of TGC was administered intraventricularly every 12 hours (slow injection into the lateral ventricles via an EVD was recommended). On the 3rd day of therapy, assuming adequate tolerability, the dose of TGC was reduced to 45 mg in sodium chloride 0.9 intravenous solution 100 mL every 12 hours, administering 5 mg TGC intraventricularly every 12 hours. The overall duration of therapy was 14 days, with microbial sterilization of the CSF and negativity of blood cultures. The TGC used in each intrathecal injection was diluted in 10 mL of 0.9% NaCl, resulting in a concentration of 1 mg/mL. After each IVT injection, the CSF drain was temporarily closed for 2 hours to prevent premature lavage of the drug. Daily chemophysical and microbiological monitoring of the CSF was performed using EVD. Complete blood counts were obtained, and C-reactive protein, procalcitonin, creatinine, creatine phosphokinase, alanine transaminase, lipase, and electrolyte levels were monitored daily. A CT scan of the head on day 14 documented shunt catheter removal along the proximal path in which air was bubbling and hypodensity due to parenchymal pain was highlighted. The ventricular system was slightly reduced in size. Together with full normalization of CSF parameters, these assessments demonstrated both efficacy and safety of TGC administered by an intrathecal route (Table 1). The patient was discharged from the hospital after confirming no residual infection or ventricular enlargement.
Laboratory and cerebrospinal fluid characteristics
The decision to use TGC both intravenously and intrathecally was based on three considerations. First, the intensive care and neurosurgery units of our hospital have a high risk of nosocomial infections due to gram-negative microorganisms, particularly Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii. Second, because the patient had been recently hospitalized for more than 4 weeks, we assumed he had been colonized by nosocomial organisms. Third, during the first days of treatment with teicoplanin, the patient continued to have a fever.
Discussion
While combined intravenous and intrathecal antibiotics have been used successfully to treat multidrug-resistant (MDR) CNS infections, most of these were nosocomial in origin, and intrathecal TGC has been used in only a few cases of spinal arachnoiditis or intracranial infections caused by MDR A. baumannii strains [2–19]. The present report is the first to apply TGC to patients with gram-positive CNS infections. TGC is a new, intravenous, broad-spectrum antibiotic that is a derivative of minocycline and a member of the glycylcyclines. It is part of a new class of semisynthetic antibacterial agents developed to treat polymicrobial infections caused by MDR to gram-positive and gram-negative pathogens, overcoming the main tetracycline-resistance genetic mechanisms associated with efflux pumps and ribosomal protection proteins that decrease the activity of other tetracyclines.
TGC is structurally similar to tetracyclines but is a chemically modified monocycline with addition of a t-butylglycylamido side chain to the C9 carbon of the “D” tetracycline ring, resulting in expansion of the TGC spectrum of antibacterial activity against a wide spectrum of gram-positive and gram-negative pathogens.
As a bacteriostatic inhibitor of bacterial protein translation via reversible binding to a helical region on the 30S subunit of bacterial ribosomes, TGC prevents the incorporation of amino acid residues into elongated peptide chains, inhibiting peptide formation and bacterial growth.
TGC is the first glycylcycline antibacterial drug that inhibits protein translation in bacteria by binding to the 30S ribosomal subunit and blocking the entry of aminoacyl transfer RNA molecules into the A site of the ribosome.
Both the dose and administration schedules of intrathecal TGC remain to be defined, but when a CNS infection is of concern, intravenous administration must be ruled out because of poor drug penetration of the blood-brain barrier. IVT administration of TGC is emerging as an effective therapeutic option for the treatment of CNS infections, particularly those caused by MDR organisms for which there are few other therapeutic opportunities.
Although the descriptions are limited, a narrative review of a letter summarized in Table 2 [2-19] highlights many relevant articles published, attesting to the strength of interest in this topic. Considering the potential neutral but irreversible effects correlated with high concentrations of TGC, further studies are needed to verify the safest and most effective dosages. IVT therapy remains an off-label therapeutic possibility and, pending further precision therapy studies, should be reserved as an individualized therapy resource for the treatment of severe infections, possibly under therapeutic drug monitoring guidance. The dose of TGC used by Soto-Hernández et al. [12] produced levels 15 to 20 times the minimum inhibitory concentration of the bacteria for up to six hours with adequate tolerance. Doses smaller than 5 mg and those administered more than twice daily have been recommended as the safest and most effective regimen [16]. Moreover, further research is necessary to determine the role of TGC in the treatment of CNS infection. The safety of IVT injections of this drug, as well as the pharmacokinetics and pharmacodynamics in this patient setting, should be analyzed in larger studies involving patients with postsurgical and serious infections by gram-positive organisms.
Characteristics of adults previously reported with CNS infection treated with intraventricular TGS (2020–2022)
We recently published a brief report, the first of its kind, documenting the safety and efficacy of high-dose TGC as a salvage therapy in five Italian patients with serious CNS rickettsiosis [1]. Despite the low concentrations of TGC in the CSF compared with the minimum inhibitory concentration, some reports describe a positive evolution of the therapy for CNS infections by MDR organisms with TGC [1]. A drug may accumulate in polymorphonuclear cells and then be delivered to the site of infection in higher-than-anticipated concentrations or lead to minor subinhibitory effects. Although penetration into the CNS is minimal (approximately 11%), TGC delivered by IVT may be able to treat patients with severe post-neurosurgical CNS infections [1]. The decision to use TGC both intravenously and intrathecally in our patient was based on three considerations. First, the intensive care unit and neurosurgery units of our hospital both have a high risk of nosocomial infections due to gram-negative microorganisms, particularly E. coli, K. pneumoniae, and A. baumannii. Second, the patient had been recently hospitalized for more than 4 weeks and was assumed to be colonized by nosocomial organisms. Third. during the first days of treatment with teicoplanin, the patient continued to run a fever.
The use of multi-route TGC appears to be effective and should be considered for managing life-threatening IVT infections.
Notes
Conflicts of Interest
No potential conflict of interest relevant to this article was reported.
Author Contributions
Conceptualization, Investigation: Mastroianni A; Data curation: Greco S, Mauro MV; Formal analysis: all authors; Writing–original draft: all authors; Writing–review and editing: all authors