New Antibiotics for the Treatment of Nosocomial Central Nervous System Infections

Abstract

Nosocomial central nervous system (CNS) infections with carbapenem- and colistin-resistant Gram-negative and vancomycin-resistant Gram-positive bacteria are an increasing therapeutic challenge. Here, we review pharmacokinetic and pharmacodynamic data and clinical experiences with new antibiotics administered intravenously for the treatment of CNS infections by multi-resistant bacteria. Cefiderocol, a new siderophore extended-spectrum cephalosporin, pharmacokinetically behaves similar to established cephalosporins and at high doses will probably be a valuable addition in our therapeutic armamentarium for CNS infections. The new glycopeptides dalbavancin, telavancin, and oritavancin are highly bound to plasma proteins. Although effective in animal models of meningitis, it is unlikely that they reach effective cerebrospinal fluid (CSF) concentrations after intravenous administration alone. The β-lactam/β-lactamase inhibitor combinations have the principal problem that both compounds must achieve adequate CSF concentrations. In the commercially available combinations, the dose of the β-lactamase inhibitor tends to be too low to achieve adequate CSF concentrations. The oxazolidinone tedizolid has a broader spectrum but a less suitable pharmacokinetic profile than linezolid. The halogenated tetracycline eravacycline does not reach CSF concentrations sufficient to treat colistin-resistant Gram-negative bacteria with usual intravenous dosing. Generally, treatment of CNS infections should be intravenous, whenever possible, to avoid adverse effects of intraventricular therapy (IVT). An additional IVT can overcome the limited penetration of many new antibiotics into CSF. It should be considered for patients in which the CNS infection responds poorly to systemic antimicrobial therapy alone.

A Difficult Case of Ventriculitis in a 40-Year-Old Woman with Acute Myeloid Leukemia

“…The choice of MVB in our case was driven by the patient's adverse response with malaise and the emergence of a rash after the first infusion of CAZ/AVI, whereas the decision in the case described by Choi S. et al [10] was motivated by the MICs (respectively, 0.064 mg/L and 2 mg/L for MVB and CAZ/AVI). However, the meropenem and vaborbactam levels in the CSF were not available in either of the two patients, and there are also just a few case reports in the literature where CAZ/AVI has been used to treat CNS infections [11][12][13][14][15][16][17]. Volpicelli L. and colleagues recently described a CNS infection caused by CAZ/AVI-resistant, KPC-producing K. pneumoniae that was successfully treated with MVB, intravenous fosfomycin, and dosed meropenem and vaborbactam concentrations in the plasma and cerebrospinal fluid [13].…”

“…The decision to re-implant the device should be based on the patient, microorganism, severity of infection, and CSF findings [1,2]. Moreover, ventriculitis patients must be closely monitored for an extended period because the ventricles and choroid plexus can act as a reservoir of infection, even if a lumbar puncture yields sterile culture results [14].…”

“…The most recent treatment guidelines for carbapenemresistant Gram-negative bacteria recommend ceftazidime/avibactam (CAZ/AVI) and meropenem/vaborbactam (MVB)-and, as a second choice, imipenem/relebactam and cefiderocol-as effective antibiotics against carbapenem-resistant, KPC-producing Enterobacterales [7][8][9]. Unfortunately, there are little data in the literature to support the use of these new drugs in CNS infections [10][11][12][13][14][15][16]. Vancomycin-resistant enterococci (VRE) are becoming increasingly prevalent nosocomial pathogens all over the world, but they seldom cause CNS infections.…”

Role of Cefiderocol in Multidrug-Resistant Gram-Negative Central Nervous System Infections: Real Life Experience and State-of-the-Art

“…However, the dose does not appear to be a major determinant of the outcome, and additional factors may play a role. For instance, as highlighted by Nau et al, the degree of meningeal inflammation influences drug penetration into the CNS [15,18,20]. Indeed, most of the literature describes cases where CNS infection occurred in the presence of neurosurgical devices, such as ventriculoperitoneal derivations.…”

“…To date, no other cases of CNS infection treated with cefiderocol have been described in the literature [18]. In view of the limited amount of data available on the use of cefiderocol in CNS infections, we report five cases from different hospitals regarding CNS infections that were treated with cefiderocol both in a combination regimen and as monotherapy.…”