New Antibiotics for the Treatment of Nosocomial Central Nervous System Infections

New Antibiotics for the Treatment of Nosocomial Central Nervous System Infections

  • Post category:Drug Updates
  • Reading time:8 mins read

Introduction

(Article introduction authored by ICU Editorial Team)

Nosocomial CNS infections with carbapenem- and colistin-resistant Gram-negative and vancomycin-resistant Gram-positive bacteria present a growing therapeutic challenge. This review examines the pharmacokinetics, pharmacodynamics, and clinical use of new intravenous antibiotics for treating these multi-resistant infections.

Cefiderocol, a new cephalosporin, shows promise due to its high-dose effectiveness similar to established cephalosporins. New glycopeptides like dalbavancin, telavancin, and oritavancin, despite their efficacy in animal meningitis models, are unlikely to achieve effective CSF concentrations through IV administration alone due to high plasma protein binding.

β-lactam/β-lactamase inhibitor combinations struggle with achieving adequate CSF levels of both components, with the β-lactamase inhibitor often being insufficient. Tedizolid offers a broader spectrum than linezolid but with less favorable pharmacokinetics.

Eravacycline fails to reach therapeutic CSF concentrations at standard IV doses. Therefore, intravenous treatment is preferred to avoid the adverse effects of intraventricular therapy (IVT).

However, IVT should be considered for patients not responding adequately to systemic therapy alone, as it can enhance CSF penetration of many antibiotics. In this review, we will present and discuss pharmacokinetic and pharmacodynamic data and clinical experiences with new antibiotics administered intravenously for the treatment of CNS infections by resistant bacteria.

β-Lactam Antibiotics

Cefiderocol is a new siderophore cephalosporin that uses iron transport systems to enter bacterial cells, effectively targeting carbapenemase- and metallo-β-lactamase-producing Gram-negative bacteria. It is primarily eliminated by the kidneys, with a half-life of 2-3 hours and about 58% protein binding.

Standard dosing for severe infections with normal renal function is 2 g every 8 hours, increased to every 6 hours for higher renal clearance. Case reports show its use in CNS infections with multi-resistant pathogens, often combined with other antibiotics like colistin.

Cefiderocol has shown some success in treating CNS infections, but its penetration into the CSF is generally lower compared to smaller β-lactam antibiotics. Other β-lactam antibiotics, such as ceftolozane (usually combined with tazobactam), also target drug-resistant bacteria but are unstable against extended-spectrum β-lactamases and carbapenemases.

Tetracyclines

Eravacycline is a synthetic halogenated tetracycline, similar to tigecycline, with broad antimicrobial activity against various bacteria, including Enterobacteriaceae, A. baumannii, and Staphylococcus species.

It is suggested for treating carbapenem-resistant A. baumannii. Pharmacokinetic studies in rabbits show low concentrations in the CNS and eye tissues, with a volume of distribution around 4 L/kg, accumulating in the kidney, liver, spleen, and lung.Eravacycline’s poor penetration into CSF limits its use for CNS infections. Omadacycline has not been reported for CNS infections, and its CSF concentrations are not documented.

Glycopeptides and Related Compounds

Dalbavancin is a highly plasma-protein-bound lipoglycopeptide (93%) with a long half-life (about 1 week). It concentrates in soft tissues but has low CSF and brain concentrations. No reports exist on its use for CNS infections.

Telavancin, derived from vancomycin, also binds strongly to plasma proteins (93%) and has a long half-life. In rabbit studies, it has poor CSF penetration, which slightly improves during meningitis.

Telavancin has shown superior activity to vancomycin and ceftriaxone in experimental penicillin-resistant S. pneumoniae meningitis, but no clinical reports on CNS infections exist.

Oritavancin is effective against Gram-positive bacteria, including resistant strains. It has a long half-life (393 hours) and is given as a single dose. CSF concentrations in humans are low and below the MICs for many resistant organisms.

Experimental studies in rabbits show some efficacy against S. pneumoniae meningitis, but it has not been successfully used for human CNS infections.

Oxazolidinones

Tedizolid is an oxazolidinone with a similar antibacterial spectrum as linezolid—some linezolid-resistant Gram-positive cocci are susceptible to tedizolid.

Approximately 8 h after a dose of tedizolid 200 mg i.v. every 12 h, CSF concentrations of 0.204 ± 0.006 mg/L were measured, and the CSF penetration based on corresponding unbound plasma concentrations was estimated around 54.8%.

In experimental rats in the absence of meningeal inflammation, the mean Cmax of tedizolid in the CSF was 0.154 mg/L, and the mean penetration ratio of tedizolid into CSF was estimated to be 2.16%.

The penetration ratio increased to 3.53% by co-administration of the P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) inhibitor elacridar, suggesting that P-gp and BCRP are involved in the removal of tedizolid from the CSF.

For this reason, intravenous tedizolid appears to be less suitable for the treatment of CNS infections than linezolid, which possesses an ideal pharmacokinetic profile for this indication.

Aminoglycosides

Plazomicin is a new semisynthetic aminoglycoside antibiotic structurally derived from sisomicin. It has not been reported to be used for the treatment of CNS infections.

β-Lactam Antibiotic/β-Lactamase Inhibitor Combinations

Novel β-lactam antibiotics and β-lactamase inhibitors share pharmacokinetic properties such as hydrophilicity, low plasma protein binding, low molecular mass, small volume of distribution, and primarily renal clearance.

β-lactam/β-lactamase inhibitor combinations face challenges in susceptibility testing due to fixed inhibitor concentrations that are often higher than those reached in CSF. This can result in underdosing of β-lactamase inhibitors like tazobactam in clinical settings.

Ceftolozane/tazobactam has been used successfully for CNS infections, showing high variability in CSF penetration. Continuous infusion in patients with meningeal inflammation achieved significant CSF concentrations.

Aztreonam/avibactam is promising for treating infections by metallo-β-lactamase-producing bacteria and has shown effectiveness in CNS infections when combined with ceftazidime.

Ceftazidime/avibactam is active against various resistant bacteria, with well-characterized CSF penetration. It has been effective in treating CNS infections.

Meropenem/vaborbactam is active against several resistant enterobacteria, but there is no specific data on vaborbactam’s CNS penetration. Imipenem/relebactam has shown activity against certain resistant bacteria but is less favored for CNS infections due to the high seizure risk associated with imipenem.

Discussion

The entry of an antibiotic into CSF depends on the drug’s properties and host factors. Key factors include lipophilicity, molecular size, and plasma protein binding. Small molecules (100–1000 g/mol) with higher lipophilicity at pH 7.4 penetrate the CSF more effectively. Active transport mechanisms, such as OAT3, can also influence antibiotic concentrations in CSF.

Host variables affecting CSF drug entry include age, CSF volume, flow, plasma albumin levels, and genetic polymorphisms in transport proteins.

Drug concentrations typically show a rostrocaudal gradient, being lowest in ventricular and highest in lumbar CSF. Predicting CSF concentrations based on drug properties and systemic pharmacokinetics is challenging due to host variability.

In the absence of strong meningeal inflammation, achieving adequate CSF concentrations is difficult for many antibiotics. Increasing the intravenous dose can help, as seen with older antibiotics like cefotaxime and meropenem.

However, high doses of β-lactam antibiotics and inhibitors are not suitable for intrathecal therapy due to their pro-convulsive properties. Intrathecal therapy with vancomycin or tigecycline, combined with intravenous therapy, may be a last resort for new glycopeptides and eravacycline.

Conclusion

Among the new intravenous antibiotics with potential for treating CNS infections, cefiderocol’s pharmacokinetics in CSF is similar to other β-lactam antibiotics.

High doses (≥6 g/day) are necessary to achieve adequate CSF concentrations for treating carbapenem-resistant bacteria, making cefiderocol a first choice for CNS infections by multi-resistant Gram-negative bacteria.

β-lactam/β-lactamase inhibitor combinations face issues in CNS infections due to β-lactamase inhibitor concentrations in susceptibility testing not being reached in CSF.

Despite this, they remain last-resort options for cefiderocol-resistant bacteria. Intravenous treatment is generally preferred to avoid adverse effects from intraventricular therapy. However, for poorly responding CNS infections, a combination of intravenous and intraventricular therapy should be considered. Eravacycline and new glycopeptides have potential for CNS infections but achieve low CSF concentrations due to their large size and tissue binding, making them suitable for combined intravenous/intraventricular therapy.

β-lactam antibiotics and inhibitors should not be administered intrathecally due to their pro-convulsive properties.

Source: Gordón Pidal, J.M., Arruza, L., Moreno-Guzmán, M. et al. Micromotor-based dual aptassay for early cost-effective diagnosis of neonatal sepsis. Microchim Acta 191, 106 (2024). https://doi.org/10.1007/s00604-023-06134-x