Linezolid

Linezolid

MRSA and MRSE (with MIC > 1 mcg/ml) or patient with vancomycin allergy Linezolid 600mg IV or PO q 12 hrs

Linezolid is an antibiotic used for the treatment of serious infections caused by Gram positive bacteria that are resistant to other antibiotics. Linezolid is active against most Gram-positive bacteria that cause disease, including streptococci, vancomycin-resistant enterococci (VRE), and methicillin resistant Staphylococcus aureus (MRSA).

The main uses are infections of the skin and pneumonia although it may be use for a variety of other infections.

When administered for short periods, linezolid is a relatively safe antibiotic. It can be used in people of all ages and in people with liver disease or poor kidney function. Common adverse effects of short-term use include headache, diarrhea, and nausea. Long-term use, however, has been associated with serious adverse effects such as bone marrow suppression and low platelet counts, particularly when used for more than two weeks. If used for longer periods still, it may cause sometimes irreversible chemotherapy-induced peripheral neuropathy and optic nerve damage, and lactic acidosis (a buildup of lactic acid in the body), all most likely due to mitochondrial toxicity.

As a protein synthesis inhibitor, it stops the growth of bacteria by disrupting their production of proteins, that is, it is a bacteriostatic agent, not bacteriocidal. Although many antibiotics work this way, the exact mechanism of action of linezolid appears to be unique in that it blocks the initiation of protein production, and not one of the later steps.

Bacterial resistance to linezolid has remained very low since it was first detected in 1999, although it may be increasing. It is a member of the oxazolidinone class of drugs.

Linezolid was discovered in the 1990s by a team at Pharmacia and Upjohn Company and first approved for use in 2000. It is on the World Health Organization’s List of Essential Medicines, the most important medications needed in a basic health system.

Linezolid costs approximately US$100 per tablet in the United States. Nonetheless, it appears to be more cost-effective than generic alternatives such as vancomycin, mostly because of the possibility of switching from intravenous to oral administration as soon as patients are stable enough, without the need for dose adjustments.


In animal studies of meningitis caused by Streptococcus pneumoniae, linezolid was found to penetrate well into cerebrospinal fluid, but its effectiveness was inferior to that of other antibiotics.

There does not appear to be enough high-quality evidence to support the routine use of linezolid to treat bacterial meningitis. Nonetheless, it has been used successfully in many cases of central nervous system infection—including meningitis—caused by susceptible bacteria, and has also been suggested as a reasonable choice for this indication when treatment options are limited or when other antibiotics have failed.

The guidelines of the Infectious Diseases Society of America recommend linezolid as the first-line drug of choice for VRE meningitis, and as an alternative to vancomycin for MRSA meningitis.

Linezolid appears superior to vancomycin in treating community-acquired MRSA infections of the central nervous system, although very few cases of such infections have been published (as of 2009).

Effectiveness in Neurosurgery

Evidence for the effectiveness of linezolid in neurosurgical infections (NSIs) is growing. The comfortable oral dosage and tolerance of linezolid opens the possibility for sequential antimicrobial treatment (SAT) in stable patients after a period of intravenous treatment 1).

Reviews

Relevant studies were identified through searches of the PubMed, Current Contents, and Cochrane databases (publications archived until October 2006).

Case reports, case series, prospective and retrospective studies, and randomized controlled trials were eligible for inclusion in our review if they evaluated the effectiveness and safety of linezolid for the treatment of patients with CNS infections.

In 18 (42.9%) of the 42 relevant cases identified, patients had undergone neurosurgical operations and/or had prosthetic devices. Meningitis was the most common CNS infection, accounting for 20 (47.6%) cases. Other CNS infections included brain abscesses (14; 33.3%), ventriculitis (5; 11.9%), and ventriculo-peritoneal shunt infection (3; 7.1%). In the 39 patients in whom the responsible pathogen was isolated, those predominantly responsible for the CNS infections were: penicillin-nonsusceptible Streptococcus pneumoniae (7; 17.9%), vancomycin-resistant enterococci (6; 15.4%), Nocardia spp. (5; 12.8%), methicillin-resistant Staphylococcus epidermidis (4; 10.3%), and methicillin-resistant Staphylococcus aureus (3; 7.7%). Of the 42 patients who received linezolid for the treatment of CNS infections, 38 (90.5%) were either cured or showed clinical improvement of the infection. The mean duration of follow-up was 7.2 months; no recurrent CNS infection was reported.

The limited published data suggest that linezolid may be considered for the treatment of patients with CNS infections in cases of failure of previously administered treatment or limited available options 2).

Case series

To evaluate the efficacy and safety of SAT with oral linezolid in patients with NSI and to analyse the cost implications, an observational, non-comparative, prospective cohort study was conducted on clinically stable consecutive adult patients at the Neurosurgical Service. Following intravenous treatment, patients were discharged with SAT with oral linezolid.

A total of 77 patients were included. The most common NSIs were: 41 surgical wound infections, 20 subdural empyemas, 18 epidural abscesses, and 16 brain abscesses. Forty-four percent of patients presented two or more concomitant NSIs. Aetiological agents commonly isolated were: Propionibacterium acnes (36 %), Staphylococcus aureus (23 %), Staphylococcus epidermidis (21 %) and Streptococcus spp. (13 %). The median duration of the SAT was 15 days (range, 3-42). The SAT was interrupted in five cases due to adverse events. The remainder of the patients were cured at the end of the SAT. A total of 1,163 days of hospitalisation were saved. An overall cost reduction of €516,188 was attributed to the SAT. Eight patients with device infections did not require removal of the device, with an additional cost reduction of €190,595. The mean cost saving per patient was €9,179.

SAT with linezolid was safe and effective for the treatment of NSI. SAT reduces hospitalisation times, which means significant savings of health and economic resources 3).

References

1)

Jahoda D, Nyc O, Pokorný D, Landor I, Sosna A. [Linezolid in the treatment of antibiotic-resistant gram-positive infections of the musculoskeletal system]. Acta Chir Orthop Traumatol Cech. 2006 Oct;73(5):329-33. Czech. PubMed PMID: 17140514.
2)

Ntziora F, Falagas ME. Linezolid for the treatment of patients with central nervous system infection. Ann Pharmacother. 2007 Feb;41(2):296-308. Epub 2007 Feb 6. Review. PubMed PMID: 17284501.
3)

Martín-Gandul C, Mayorga-Buiza MJ, Castillo-Ojeda E, Gómez-Gómez MJ, Rivero-Garvía M, Gil-Navarro MV, Márquez-Rivas FJ, Jiménez-Mejías ME. Sequential antimicrobial treatment with linezolid for neurosurgical infections: efficacy, safety and cost study. Acta Neurochir (Wien). 2016 Oct;158(10):1837-43. doi: 10.1007/s00701-016-2915-0. Epub 2016 Aug 13. PubMed PMID: 27520361.

Fungal Infections of the Central Nervous System Pathogens, Diagnosis, and Management

Fungal Infections of the Central Nervous System Pathogens, Diagnosis, and Management

by Mehmet Turgut (Editor), Sundaram Challa (Editor), Ali Akhaddar (Editor)

List Price:$199.99

Buy

This book provides comprehensive information on fungal infections of the central nervous system (CNS). Fungal infections are still a major public health challenge for most of the developing world and even for developed countries due to the rising numbers of immune compromised patients, refugee movements, and international travel. Although fungal infections involving the CNS are not particularly common, when they do occur, the results can be devastating in spite of recent advances and currently available therapies. Further, over the past several years, the incidence of these infections has seen a steep rise among immunodeficient patients. In this context, aggressive surgery remains the mainstay of management, but conservative antifungal drug treatment complemented by aggressive surgical debridement may be necessary. Yet the optimal management approach to fungal infections of the CNS remains controversial, owing to the limited individual experience and the variable clinical course of the conditions. Addressing that problem, this comprehensive book offers the ideal resource for neurosurgeons, neurologists and other specialists working with infectious diseases.

Ventriculostomy related infection risk factors

Ventriculostomy related infection risk factors

A total of 15 supposed influencing factors includes: age, age & sex interactions, coinfection, catheter insertion outside the hospital, catheter type, CSF leakage, CSF sampling frequency, diagnosis, duration of catheterization, ICP > 20 mmHg, irrigation, multiple catheter, neurosurgical operation, reduced CSF glucose at catheter insertion and sex 1).


In a large series of patients, ventriculostomy related infection (VRI) was associated with a longer ICU stay, but its presence did not influence survival. A longer duration of ventriculostomy catheter monitoring in patients with VRI might be due to an increased volume of drained CSF during infection. Risk factors associated with VRIs are SAH, IVH, craniotomy, and coinfection 2).


A retrospective cohort study strengthens a growing body of works suggesting the importance of inoculation of skin flora as a critical risk factor in ventriculostomy related infections, underscoring the importance of drain changes only when clinically indicated and, that as soon as clinically permitted, catheters should be removed 3).


Associated with a longer ICU stay, but its presence did not influence survival. A longer duration of ventriculostomy catheter monitoring in patients with VAI might be due to an increased volume of drained CSF during infection. Risk factors associated with VAIs are subarachnoid hemorrhage(SAH), intraventricular hemorrhage IVH, craniotomy, and coinfection 4).

The risk of infection increases with increasing duration of catheterization and with repeated insertions. The use of local antibiotic irrigation or systemic antibiotics does not appear to reduce the risk of VAI. Routine surveillance cultures of CSF were no more likely to detect infection than cultures obtained when clinically indicated. These findings need to be considered in infection control policies addressing this important issue 5).


An increased risk of infection has been observed in patients with subarachnoid or intraventricular hemorrhage, in patients with concurrent systemic infections as well as with longer duration of catheterization, cerebrospinal (CSF) leakage, and frequent manipulation of the EVD system 6) 7) 8).

Many studies have been conducted to identify risk factors of EVD-related infections. However, none of these risk factors could be confirmed in a cohort of patients. Furthermore they not show any difference in infection rates between patients who were placed in single- or multibed rooms, respectively 9).


Interestingly no risk factor for EVD-related infection could be identified in a retrospective single center study 10).

References

1)

Sorinola A, Buki A, Sandor J, Czeiter E. Risk Factors of External Ventricular Drain Infection: Proposing a Model for Future Studies. Front Neurol. 2019 Mar 15;10:226. doi: 10.3389/fneur.2019.00226. eCollection 2019. Review. PubMed PMID: 30930840; PubMed Central PMCID: PMC6428739.
2)

Bota DP, Lefranc F, Vilallobos HR, Brimioulle S, Vincent JL. Ventriculostomy-related infections in critically ill patients: a 6-year experience. J Neurosurg. 2005 Sep;103(3):468-72. PubMed PMID: 16235679.
3)

Katzir M, Lefkowitz JJ, Ben-Reuven D, Fuchs SJ, Hussein K, Sviri G. Decreasing external ventricular drain related infection rates with duration-independent, clinically indicated criteria for drain revision: A retrospective study. World Neurosurg. 2019 Aug 2. pii: S1878-8750(19)32121-7. doi: 10.1016/j.wneu.2019.07.205. [Epub ahead of print] PubMed PMID: 31382072.
4)

Bota DP, Lefranc F, Vilallobos HR, Brimioulle S, Vincent JL. Ventriculostomy-related infections in critically ill patients: a 6-year experience. J Neurosurg. 2005 Sep;103(3):468-72. PubMed PMID: 16235679.
5)

Arabi Y, Memish ZA, Balkhy HH, Francis C, Ferayan A, Al Shimemeri A, Almuneef MA. Ventriculostomy-associated infections: incidence and risk factors. Am J Infect Control. 2005 Apr;33(3):137-43. PubMed PMID: 15798667.
6)

Camacho E. F., Boszczowski Í., Basso M., Jeng B. C. P., Freire M. P., Guimarães T., Teixeira M. J., Costa S. F. Infection rate and risk factors associated with infections related to external ventricular drain. Infection. 2011;39(1):47–51. doi: 10.1007/s15010-010-0073-5.
7)

Kim J.-H., Desai N. S., Ricci J., Stieg P. E., Rosengart A. J., Hrtl R., Fraser J. F. Factors contributing to ventriculostomy infection. World Neurosurgery. 2012;77(1):135–140. doi: 10.1016/j.wneu.2011.04.017.
8)

Mayhall C. G., Archer N. H., Lamb V. A., Spadora A. C., Baggett J. W., Ward J. D., Narayan R. K. Ventriculostomy-related infections. A positive epidemiologic study. The New England Journal of Medicine. 1984;310(9):553–559. doi: 10.1056/NEJM198403013100903.
9)

Hagel S, Bruns T, Pletz MW, Engel C, Kalff R, Ewald C. External Ventricular Drain Infections: Risk Factors and Outcome. Interdiscip Perspect Infect Dis. 2014;2014:708531. Epub 2014 Nov 17. PubMed PMID: 25484896; PubMed Central PMCID: PMC4251652.
10)

Hagel S, Bruns T, Pletz MW, Engel C, Kalff R, Ewald C. External ventricular drain infections: risk factors and outcome. Interdiscip Perspect Infect Dis. 2014;2014:708531. doi: 10.1155/2014/708531. Epub 2014 Nov 17. PubMed PMID: 25484896; PubMed Central PMCID: PMC4251652.
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