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.

Radiation necrosis treatment

Radiation necrosis treatment

Radiation necrosis (RN) will be increasingly encountered due to the widespread use of SRS. Symptomatic RN can cause significant morbidity and should be managed pro-actively. There is no single modality which can reliably distinguish RN from recurrent tumor, and a multi-modal approach is often required. For patients with symptomatic RN, oral corticosteroid therapy and bevacizumab are both effective. A minority of patients, with an unclear diagnosis, or refractory symptoms, will require surgical resection. As RN proves to be a challenging condition to diagnose and manage, risk factor mitigation becomes important in clinical decision making 1).


Using the internal database for pharmaceutical products, all patients who received BEV in the University of Munich were identified. Only patients who received BEV as symptomatic treatment for radiation necrosis were included. Patient characteristics, symptoms before, during, and after treatment, and the use of dexamethasone were evaluated using medical reports and systematic internal documentation. The symptoms were graded using CTCAE version 5.0 for general neurological symptoms. Symptoms were graded directly before each cycle and after the treatment (approximately 6 weeks). Additionally, the daily steroid dose was collected at these timepoints. Patients who either improved in symptoms, received less dexamethasone after treatment, or both were considered to have a benefit from the treatment.

Twenty-one patients who received BEV due to radiation necrosis were identified. For 10 patients (47.6%) symptoms improved and 11 patients (52.4%) remained clinically stable during the treatment. In 14 patients (66.7%) the dexamethasone dose could be reduced during therapy, 5 patients (23.8%) received the same dose of dexamethasone before and after the treatment, and 2 patients (9.5%) received a higher dose at the end of the treatment. According to this analysis, overall, 19 patients (90.5%) benefited from the treatment with BEV. No severe adverse effects were reported.

BEV might be an effective and safe therapeutic option for patients with radiation necrosis as a complication after cranial radiation therapy. Patients seem to benefit from this treatment by improving symptomatically or through reduction of dexamethasone 2).


Perez-Torres et al. validated the VEGF specificity by comparing the therapeutic efficacy of anti-VEGF with non-specific isotype control antibody. Additionally, they found that VEGF over-expression and radionecrosis developed simultaneously, which precludes preventative anti-VEGF treatment 3).

References

1)

Vellayappan B, Tan CL, Yong C, Khor LK, Koh WY, Yeo TT, Detsky J, Lo S, Sahgal A. Diagnosis and Management of Radiation Necrosis in Patients With Brain Metastases. Front Oncol. 2018 Sep 28;8:395. doi: 10.3389/fonc.2018.00395. eCollection 2018. Review. PubMed PMID: 30324090; PubMed Central PMCID: PMC6172328.
2)

Bodensohn R, Hadi I, Fleischmann DF, Corradini S, Thon N, Rauch J, Belka C, Niyazi M. Bevacizumab as a treatment option for radiation necrosis after cranial radiation therapy: a retrospective monocentric analysis. Strahlenther Onkol. 2019 Oct 4. doi: 10.1007/s00066-019-01521-x. [Epub ahead of print] PubMed PMID: 31586230.
3)

Perez-Torres CJ, Yuan L, Schmidt RE, Rich KM, Drzymala RE, Hallahan DE, Ackerman JJ, Garbow JR. Specificity of vascular endothelial growth factor treatment for radiation necrosis. Radiother Oncol. 2015 Sep 12. pii: S0167-8140(15)00462-4. doi: 10.1016/j.radonc.2015.09.004. [Epub ahead of print] PubMed PMID: 26376163.

Oral anticoagulant

Oral anticoagulant

Oral anticoagulation was first established in 1941 by Karl Paul Link, who discovered dicumarol 1).

Novel oral anticoagulants (NOAs) which directly inhibit thrombin (dabigatran) or factor Xa (rivaroxaban and apixaban) have recently been developed.

The purpose of a study was the evaluation of the reporting quality of RCTs for novel oral anticoagulants (NOACs) in venous thromboembolism (VTE) based on the CONSORT statement. MEDLINE was meticulously searched, while quoted references by retrieved RCTs were manually screened. The primary objective was to establish the mean CONSORT compliance of RCTs for NOACs in VTE. Secondary objectives were the calculation of compliance per CONSORT item and the investigation for probable determining factors with regards to the reporting quality of RCTs. Reporting above 70% of the items was defined as adequate compliance to the CONSORT statement. A total of 83 articles were considered eligible. Mean adherence to the CONSORT statement was 61.84%, standard deviation (SD) = 18.72. Among retrieved studies, 35 (42.17%) reported above 70% of the items, while 48 (57.83%) described less than 70% of the items. Inter-rater agreement was satisfactory (Cohen’s kappa ≥ 0.75). Items with respect to randomization and blinding were principally underreported, whereas the rest of the methodological features and results were more sufficiently reported. Logistic regression failed to demonstrate significant effect for any of the factors investigated. Impact factor [odds ratio (OR) = 1.347, 95% confidence interval (CI) (0.994, 1.826), p = 0.055], number of authors [OR = 1.277, 95% CI (0.975, 1.672), p = 0.076] and presentation of participant flow-diagram [OR = 55.358, 95% CI (0.914, 3351.765), p = 0.055], came closer to significance. Exploratory analysis revealed significant, strong, positive correlation between abstract and article adherence to the CONSORT guidelines (r = 0.851, p < 0.001). Reporting quality of RCTs for NOACs in VTE is moderate. A superior reporting quality is desirable, especially relating to randomization and blinding 2)

Vitamin K oral anticoagulant

Non vitamin K oral anticoagulant

Complications

Patients with minor and moderate associated bleeding can be treated with supportive care and general hemostatic measures. Nonspecific reversal agents (eg, prothrombin complex concentrate, activated prothrombin complex concentrate) are of unproven benefit, carry a risk of thrombosis, and should be reserved for severe bleeding. Specific reversal agents, such as idarucizumab (a monoclonal antibody fragment that binds dabigatran) and andexanet alfa (a recombinant factor Xa variant that binds factor Xa inhibitors but lacks coagulant activity), are in clinical development 3).

References

1)

Campbell HA, Roberts WL, Smith WK, Link KP. Studies of the hemorrhagic sweet clover disease. I. The preparation of hemorrhagic concentrates. J Biol Chem. 1940;136:47–55.
2)

Liampas I, Chlinos A, Siokas V, Brotis A, Dardiotis E. Assessment of the reporting quality of RCTs for novel oral anticoagulants in venous thromboembolic disease based on the CONSORT statement. J Thromb Thrombolysis. 2019 Aug 10. doi: 10.1007/s11239-019-01931-9. [Epub ahead of print] Review. PubMed PMID: 31401718.
3)

Cuker A, Siegal D. Monitoring and reversal of direct oral anticoagulants. Hematology Am Soc Hematol Educ Program. 2015 Dec 5;2015(1):117-24. doi: 10.1182/asheducation-2015.1.117. PubMed PMID: 26637710.
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