Should I treat my patient with Covid-19 with ivermectin?

Despite its potential antiviral activity,1 there is insufficient data at this time to recommend either for or against the use of ivermectin for the treatment of Covid-19, per NIH Covid-19 guidelines.2 This conclusion is based on lack of robust, adequately powered and designed clinical trials.The Infectious Diseases Society of America (IDSA) recommends against its use in ambulatory or hospitalized patients with Covid-19 (mild to moderate or severe, respectively) except in clinical trials.

Although some studies (published or preprint) have reported benefits of ivermectin (eg, shorter time to resolution of disease or viral clearance, greater reduction in inflammatory markers, and lower mortality rates) in Covid-19, others have found either no benefit or worsening of disease with ivermectin therapy.2-6

Unfortunately, methodological problems have plagued many of these studies.1 For example, a randomized-controlled preprint study from Egypt reported clinical improvement and decreased mortality in Covid-19 patients treated with ivermectin.  Noteworthy,  the ivermectin group also received hydroxychloroquine plus a “standard therapy”, defined in the study as azithromycin, vitamin C, zinc, lactoferrin and acetylcysteine.This preprint article has since been withdrawn due to allegations of plagiarism and data manipulation, including duplicate patient records and patients whose records indicated that they had died before the study’s start date (Nature, 12 Aug 2021).

A retrospective study from Bangladesh involving hospitalized patients with Covid-19,  reported lower mortality in those receiving only 1 dose of ivermectin (12 mg) within 24 h of admission.  However, 60% of the non-ivermectin group also received antibiotics, often for undefined “secondary infection” (vs 15% of ivermectin group)4, making it difficult to interpret the results.

In contrast, a randomized double-blind trial in mild Covid-19 failed to find any improvement in time to resolution of symptoms  after a 5-day course of Ivermectin. In a retrospective preprint study from Peru found significantly higher rates of death and/or ICU transfer among hospitalized patients treated with ivermectin or hydroxychloroquine+azithromycin.7

The plausibility of studies supporting treatment of Covid-19 with ivermectin has been further questioned because, despite its apparent antiviral activity in vitro,1 pharmacokinetic and pharmacodynamic studies suggest that doses up to 100 times higher than those approved for use in humans would be needed to achieve potentially effective plasma concentrations.2,8

Bonus Pearl: Did you know that ivermectin enhances the activity of GABA receptors, resulting in paralysis of somatic muscles, poor pharyngeal function and starvation of parasites and worms? 9 Fortunately, ivermectin’s affinity for parasite is 100 times more than for brain of mammals because of the blood brain barrier.

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References

  1. Lehrer S, Rheinstein PH. Ivermectin docks to the SARS-CoV-2 spike receptor-binding domain attached to ACE2. In vivo 2020;34:3023-6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652439/pdf/in_vivo-34-3023.pdf
  2. NIH. The Covid-19 treatment guidelines panel’s statement on the use of ivermectin for the treatment of COVID-19. Last updated Jan 14, 2021. https://www.covid19treatmentguidelines.nih.gov/statement-on-ivermectin/. Accessed January 18, 2021.
  3. Elgazzar A, Hany B, Abo Youssef S, et al. Efficacy and safety of ivermectin for treatment and prophylaxis of COVID-19 pandemic. Research Square Preprint 2020. https://assets.researchsquare.com/files/rs-100956/v2/39b225ad-5df4-4da7-9cbd-233bf26a0eb4.pdf
  4. Ahmed S, karim MM, Ross AG, et al. A five-day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness. International J Infect Dis 2021;103:214-16. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709596/
  5. Soto-Becerra P, Culquichicon C, Hurtado-Roca Y, et al. Real-world effectiveness of hydroxychloroquine, azithromycin, and ivermectin among hospitalized COVID-19 patients: results of a target trial emulation using observational data from a nationwide healthcare system in Peru. MedRxive 2020. https://www.medrxiv.org/content/10.1101/2020.10.06.20208066v3.full.pdf
  6. Chachar AZ, Khan KA, Asif M, et al. Effectiveness of ivermetctin in SARS-CoV-1/COVID-19 patients. International J Sciences 2020; 9:31-35. https://c19ivermectin.com/chachar.html
  7. Lopez-Medina E, Lopez P, Hurtado IC, et al. Effect of ivermectin on time to resolutoin of symptoms among adults with mild COVID-19. JAMA 202;325:1426-35.  https://jamanetwork.com/journals/jama/fullarticle/2777389
  8. Chaccour C, hammann F, Ramon-Garcia S, et al. Ivermectin and COVID-19: Keeping rigor in times of urgency. Am J Trop med hyg 2020;102:1156-7. https://pubmed.ncbi.nlm.nih.gov/32314704/  
  9. Kaur H, Shekhar N, Sharma S, et al. Ivermectin as a potential drug for treatment of COVID-19:an in-sync review with clinical and computational attributes. Pharmacological Reports. Published online January 3, 2021. Great review https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778723/pdf/43440_2020_Article_195.pdf

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis or its affiliate healthcare centers. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

Should I treat my patient with Covid-19 with ivermectin?

Is neurotoxicity caused by cefepime common?

The incidence of cefepime-induced neurotoxicity (CIN) has varied from 1% to 15%.1 Potential clinical manifestations of CIN include delirium, impaired level of consciousness, disorientation/agitation, myoclonus, non-convulsive status epilepticus, seizures, and aphasia.1  Many of these signs and symptoms (eg, delirium) are common among hospitalized patients.

Although renal dysfunction and inadequately adjusted dosages are often cited as risk factors, one-half of patients develop suspected CIN despite apparently proper adjustment for renal function.In addition,  several case reports of CIN have involved patients with normal renal function. 2  A study of 1120 patients receiving cefepime found epileptiform discharges in 14 cases, most having normal renal function.3 Of interest, in the same study, the prevalence of epileptiform discharges was 6-fold higher than that of meropenem!

Proposed mechanisms for CIN include its avidity for central nervous system GABA-A receptors (higher than that of many beta-lactam antibiotics) combined with its high concentration in brain tissue.1 Renal impairment, decreased protein binding, and increased organic acid accumulation can increase transfer of cefepime across the blood brain barrier from an expected 10% to up to 45% of its serum concentration, further contributing to its neurotoxicity.4

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 References

 

  1. Appa AA, Jain R, Rakita RM, et al. Characterizing cefepime neurotoxicity: a systematic review. Open Forum Infectious Diseases 2017 Oct 10;4(4):ofx170. doi: 10.1093/ofid/ofx170. eCollection 2017 Fall. https://www.ncbi.nlm.nih.gov/pubmed/29071284
  2. Meillier A, Rahimian D. Cefepime-induced encephalopathy with normal renal function. Oxford Medical Case Reports, 2016;6, 118-120. https://academic.oup.com/omcr/article/2016/6/118/2362353
  3. Naeije G, Lorent S, Vincent JL, et al. Continuous epileptiform discharges in patients treated with cefpime or meropenem Arch Neurol 2011;68:1303-7. https://www.ncbi.nlm.nih.gov/pubmed/21987544
  4. Payne LE, Gaganon DJ, Riker RR, et al. Cefepime-induced neurotoxicity: a systematic review. Critical Care 017;21:276. https://www.ncbi.nlm.nih.gov/pubmed/29137682

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

 

Is neurotoxicity caused by cefepime common?