Antibiotics in myasthenia gravis: Thinking outside the black box

Abstract

Physicians need to make the best decisions for their patients care, but this is not always straightforward. The balance between the benefits and risks of a drug needs to be determined by the best evidence and may change with time. However, it can be difficult to collect information about drug risks in rare diseases, particularly when the side effects of the drugs may also be rare. Drug warning systems tend to be based on case reports without analytical observational studies and on occasions may prevent patients benefitting from a potentially useful drug without solid evidence. This is the discussion put forward in the article Pharmacosafety of Fluoroquinolone and Macrolide Antibiotics in the Clinical Care of Patients with Myasthenia Gravis by Nguyen et al. in this issue, in which a cohort of 1556 myasthenia gravis (MG) patients were retrospectively reviewed, assessing the proportion who worsened after being prescribed macrolides or fluoroquinolones, antibiotics thought to be associated with worsening of MG, compared with the proportion showing a similar outcome after receiving beta-lactam antibiotics, not believed to be associated with worsening of MG. The article calculated the odds for acute hospital admission due to worsening of MG, within 15, 30, and 90 days after the antibiotics were prescribed. This cohort tests the validity of the existing black box warning for the use of fluoroquinolones in MG and analyzes the arguments that suggest weaknesses in the United States Food and Drug Administration (FDA) mechanism that designates a warning box (black box), based mainly on case reports of serious side effects. The FDA Adverse Event Reporting System is based on two sources of information: voluntary reports of adverse drug reactions by health-care professionals to the FDA ́s Safety and Adverse Event Reporting Program (MedWatch) and mandatory reports from pharmaceutical companies of adverse events that have been spontaneously reported to the companies by physicians and pharmacists. Once a warning signal is detected, a specially trained evaluator from the FDA initiates an investigation into the potential severity of the safety issue of the drug in question and all the aspects related to its safety for use in human subjects. Risk assessments are undertaken, and a “black box” warning may be given, a risk management program may be implemented, and at times the decision may be made to withdraw the drug from the market. A black box warning does not represent a formal contraindication, but it means that the medication should be used with caution in specific medical conditions. Despite relying mostly on case reports, the black box system has been a dependable method for protecting the population from serious adverse events, identified through post-marketing surveillance. About 10% of drugs accepted by the FDA end up with a black box warning or have to be withdrawn from the market, the most common reason being the presence of hepatotoxicity that had not been identified in the randomized trials leading to the approval of the drug. In these cases, it does not seem appropriate to wait for the results of more sophisticated epidemiological evaluations to decide whether to issue a “black box” or not for a drug in which serious adverse events have been reported. However, there needs to be balance between this system based on case reports and the slower process of building more solid evidence about the causal relationship between drugs and alleged harms. Cohort studies such as that published in this issue can give us more insight and can contribute to adverse event reporting systems. MG is an autoimmune disease of the neuromuscular junction caused by antibodies that attack postsynaptic structures, leading to impaired neuromuscular transmission, which in turn induces localized or generalized weakness and fatigue of skeletal muscles. Specific involvement of the bulbar and respiratory muscles can lead to sudden worsening of MG or myasthenic crisis, a life-threatening condition. Myasthenic crisis can be induced by several factors, such as emotional stress, infections, surgical interventions, hasty reduction of immunosuppression, rapid introduction of high-dose corticosteroids, and numerous medications, possibly including several antibiotics. Myasthenic crisis occurs during the lifetime of one out of five MG patients. Special efforts have been made to identify those drugs that may be involved in triggering these crises. Lists of these drugs have been included in guidelines produced by professional organizations and patient-oriented associations, and warnings have been issued by medicine regulatory agencies, in attempts to minimize the use of these drugs in those with MG. The Myasthenia Gravis Foundation of America (MGFA) in 2013 appointed a task force to develop treatment guidance on MG, resulting in an International Consensus Guidance for the Management of MG in 2016 and an update in 2020. The guideline states “Many drugs are associated with worsening of MG. However reported association do not necessarily mean these medications should never be prescribed in MG”. Fluoroquinolones and macrolides are both included in these guidelines in tables of “Drugs to avoid or use with caution in MG”. However, these antibiotics are often required in the treatment of serious infections. MG patients are susceptible to serious infections Abbreviations: MG, myasthenia gravis; FDA, Food and Drug Administration; MGFA, Myasthenia Gravis Foundation of America. Received: 3 May 2021 Revised: 29 May 2021 Accepted: 31 May 2021