Guidance for Antibiotic Use in Myasthenia Gravis

All prescribers should be aware of the range of possible adverse effects associated with antibiotics. Though perhaps less well recognized than other adverse effects, various neurotoxicities — including seizure, optic neuropathy, encephalopathy, peripheral neuropathy, and exacerbation of myasthenia gravis (MG) — may result from antibiotic use.¹ This risk is increased in older patients, patients with impaired renal function, and patients with preexisting neurologic conditions.¹

Safe prescribing practices can be particularly difficult in patients with MG due to myriad medications that can interfere with neuromuscular transmission. While the mechanism by which drugs affect the neuromuscular junction varies, medications commonly known to cause drug-induced neuromuscular blockade include certain antibiotics, anticonvulsants such as phenytoin, antirheumatic drugs such as penicillamine and chloroquine, cardiovascular drugs such as calcium channel blockers and β-blockers, and psychotropic drugs such as lithium.^1,2 

The relationship between antibiotic use and exacerbation of MG is particularly complicated as MG flares can also be triggered by infection and surgery.¹ This requires clinicians to balance prompt and adequate treatment of infection with the risk that some antibiotics can aggravate the condition. This article is focused on a practical review of the relationship between MG, infection, and the possibility for certain antibiotics to cause clinical deterioration in patients with the condition.

Infection and Myasthenia Gravis

The potential for antibiotics to unmask or worsen MG is particularly significant given that patients with MG may be predisposed to acquiring infectious diseases. Possible factors that could contribute to an increased risk for infection include an autoimmune disease process, muscle weakness, and possible immunosuppressive treatments.³ Most patients with MG require immunosuppressive medication such as prednisone, azathioprine, mycophenolate mofetil, or rituximab.⁴ 

Additionally, approximately 15% of patients with MG have a second autoimmune disease such as lupus or rheumatoid arthritis, which may also require immunosuppressive medications.⁴ Currently available immunosuppressive medications used in MG broadly suppress immune reactivity, including the ability to react against microbes.³ While the exact increase in rate of infection is not known, it is estimated that the risk for infection while on corticosteroids increases 20% to 50%.³

Baseline respiratory muscle weakness from MG can predispose patients to infection in the lower respiratory tract.³ Conversely, infection is a common cause of exacerbation of MG that may lead to complications such as respiratory weakness and failure.³ This underscores the importance of adequate disease control and treatment of infection in patients with MG. Neurology and primary care providers should educate patients about the risk of infection leading to possible worsening of their MG. 

Although vaccines are generally recommended for patients with MG, live-attenuated vaccines should be avoided in those who are immunosuppressed, and vaccination should be avoided during an acute exacerbation.³ If vaccination with live-attenuated doses is necessary, it is ideal to do so before immunosuppressive therapy is started.³

Antibiotics and Myasthenia Gravis

As infection can cause a myasthenic exacerbation or crisis, it should be treated swiftly while taking care to avoid additional patient harm. Certain antibiotic agents should be avoided, if possible, in patients with MG. Antibiotics can impede neuromuscular transmission by blocking the release of acetylcholine presynaptically, competitively binding with the acetylcholine receptors postsynaptically, or acting at both sites in combination.^2,5 

Most notably, aminoglycosides, fluoroquinolones, macrolides, and telithromycin may interfere with neuromuscular transmission and lead to worsening muscle weakness. When this occurs, clinical deterioration typically begins within 24 to 48 hours after the new antibiotic is begun; however, there have been cases in which clinical decline occurs within minutes.^2,5,6 

The severity of the reaction also varies, with patients experiencing mild to severe weakness requiring differing levels of clinical intervention.^2,6 Additionally, patients with no known history of MG have been reported to first experience myasthenic weakness after antibiotic use.^2,6 Therefore, all providers should be aware that in addition to the potential for antibiotics to aggravate existing MG, antibiotics may also unmask undiagnosed MG.

Aminoglycosides

Aminoglycosides affect neuromuscular transmission by both inhibiting acetylcholine release presynaptically and blocking the acetylcholine receptor postsynaptically.² This class of antibiotics has been associated with aggravating pre-existing MG and postoperative respiratory distress.² Though this association was originally reported in streptomycin, further studies have led neuromuscular blockade by aminoglycosides to be considered a class effect.⁷ There have been documented cases of aminoglycosides precipitating a myasthenic reaction in the absence of concomitant infection, as well as cases implicating aminoglycosides in causing intensive care unit-related weakness in patients who do not have MG.⁵ In addition to neuromuscular blockade, aminoglycosides are also associated with other neurotoxic effects including ototoxicity, peripheral neuropathy, and encephalopathy.⁷

Fluoroquinolones

Fluoroquinolones have been associated with unmasking and worsening MG.² In 2011, the US Food and Drug Administration (FDA) added a boxed warning to fluoroquinolones related to the risk of worsening symptoms for patients with MG.⁸ The same year, a review of case reports and FDA adverse event reports concluded that fluoroquinolones may result in significant MG exacerbations as a class effect.⁹ 

The exact mechanism by which fluoroquinolones affect neuromuscular transmission is not known; however, theories include inhibition of acetylcholine release presynaptically and a direct toxic effect on the acetylcholine channel.^5,9 Fluoroquinolones do share structural similarities with other medications that impair neuromuscular transmission such as quinine.⁹ Other neurotoxicities associated with fluoroquinolones include seizures, encephalopathy, myoclonus, and psychosis.⁷

Macrolides and Telithromycin

Macrolides should also be avoided, if possible, in patients with MG. There have been cases of erythromycin both aggravating and unmasking MG.^2,5 Similar reports exist for clarithromycin and azithromycin.^5,10 Telithromycin, a ketolide antibiotic closely related to erythromycin, carries an FDA black box warning stating it should not be used in patients with MG as it has been associated with respiratory failure.^5,6 It is believed that telithromycin affects the neuromuscular junction peripherally, and while the exact target is unknown, cases of worsening myasthenic weakness related to telithromycin use have been described in both patients with acetylcholine and muscle-specific-receptor tyrosine kinase antibodies.⁶ 

In an article examining cases in which telithromycin was implicated in exacerbating or unmasking MG, although patients had concomitant respiratory infection, the temporal relationship between administering the medication and symptom worsening seemed to support telithromycin use as the main causative factor in patient deterioration.⁶ Of note, telithromycin was discontinued in the United States in 2016.¹¹

Other Antibiotics

Other antibiotics have been associated with precipitating a worsening of myasthenic symptoms. Clindamycin and tetracycline have been linked to cases of aggravated MG, but less data exist about these relationships.^1,2,5 Case reports exist of the β-lactam class of antibiotics possibly causing worsening of myasthenic symptoms.^1,5 Furthermore, polymyxin has been associated with neuromuscular blockade.⁷ As there are multiple factors that have an impact on the clinical course of a patient with MG and infection, these patients should be closely monitored when any new antibiotics are initiated.

Patient Management Considerations

Given the possible interactions and adverse effects described above, treating infection in patients with MG without causing further harm can be difficult. For example, while typical first-line treatment for a patient with community-acquired pneumonia (CAP) may consist of a fluoroquinolone or a β-lactam plus a macrolide, both fluoroquinolones and macrolides can be especially problematic for patients with MG. One case study reported success using tigecycline to treat a patient with MG, CAP, penicillin allergy, and previous MG exacerbation following moxifloxacin use.⁵

Providers need to obtain a thorough history, including allergies and any previous MG flares with antibiotic use, and consider the full clinical picture before selecting an antibiotic. Medications used around the time of surgery should be given careful consideration as patients with MG may be sensitive to certain types of anesthesia and muscle relaxants; aminoglycosides should be avoided as they are associated with postoperative respiratory depression.²

If a patient with MG being treated with antibiotics begins to decompensate, it may be difficult to determine whether the worsening is caused by the MG, acute infection, or medication. In the event the antibiotic is implicated as the causative factor for the deterioration, it may be necessary to discontinue the treatment and begin a non-neurotoxic antibiotic.⁷ 

Symptoms typically resolve hours to days after the antibiotic is discontinued, but additional therapy may be required, particularly in the case of bulbar or respiratory weakness.^2,5 Patients may respond to anticholinesterase drugs such as neostigmine or pyridostigmine; however, resulting cholinergic side effects may include increased secretions, which can complicate clinical management.² Treatment with intravenous immunoglobulin and plasma exchange should be considered for severe exacerbations of MG. Respiratory function should be closely monitored, and hospital admission may be required.

Conclusion

Certain classes of antibiotics have been associated with aggravating or unmasking MG and should ideally be avoided in patients with the condition. Primary care and emergency room providers are often the first line of care when treating patients with MG and infection. Given the complex relationship between infection and MG, all providers should be aware of the possible effects of antibiotic treatment on MG and promptly treat infection while avoiding patient harm. Proper patient education and counseling before starting medications that may affect the neuromuscular junction are essential. As many medications can affect neuromuscular transmission and it may be impractical to avoid use of all of these medications, clinicians should closely monitor patients with MG who are started on new medications.

Carrie Smith Nold, MPA, PA-C, is assistant professor and didactic coordinator in the Physician Assistant Program at the Philadelphia College of Osteopathic Medicine, Georgia Campus.

References

1. Bhattacharyya S, Darby R, Berkowitz AL. Antibiotic-induced neurotoxicity. Curr Infect Dis Resp. 2014;16(12):448.
2. Barrons RW. Drug-induced neuromuscular blockade and myasthenia gravis. Pharmacotherapy. 1997;17(6):1220-1232.
3. Gilhus NE, Romi F, Hong Y, Skeie GO. Myasthenia gravis and infectious disease. J Neurol. 2018;265(6):1251-1258.
4. Gilhus NE. Myasthenia gravis. N Engl J Med. 2016;375(26):2570-2581.
5. Vak Berkel MA, Twilla JD, England BS. Emergency department management of a myasthenia gravis patient with community-acquired pneumonia: does initial antibiotic choice lead to cure or crisis? J Emerg Med. 2016;50(2):281-285.
6. Perrot X, Bernard N, Vial C, et al. Myasthenia gravis exacerbation or unmasking associated with telithromycin treatment. Neurology. 2006;67(12):2256-2258.
7. Grill MF, Maganti RK. Neurotoxic effects associated with antibiotic use: management considerations. Br J Clin Pharmacol. 2011;72(3):381-393.
8. FDA updates warning for fluoroquinolone antibiotics [news release]. US Food and Drug Administration website. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm513183.htm. Updated August 15, 2016. Accessed November 7, 2018.
9. Jones SC, Sorbello A, Boucher RM. Fluoroquinolone-associated myasthenia gravis exacerbation: evaluation of postmarketing reports from the US FDA adverse event reporting system and a literature review. Drug Saf. 2011;34(10):839-847.
10. Pradhan S, Pardasani V, Ramteke K. Azithromycin-induced myasthenic crisis: reversibility with calcium gluconate [letter]. Neurol India. 2009;57(3):352-353.
11. Ernst D. Antibiotic with history of safety issues discontinued. Monthly Prescribing Reference website. https://www.empr.com/news/antibiotic-with-history-of-safety-issues-discontinued/article/482628. March 11, 2016. Accessed November 7, 2018.

This article originally appeared on Clinical Advisor