What is the risk of myasthenia gravis associated with azithromycin? Based on the risk should it be avoided as an agent used for meningococcal prophylaxis in patients receiving complement inhibitors?

Comment by InpharmD Researcher

Available literature suggests that azithromycin is associated with a risk of myasthenia gravis (MG) exacerbation and, therefore, may not be an ideal agent for meningococcal prophylaxis in patients with MG who are receiving complement inhibitors. Evidence from case reports, retrospective studies, and reviews indicate that azithromycin can impair neuromuscular transmission and has been linked to worsening MG, although a retrospective analysis found that exacerbations occurred in fewer than 2.5% of treatment episodes. For meningococcal prophylaxis in patients receiving complement inhibitors, penicillin VK is generally recommended as the preferred first-line agent, with azithromycin reserved for patients with penicillin allergy. Given the potential for MG worsening and the availability of effective alternatives, azithromycin should be generally avoided in patients with MG unless other prophylactic options are contraindicated or not tolerated. In situations where azithromycin is being considered, the decision should be individualized and made in collaboration with a healthcare provider, taking into account the severity of MG, the risk of meningococcal disease, available alternative agents, and the patient’s overall clinical status.

A comprehensive literature review identified 1 clinical guideline, 3 tertiary sources, and 4 primary sources (including case reports) relevant to this inquiry.

Background

The Centers for Disease Control and Prevention (CDC) clinical guidance for managing meningococcal disease risk in patients receiving complement inhibitors does not provide specific recommendations for the choice of medication for meningitis prophylaxis in these patients. The panel recommends administering both MenACWY and MenB vaccines to individuals receiving a complement inhibitor. Ideally, these meningococcal vaccines should be administered at least 2 weeks before starting the complement inhibitor. However, CDC data suggest that meningococcal vaccines may offer incomplete protection against invasive meningococcal disease in individuals receiving the C5 complement inhibitor eculizumab, with a similar risk likely for those on ravulizumab. Most identified infections in eculizumab patients were caused by non-groupable Neisseria meningitidis, which typically does not lead to invasive disease in individuals with normal immune systems. It has been suggested that, in addition to vaccination, healthcare providers consider antimicrobial prophylaxis for complement inhibitor recipients to potentially reduce the risk of meningococcal disease; however, a specific regimen was not provided. [1]

A 2019 critical review examined the infectious complications associated with the treatment of non-malignant immune-mediated hematologic disorders. For meningococcal disease prevention, the Advisory Committee on Immunization Practices (ACIP) advises eculizumab patients to receive MenACWY and MenB vaccines at least two weeks before starting therapy, unless treatment delays pose greater risks. Antimicrobial prophylaxis remains a consideration despite vaccination because of the residual risk of disease. The Infectious Disease Society of America (IDSA) and other health agencies suggest antibiotic prophylaxis with penicillin during eculizumab treatment. U.S. guidelines recommend first-line prophylaxis with oral penicillin V (500 mg twice daily), though ciprofloxacin, rifampin, and azithromycin are alternatives. Macrolides are suitable for penicillin-allergic patients. The FDA advises antibiotic prophylaxis for at least two weeks after vaccination if eculizumab precedes it or earlier if immediate therapy is required, to minimize meningococcal infection risks. Long-term penicillin prophylaxis is generally regarded as safe. [2], [3]

Similarly, a 2021 international consensus update states vaccination against Neisseria meningitidis is essential before initiating treatment with eculizumab, with both the meningococcal conjugate MenACWY and serogroup B (MenB) being required at least two weeks prior. If eculizumab treatment begins before the two-week post-vaccination period, it's recommended to maintain antibiotic coverage for at least four weeks. The first-line chemoprophylaxis usually involves penicillin VK at 250-500 mg every 12 hours. For patients allergic to penicillin, alternatives include erythromycin (500 mg twice daily), azithromycin (500 mg daily), or ciprofloxacin (500 mg daily). However, fluoroquinolones and macrolides can exacerbate MG, complicating chemoprophylaxis in penicillin-allergic individuals. In such cases, seeking consultation from an infectious disease specialist may be necessary to determine the most appropriate course of action. [2], [3]

A review of drugs that induce or cause deterioration of myasthenia gravis (MG) notes that macrolide antibiotics, such as azithromycin, can impair neuromuscular transmission, possibly at a pre-synaptic level, and should be avoided in MG patients if there is another available alternative. This recommendation is based on multiple studies indicating an increased risk of MG exacerbation associated with azithromycin. In one retrospective study of 212 MG exacerbations, azithromycin was the most common medication associated with deterioration of MG. In separate reports, patients have been found to develop severe MG after both intravenous and oral azithromycin exposure. Additionally, exacerbation of MG has also been reported with erythromycin. [4]

References: [1] Centers for Disease Control and Prevention. Clinical Guidance for Managing Meningococcal Disease Risk in Patients Receiving Complement Inhibitor Therapy. Accessed June 25, 2026. https://www.cdc.gov/meningococcal/hcp/clinical-guidance/complement-inhibitor.html
[2] Malpica L, van Duin D, Moll S. Preventing infectious complications when treating non-malignant immune-mediated hematologic disorders. Am J Hematol. 2019;94:1396–1412. doi:10.1002/ajh.25642
[3] Narayanaswami P, Sanders DB, Wolfe G, et al. International Consensus Guidance for Management of Myasthenia Gravis: 2020 Update. Neurology. 2021;96(3):114-122. doi:10.1212/WNL.0000000000011124
[4] Sheikh S, Alvi U, Soliven B, Rezania K. Drugs That Induce or Cause Deterioration of Myasthenia Gravis: An Update. J Clin Med. 2021;10(7):1537. Published 2021 Apr 6. doi:10.3390/jcm10071537
Relevant Prescribing Information

Warnings and Precautions [1]

Exacerbation of Myasthenia Gravis:
Exacerbations of symptoms of myasthenia gravis and new onset of myasthenic syndrome have been reported in patients receiving azithromycin therapy.

References: [1] Azithromycin monohydrate injection. Prescribing information. Fresenius Kabi USA, LLC; October 2024.
Literature Review

A search of the published medical literature revealed 4 studies investigating the researchable question:

What is the risk of myasthenia gravis associated with azithromycin? Based on the risk should it be avoided as an agent used for meningococcal prophylaxis in patients receiving complement inhibitors?

Level of evidence

B - One high-quality study or multiple studies with limitations  Read more→


Please see Tables 1-4 for your response.

Factors associated with acute exacerbations of myasthenia gravis
Design

Retrospective, single-center, cohort study

N= 127
Objective To characterize factors contributing to myasthenia gravis (MG) exacerbations with an emphasis on the impact of infections and medications to be avoided or used cautiously in patients with MG (MAUC-MG) on emergency department (ED) visits, hospitalizations, and admission durations
Study Groups All patients (N= 127)
Inclusion Criteria Patients with the International Classification of Diseases, Ninth Revision, code for MG (358.00). Confirmation of MG diagnosis was determined by fulfillment of one of the following criteria: (1) seropositivity (anti-acetylcholine receptors or anti-muscle specific kinase), (2) significant decrement (>10%) on low frequency repetitive nerve stimulation or increased jitter with single fiber electromyogram, (3) long standing documented history of MG, referred from an outside MG center, responsive to treatment, but without electronic records of initial diag nostic tests.
Exclusion Criteria Patients with an unestablished MG diagnosis, one-time consultation, or less than one follow-up in the neurology clinic annually
Methods

This study utilized retrospective electronic medical record (EMR) reviews. The retrieved data focused on documented date, presumed cause, and severity of exac erbation, along with subsequent ED visit, hospital admission, and admission duration. Exacerbations were categorized into 9 classes including infections and MAUC-MG: unknown, MAUC-MG, vaccine-preventable infections (VPI), vaccine non-preventable infections (VNPI), medical noncompliance, inadequate treatment (not on target/therapeutic doses), procedure related, social stress, and diagnostic error. MAUG-MG medications were those listed in the Myasthenia Gravis Foundation of America (MGFA) list.  Statistical analysis was performed using logistic regression and Poisson regression. 

The therapeutic doses for managing MG include a range of medications frequently utilized in treatment regimens. Pyridostigmine is used in dosages ranging from 40-600 mg daily, while prednisone is administered at 5-100 mg daily. Azathioprine is commonly dosed at 50 mg, and mycophenolate mofetil is administered at 1-2 g daily. Rituximab is used in doses of 0.5-1 g, whereas methotrexate is given at 10-20 mg per week. Cyclosporine is provided at 100 mg twice daily, and tacrolimus is prescribed at 3 mg daily. Cyclophosphamide is dosed between 1-5 mg/kg monthly. Intravenous immune globulin (IVIG) is administered at 2 g/kg at specified intervals. These dosing regimens reflect the broad spectrum of therapeutic agents and strategies employed in addressing the challenges of MG treatment.
Duration 2011 to 2016
Outcome Measures

Primary: Factors contributing to MG exacerbations

Secondary: Impact of infections and MAUC-MG on ED visits, hospitalizations, and admission durations
Baseline Characteristics  

All patients

(N= 127)
Total MG exacerbations, n 212
Mean age, years 64.9 (18.8)
Mean disease duration, years 10.3 (10.7)
Male sex, n (%) 58 (45.6%)
Caucasian, n (%) 119 (93.7%)
African American, n (%) 8 (6.3%)
MGFA class I at diagnosis, n (%) 66 (52%)
MGFA class II at diagnosis, n (%) 22 (17%)
MGFA class IIa at diagnosis, n (%) 14 (11%)
MGFA class IIb at diagnosis, n (%) 19 (15%)
MGFA class III at diagnosis, n (%) 4 (3%)
MGFA class IV at diagnosis, n (%) 2 (2%)
MGFA class V at diagnosis, n (%) 0 (0%)
Results  

Patients with

exacerbation

(n=77) 

Patients with no

exacerbations

(n=50)

Seropositive, n (%)

53 (69%)

27 (54%)

Thymectomy, n (%)

16 (21%)

7 (14%)

Total MAUC-MG prescribed

119

67

Zithromax

  

21 (18%)

  

10 (15%)

Fluoroquinolones

  

29 (24%)

  

20 (30%)

Beta-blocker

 45 (38%) 16 (24%)

MAUC-MG were factors in 19% of the recorded exacerbations. Of the 127 patients reviewed, 84 had at least one documented MAUC-MG. Beta-blockers were most often prescribed (61), followed by fluoroquinolones (49) and azithromycin (31). 

The most common medication associated with an exacerbation was azithromycin, followed by fluoroquinolones and beta blockers. 
Adverse Events Infections and medications that may worsen MG are frequently factors in acute MG exacerbations needing urgent medical attention. 
Study Author Conclusions Infections and cautioned medications are frequently factors in acute MG exacerbations needing urgent medical attention and warrant caution.
Critique The study was limited by its retrospective nature and lack of adequate documentation of some patients’ MG exacerbations. These limitations may have contributed to the large number of exacerbations in the unknown category. Furthermore, some patients in this study did not have electronic documentation of their diagnostic testing. The findings were also limited to a single academic center and may not be generalizable. Although an association existed between certain medications and exacerbations, the study's retrospective nature did not allow us to exclude confounding factors such as underlying diseases other than MG to show direct causality. 
References:
[1] Gummi RR, Kukulka NA, Deroche CB, Govindarajan R. Factors associated with acute exacerbations of myasthenia gravis. Muscle & Nerve. 2019;60(6):693-699. doi:10.1002/mus.26689.

 

Exacerbation of pseudoparalytic myasthenia gravis following azithromycin (Zithromax)

Design

 Case Report 

Case presentation

 A 25-year-old female patient experienced severe aggravation of myasthenia gravis. An hour after taking a 500 mg dose of azithromycin as treatment for an influenza syndrome, the patient developed significant leg weakness and respiratory distress, attributed to respiratory muscle failure. This rapid deterioration necessitated hospitalization where the patient was admitted in a comatose state and required intubation and mechanical ventilation for 6 days. Notably, several years prior the patient had a similar reaction to parenteral administration of erythromycin. 

Study Author Conclusions

 Azithromycin can exacerbate myasthenia gravis and should be used with caution in these patients. Azithromycin should be added to the list of drugs to be used with caution in patients with myasthenia gravis.
References:
[1] Cadisch R, Streit E, Hartmann K. Exazerbation einer Myasthenia gravis pseudoparalytica nach Azithromycin (Zithromax) [Exacerbation of pseudoparalytic myasthenia gravis following azithromycin (Zithromax)]. Schweiz Med Wochenschr. 1996;126(8):308-310.
Frequency and Severity of Myasthenia Gravis Exacerbations Associated With the Use of Ciprofloxacin, Levofloxacin, and Azithromycin
Design

Retrospective, single-center, cohort study

N= 365
Objective To investigate the association between ciprofloxacin, levofloxacin, azithromycin, and myasthenia gravis (MG) exacerbation
Study Groups

Ciprofloxacin (n= 339)

Levofloxacin (n= 187)

Azithromycin (n= 392)

Amoxicillin (n= 603)
Inclusion Criteria Confirmed diagnosis of MG; use of ciprofloxacin, levofloxacin, or azithromycin; availability of clinical information for at least 6 months prior to and 3 months after antibiotic use
Exclusion Criteria MG patients with a single visit without follow-up; antibiotic use prior to MG diagnosis
Methods Antibiotic usage was scored using the Adverse Drug Reactions Probability Scale. A mixed-effects logistic regression model evaluated predictors of antibiotic-associated MG exacerbation (AAMGE).
Duration 2002 to 2022
Outcome Measures

Primary: Frequency of MG exacerbation following antibiotic use

Secondary: Predictors of AAMGE
Baseline Characteristics  

All patients

(N= 365)
Female sex, n (%) 179 (49.0%)
Caucasian, n (%) 304 (83.3%)
Generalized MG, n (%) 275 (75.3%)
Prior thymectomy, n (%) 96 (26.3%)
Diabetes, n (%) 106 (29.0%)
Results   Episodes MG Exacerbation, n (%)
Mean age at time of antibiotic use, years 62.4 ± 16.8 59.6 ± 16.1
Ciprofloxacin 339 8 (2.4%)
Levofloxacin 187 3 (1.6%)
Azithromycin 392 6 (1.5%)
Amoxicillin 603 8 (1.3%)
Adverse Events MG exacerbation was associated with MG-related hospitalization or ED visit in the preceding 6 months, female sex, and diabetes. Infection was the most common confounder in exacerbations (88.2%). 
Study Author Conclusions Usage of ciprofloxacin, levofloxacin, or azithromycin was associated with MG exacerbation in less than 2.5% of episodes. Underlying infection may play a role in AAMGE. As AAMGE can be severe, decision-making regarding the use of these antibiotics should be individualized.
Critique The study's retrospective design and single-center nature may limit generalizability. The small number of exacerbation cases could hinder the robustness of conclusions. The study did not account for the severity of infections, which could influence AAMGE outcomes.
References:
[1] [1] Uysal SP, Li Y, Thompson NR, Li Y. Frequency and severity of myasthenia gravis exacerbations associated with the use of ciprofloxacin, levofloxacin, and azithromycin. Muscle Nerve. 2025;71(6):1063-1071. doi:10.1002/mus.28410.

 

Azithromycin-induced myasthenic crisis: reversibility with calcium gluconate

Design

 Case report

Case presentation

A 13-year-old boy presented to the emergency department in India with acute onset painless difficulty in swallowing with drooling of saliva for 2 days and generalized weakness for 1 day. Similar symptoms had occurred twice in the previous year, and, on both occasions, he responded adequately to intravenous (IV) corticosteroids. Examination revealed bilateral ptosis without other extraocular weakness, pharyngeal weakness with a nasal change in voice, neck weakness, and proximal limb weakness. There were no sensory signs and deep tendon reflexes were normal. The patient also had tonsillitis with bilateral tonsilar hypertrophy, and chest X-ray and computed tomography revealed pneumonia  of the left lower lobe without mediastinal enlargement.

A conditional diagnosis of myasthenia gravis (MG) was made, and a neostigmine test was performed with an immediate response. The patient also received low-dose oral steroids (prednisolone 10 mg/day) and pyridostigmine (60 mg orally 3 times daily) for 2 days, and a single IV dose of azithromycin 500 mg was given for the tonsilitis and pneumonia. Within 10 minutes of receiving the azithromycin dose, the patient developed respiratory distress and became cyanotic and unresponsive. He was immediately intubated and IV calcium gluconate was given. Ten minutes later he regained consciousness and started flexing his neck and moving his limbs against gravity. The patient was extubated by the next hospital day. Over the next 10 days, the dose of prednisolone was gradually increased while pyridostigmine was continued. The ptosis and extraocular paresis improved almost completely, the nasal twang in speech decreased, and the swallowing improved. At the time of discharge, the boy was able to walk and perform his self-care activities.

Study Author Conclusions

 This case report advocates for pharmacovigilance post-drug marketing and suggests that, in cases of acute worsening of MG symptoms due to antibiotic administration, IV calcium gluconate might be a beneficial empirical treatment. The authors emphasized the need for further studies to substantiate these findings, given that this was a single case report. The conclusion serves as a call to action for healthcare professionals to consider the neuromuscular impacts of antibiotics and to explore alternative therapeutic interventions when faced with similar clinical scenarios.
References:
[1] [1] Pradhan S, Pardasani V, Ramteke K. Azithromycin-induced myasthenic crisis: reversibility with calcium gluconate. Neurol India. 2009 May-Jun;57(3):352-3. doi:10.4103/0028-3886.53270