The Journal of Emergency Medicine, Vol. -, No. -, pp.

1–5, 2015
Copyright Ó 2015 Elsevier Inc.
Printed in the USA. All rights reserved
0736-4679/$ - see front matter

http://dx.doi.org/10.1016/j.jemermed.2015.04.019

Selected Topics:
Neurological Emergencies

EMERGENCY DEPARTMENT MANAGEMENT OF A MYASTHENIA GRAVIS PATIENT

WITH COMMUNITY-ACQUIRED PNEUMONIA: DOES INITIAL ANTIBIOTIC CHOICE
LEAD TO CURE OR CRISIS?

Megan A. Van Berkel, PHARMD, BCPS,* Jennifer D. Twilla, PHARMD, BCPS,* and Bryan S. England, MD†
*Department of Pharmacy, Methodist Healthcare University Hospital, University of Tennessee Health Sciences Center, Memphis, Tennessee
and †Department of Emergency Medicine, Methodist Healthcare University Hospital, University of Tennessee Health Sciences Center,
Memphis, Tennessee
Reprint Address: Megan A. Van Berkel, PharmD, BCPS, Department of Pharmacy, Methodist Healthcare University Hospital, University of
Tennessee Health Sciences Center, 1265 Union Avenue, Memphis, TN 38104

, Abstract—Background: Myasthenic crisis is a rare, yet
serious condition that carries a 3% 8% mortality rate.
Although infection is a common cause of decompensation
in myasthenia gravis, several antibiotics classes have also
been associated with an exacerbation. Selecting antibiotics
can be a daunting clinical task and, if chosen inappropri-
ately, can carry significant deleterious consequences. Not
only do clinicians have to focus on treating the underlying
infection appropriately, but avoiding antibiotics that may
potentiate a myasthenic crisis is also vital. Case Report:
An 85-year-old female with a history of myasthenia
gravis presented to the emergency department (ED) with
increasing generalized weakness and shortness of breath.
Clinical work-up was consistent with a community-
acquired pneumonia (CAP) diagnosis. Her medical history
included a myasthenia gravis exacerbation shortly after
receiving moxifloxacin for CAP. After reviewing the
patient’s allergies, as well as potential antibiotic triggers,
the decision was made to treat with tigecycline. The patient
responded well to tigecycline therapy and was deemed stable
for discharge on day 4 of hospitalization. Why Should an
Emergency Physician Be Aware of This?: Evaluation of
the myasthenia gravis patient frequently originates in the
ED. It is important for clinicians to be able to distinguish be-
tween an underlying illness and a myasthenic crisis. In the
event of an infectious process causing clinical deterioration
in a myasthenia patient, optimal antibiotic selection be-
comes paramount. This patient case highlights the addition
of tigecycline to the armamentarium of therapies available
to treat myasthenia gravis patients presenting to the emer-
gency department with CAP. Ó 2015 Elsevier Inc.
, Keywords—myasthenia gravis; community-acquired
pneumonia; tigecycline; myasthenic crisis; infection
INTRODUCTION
Myasthenia gravis is an autoimmune disorder affecting
5 15 people per 100,000 (1). A myasthenic crisis occurs
when antibodies are formed against nicotinic acetylcho-
line receptors, causing the inability to sustain a neuro-
muscular contraction, and is often defined as acute
respiratory failure prompting intubation. Although
many patients with myasthenia are controlled with
acetylcholinesterase inhibitor medications, acute myas-
thenic crisis affects 15% 20% of patients with myas-
thenia and carries a 3% 8% mortality rate (1). A
myasthenic crisis can be precipitated by a number of fac-
tors; however, infection is responsible for 40% 70% of
crisis episodes (1,2). Additionally, several medications,
including antibiotics, have been implicated in causing a
myasthenic crisis. The unique situation of treating an
underlying infection without precipitating or worsening

RECEIVED: 20 November 2014; FINAL SUBMISSION RECEIVED: 30 March 2015;

ACCEPTED: 7 April 2015

1
2 M. A. Van Berkel et al.
a myasthenia crisis can be difficult to accomplish,
especially in a patient with medication allergies. We
present a case of success using tigecycline for treatment
of community-acquired pneumonia (CAP) in a patient
with myasthenia gravis and to provide a brief overview
of other antibiotics associated with the development of
myasthenic crises.
CASE REPORT
An 85-year-old female presented to the emergency
department (ED) with a 1-week history of shortness of
breath, cough, increasing generalized weakness, and
decreased appetite. The family of the patient reported
seeing increased work for breathing and inability to
expectorate. She was still able to complete activities of
daily living and did not complain of any arthralgias, my-
algias, or chills. Her medical history included myasthenia
gravis for 18 years; controlled, treated hypertension;
atrial fibrillation with a rapid ventricular response,
controlled and in normal sinus rhythm throughout hospi-
talization; congestive heart failure with an estimated ejec-
tion fraction of 35% 40% 6 months prior; pacemaker
placement; right breast cancer diagnosed 7 months prior,
undergoing treatment; colon cancer status post resection
14 years prior; and chronic hearing loss. The patient re-
ported an allergy to penicillin, but was unable to recall
the previous reaction to the medication. Per the patient’s
report, there was a family history of severe anaphylactic
reactions to penicillins. Our medical records did not
reveal a previous administration of a penicillin or cepha-
losporin. Her home medications included pyridostigmine
180 mg orally (p.o.) daily, azathioprine 50 mg p.o. daily,
prednisone 7.5 mg p.o. every other day, rivaroxaban
15 mg p.o. daily, digoxin 0.25 mg p.o. daily, aspirin
81 mg p.o. daily, omeprazole 40 mg p.o. daily, lisinopril
2.5 mg p.o. daily, carvedilol 3.125 mg twice daily, furose-
mide 20 mg p.o. daily, exemestine 25 mg p.o. daily, and
calcium carbonate 200 mg p.o. daily.
Upon physical examination, the patient was noted to
be mildly tachypnic at a respiratory rate of 22 breaths/
min with some use of accessory muscles, but was able
to speak in full sentences. Heart rate and blood pressure
were stable at 80 beats/min and 132/55 mm Hg, and the
patient had an oral temperature of 39.3 C. Her initial ox-
ygen saturation was 96% on room air, which increased to
100% on 2 L oxygen delivered via nasal cannula. On
auscultation, breath sounds were clear bilaterally without
wheezes, rales or rhonchi appreciated. A negative inspira-
tory force was obtained and felt to be adequate for the
patient to proceed without ventilator support (value not
documented). She had a 4 out of 5 strength in bilateral
upper and lower extremities and was able to do repetitive
motion without tiring. Her cranial nerves and sensation
were noted to be fully intact. Admission laboratory values
included a basic metabolic panel within normal limits,
pro brain natriuretic peptide of 1394 pg/mL (normal
range 0 125 pg/mL), and a white blood cell count of
10.7 thousand cells/mL with 9% bands. Blood cultures
obtained on admission were negative for growth, and a
urinalysis was not performed.
A chest x-ray study was initially obtained and was in-
terpreted by radiology as cardiomegaly with central
vascular congestion, an elevated left hemi-diaphragm
and trace pleural effusion in the left lung base. Given
these findings and an overall lack of clarity for a clinical
diagnosis, a chest computed tomography was obtained
showing ‘‘bibasilar airspace disease and consolidation,
pneumonia and atelectasis are primary differential
considerations,’’ and the decision was made to initiate
antibiotics for CAP. Tigecycline 100 mg i.v. bolus was
administered, followed by 50 mg every 12 h until the
patient was discharged on doxycycline. The patient
responded well to antibiotics and was stable for discharge
after 3.5 days.
It is notable that 6 months before this hospitalization,
the patient was admitted for a similar shortness of breath
episode due to myasthenia gravis and CAP. She presented
in a similar fashion with progressive worsening of short-
ness of breath and wheezing. The diagnostic differential
included both myasthenia gravis and CAP, and the patient
had initial doses of aztreonam, azithromycin, and moxi-
floxacin (two doses). Approximately 16 h after the second
administration of moxifoxacin, the patient required intu-
bation and was placed on mechanical ventilation. Addi-
tionally, the patient had a diffuse, morbilliform rash
involving the chest and abdomen, as well as some of
the upper extremities, and an erythematous face. At the
advisement of neurology, the patient underwent plasma-
pheresis and antibiotics were changed to tigecycline. It
was not possible to fully determine during chart review
whether the intubation was required secondary to wors-
ening myasthenic crisis (due to either infection or medi-
cation administration), acute pneumonia, or both. The
patient was extubated 7 days later and discharged to a
rehabilitation facility on hospital day 16.
DISCUSSION
We report a case of successful use of tigecycline for
presumed CAP in a patient with myasthenia gravis and
an antibiotic allergy. Given her history of potential
antibiotic-induced myasthenic crisis, antibiotic selection
in the ED for treatment of CAP (in accordance with cur-
rent Infectious Disease Society of America recommenda-
tions) and avoidance of trigger medications were of
crucial importance. Choice of antibiotic therapy in a
patient with myasthenia can be challenging, as many
Myasthenia Gravis and Community-Acquired Pneumonia
antibiotic medications are temporally associated with a
myasthenic crisis. However, evidence consists almost
exclusively of case report experiences, as randomized
controlled trials would largely be considered unethical.
Antibiotics commonly associated with precipitating a
myasthenic crisis include fluoroquinolones, aminoglyco-
sides, macrolides, and b-lactams (2–4). Although rare,
clindamycin and tetracyclines have also been
implicated, however, there is a paucity of data
regarding these medications, and they will not be
further discussed in this report (3,5). As mentioned
previously, initial antibiotic therapy is often chosen in
the ED, which may occur before a consultation with a
neurology or infectious disease specialist. For this
reason, it is increasingly important for the emergency
medicine physician to be aware of the potential reaction
between antibiotic medication administration and
precipitating a myasthenic crisis.
Antibiotics can have a presynaptic effect, by blocking
the release of acetylcholine, impairing the acetylcholine
receptor post synapse, or a combination of the two. Un-
fortunately, the mechanism of effect for many of the anti-
biotic classes that elicit a myasthenic response is largely
unknown. In reviewing the literature, myasthenia symp-
toms unfold within the first 24 48 h after initiation of
new therapy and resolve shortly after drug cessation.
Our patient received moxifloxacin during a previous
admission, which was thought to be a possible culprit in
inducing a myasthenic crisis. The ubiquitous use of fluoro-
quinolones sheds light on adverse effects that may be asso-
ciated with these agents. Although common adverse
reactions include gastrointestinal disturbances, headache,
and dizziness, less frequent reactions have now been eluci-
dated with increased medication exposure, including
myasthenic crisis. In 1988, Moore et al. described a
possible case of myasthenia gravis exacerbation which
was thought to be due to ciprofloxacin (6). Since this
time, numerous post-marketing and case reports have
been published regarding this adverse effect. Jones et al.
reviewed not only post-marketing reports, but case reports
published in the literature identifying 37 unique cases of
fluoroquinolone-induced myasthenia gravis exacerbations
(7). It was concluded from this review that myasthenia
gravis exacerbation with systemic fluoroquinolone use is
a class effect. Although not fully understood, it has been
theorized that fluoroquinolones attenuate neuromuscular
transmission through chelation of ionized calcium, thereby
inhibiting acetylcholine release presynaptically (8).
Conversely, it has also been surmised that fluoroquino-
lones exhibit a direct toxic effect on the acetylcholine
ion channel (9). As with the mechanism of injury associ-
ated with these medications, the exact incidence and risk
of myasthenic crisis after exposure to a fluoroquinolone
is not known. Despite lack of information in these areas,
3
most reports suggest a timeframe of 24 48 h for develop-
ment of symptoms, with dyspnea being the most
commonly reported event, followed by muscle weakness
and fatigue (7). In cases that reported a recovery time after
withdrawal of the medication, a rapid improvement was
typically seen. This recovery period ranged from immedi-
ate or within 8 h to days (7). Similarly, our patient devel-
oped respiratory symptoms that necessitated intubation
approximately 38 h after the first two doses of moxifloxa-
cin were administered, with a recovery period that lasted 1
week.
Antibiotics from the macrolide class have also been re-
ported to be associated with inducing a myasthenic crisis.
Erythromycin has been classified previously as having a
‘‘possible association’’ with inducing a crisis after two
case reports were reviewed implicating it as a potential
cause (10,11). The first report described an unmasking of
the disease in a pediatric patient; and the second report,
in an adult patient, identified an exacerbation that
resolved 3 h after administration. In the second case, the
patient experienced recurrent symptoms after a lower
dose was given in a rechallenge. Clarithromycin was also
described as unmasking the disease in a patient infected
with human immunodeficiency virus, also concomitantly
receiving fluconazole. Weakness resembling myasthenia
occurred after 2 days of therapy, but an electromyogram
was negative. The symptoms resolved 6 h after
discontinuing the drug and a rechallenge was not
performed (12). The timelines reported here are consistent
with those of the fluoroquinolones, with symptom onset
within 24 48 h and resolution shortly after cessation of
therapy.
Telithromycin is a ketolide antibiotic derived from the
erythromycin compound and the only medication with a
manufacturer and US Food and Drug Administration
(FDA) warning against use in patients with myasthenia
gravis (13–16). However, a review article closely
examining 8 patient cases of myasthenia exacerbations
postulated that most of these events could be explained
by a concomitant respiratory illness and not solely the
drug (17). The authors theorized that the mechanism for
causing an exacerbation is most likely peripherally,
because the drug does not readily cross the blood brain
barrier. Recent experiences have not been described, as
this medication is heavily avoided in the myasthenia
gravis population and the drug is no longer commonly
used due to the black box warning against severe hepato-
toxicity (16,18).
The b-lactam class of antibiotics may also have a
possible association with causing a myasthenic reaction.
Ampicillin has been implicated in two case reports
describing reactions in adult females in which pre-
existing symptoms of myasthenia gravis worsened
shortly after administration (19). One of the cases was
4 M. A. Van Berkel et al.
able to reproduce symptoms during a patient-consented
rechallenge. The same authors performed an animal
study, which did not produce any disease-related symp-
toms (19). The carbapenem combination imipenem-
cilastatin is also considered to have a possible association
with causing a worsening of outcomes after one case
report described a myasthenia gravis exacerbation occur-
ring 48 h after administration, along with symptom
improvement to edrophonium (4). The patient’s symp-
toms resolved fully 48 h later. Penicillins do not have a
prominent neuromuscular blocking property, so the
mechanism of action is largely unknown (19). To our
knowledge, cephalosporins have not yet been associated
with causing an exacerbation.
Finally, the class that is perhaps the most heavily asso-
ciated with precipitating a myasthenia reaction is amino-
glycosides. Aminoglycoside antibiotics affect both
impairment of acetylcholine release in the presynapse
and post-synaptic blockage of the acetylcholine receptor
(4,10,20). A letter to the British Medical Journal in 1964
first described symptom appearance in a patient with a
history of myasthenia gravis that was temporally
associated with the administration of streptomycin and
penicillin for appendicitis (21). Weeks after resolution
of the infection, streptomycin and penicillin were given
independently. Streptomycin elicited the same symptom-
atic response, and penicillin administration had no effect.
Another report the same year described five cases of
myasthenia symptoms after receiving 1 g streptomycin
(22). Upon review, only 1 patient had a concomitant
infection. McQuillen et al. described a case report of res-
piratory weakness after administration of kanamycin,
colistin, and sulfadiazine without response to edropho-
nium (23). In the same report, the authors further evalu-
ated 120 previously published cases of post-surgical
neuromuscular blockade in patients given neomycin,
streptomycin, kanamycin, polymyxin, and colistin. Clin-
ically relevant information was available for only 25 pa-
tients. The routes of administration of these medications
ranged from intramuscular, intrapleural, intravenous,
retroperitoneal, and others. The authors found that
many patients had concomitant administration of intrao-
perative paralytics (such as tubocurarine), and other vari-
ables that could have contributed to neuromuscular
weakness. A review article of medication administration
and myasthenia exacerbations stated that aminoglyco-
sides have definitely been associated with symptoms
and should be avoided (3). Muscle weakness due to ami-
noglycoside administration is not unique to myasthenia
patients, and aminoglycosides have been implicated in
causing intensive care unit (ICU) related weakness,
more recently referred to as critical illness polyneurop-
athy (24,25). Because of the high association of
aminoglycosides with both myasthenia and ICU-related
weakness, this class of medications should be highly
avoided in a myasthenia gravis patient unless clinically
necessary.
Limited options are available for antibiotic therapy in
patients with myasthenia gravis that have not been asso-
ciated with precipitating an exacerbation. Tigecycline, a
glycylcycline derivative of minocycline, is a bacteriostatic
antibiotic approved for use by the FDA in 2005 for compli-
cated skin and skin structure infections and for complicated
intra-abdominal infections (26). In 2009, tigecycline was
approved for use in CAP. Although not considered a mem-
ber of the tetracycline antibiotic class, tigecycline may
share some of the tetracycline class-associated adverse
effects. Although tetracyclines have been loosely asso-
ciated with causing a myasthenia crisis, to date there is
no report of tigecycline precipitating a myasthenic crisis
(Pfizer, personal communication. April 2014).
Current guidelines for the treatment of CAP, as well as
the Centers for Medicare and Medicaid Services require-
ments, recommend a respiratory fluoroquinolone or a
b-lactam plus a macrolide as initial inpatient therapy
(27,28). Given our patient’s comorbid condition and
allergy history, we concluded that this agent was the
most appropriate, despite the FDA warning regarding
tigecycline use and the risk for increased mortality in
patients treated for CAP (29). Although the increased
risk of mortality has been much debated, it is noted that
particularly high mortality rates were observed in patients
treated with tigecycline for ventilator-associated pneu-
monia and bacteremia at baseline (30,31). A recent
analysis of tigecycline use in the critically ill
population showed success rates of infection resolution
in patients receiving tigecycline were comparable to
patients receiving alternative therapy without significant
safety concerns (32). It is notable, however, that only
approximately 40% of the study patients were receiving
tigecycline as monotherapy.
WHY SHOULD AN EMERGENCY MEDICINE
PHYSICIAN BE AWARE OF THIS?
Many patients present with a complicated clinical picture,
where it is difficult to delineate if acute shortness of breath
is caused by either a myasthenic crisis or underlying
illness. In addition, clinical deterioration of the patient sta-
tus can be attributed to progression of the underlying acute
illness, myasthenia, or medications administered during
the hospital stay. When initiating new antibiotic medica-
tions in a patient with a history of myasthenia gravis, it
may be wise to observe the patient for the first 1 2 days
of therapy to determine the safety. If any symptoms of
myasthenia gravis exacerbation are noted in a patient
receiving any antibiotics, it is recommended to stop the
agent and use an alternative antibiotic if feasible. We
Myasthenia Gravis and Community-Acquired Pneumonia
report a case where tigecycline was successfully used to
treat CAP in a patient with myasthenia gravis and should
be considered as an alternative agent for future therapy.
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