levofloxacin induced seizures
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PHARMACOVIGILANCE CASE PRESENTATION
LEVOFLOXACIN INDUCED
SEIZURES
DR. PRANESH PAWASKAR
FYR
DEPT. OF PHARMACOLOGY
L.T.M.M.C., SION, MUMBAI 400022
2
COURSE OF REACTION
4th April 2016
Mild Fever, Malaise, Nausea, Abdominal pain in central quadrant
Fever went on increasing, Vomiting started initially 1-2 episodes per day
8th April 2016
Fever increasingly becoming high grade, Appearing in spikes, Pain in all over
abdomen, Vomiting increased to 7-8 episodes per day.
4
COURSE OF REACTION
On Same Day Patient Came To Our Institute
He Got Admitted In Our Medicine Ward no. 6
Patient work up started
5
GENERAL EXAMINATION
Temperature
39.9˚ C
Without Chills
With Malaise
Vomiting
Non Bilious
7-8 Times Per Day
Conscious
In Time Place And Person
6
SYSTEMIC EXAMINATION
R.S.
Respiratory Sounds
Normal
C.V.S.
S1 S2 Normal, No
Murmur
C.N.S.
Mild Drowsiness, Oriented, Reflexes
Normal8
SYSTEMIC EXAMINATION
ON PER ABDOMINAL EXAMINATION
1. Pain All Over Abdomen.
2. Pain On Deep Palpation.
3. No Organomegaly.
4. No Engorged Veins.
9
TREATMENT GIVEN TO PATIENT
At Our Institute Patient Was Given
Inj. Ceftriaxone (1 gm) i.v. TDS
Inj. Pantoprazole (40 mg) i.v. BD
Inj. Ondansetrone (4 mg) i.v. TDS
Inj . Paracetamol 5ml (100mg/ml) i.v. TDS
Patient Condition Did Not Improve
10
COURSE OF REACTION
9TH APRIL 2016
Patient suspected As Having Sepsis Shifted To MICU on the same day
Patient was added with LEVOFLOXACIN (500mg) i.v. OD on same day
Other medications continued…
11
COURSE OF REACTION
Within next 10 minutes of starting of i.v. levofloxacin patient lost
consciousness and had a seizure episode…
Patient’s Family reported seizure activity consisting of approximately
30 s of upper-extremity tonic-clonic contractions and loss of bowel
control…
Suspecting levofloxacin as a culprit it was immediately stopped. Rest all
medications were continued…12
COURSE OF REACTION
Patient improved on the same day from seizures, no further seizure activity noted
ADR reported on 10th April 2016 to us.
Levofloxacin replaced by Inj. Amikacin 1gm/d BD
Patient recovered from sepsis on 20th April 2016.
and discharged on same day.13
INVESTIGATIONS
14
Parameters 8 April 2016 9 April 2016 Normal Range
WBC 19800…..(Neutrophils 86%)
13000 …. (Neutrophils 70%)
4300 -10800/mcL
Hb 9.4 g/dl 9.5 g/dl 12-15 g/dl
Sr. Na 133 mEq/L 136 mEq/L 135-145 mEq/L
Sr. Ca 8.7 mg/dl 9.0 mg/dl 9 -11 mg/dl
Sr. Mg 1.7 mg/dl 1.8mg/dl 1.7 – 2.2 mg/dl
RBS 98 mg/dl 105 mg/dl 80-140 mg/dl
DIFFERENTIAL DIAGNOSIS
15
Seizur
e
Epilepti
c
Idiopathi
cSecondar
y
Epilepsy
Non-
Epileptic
Febrile
Metaboli
c
Head
traumaMeningit
is/Infecti
onDrugs
/Toxins
DISCUSSION
1. Patient do not give any prior history of Seizure Disorder, hence patient
getting Idiopathic And Secondary Seizures are ruled out.
2. Possibility of Febrile Seizures can be ruled out because patient had
body temperatures of up to 39.9°C without associated convulsions on
several occasions before treatment with levofloxacin was initiated.
3. Hypoglycaemia can be ruled out because on the day of admission and
the day of reaction both occasions the Random Blood Sugar was within
Normal Range.
4. Sr. Na levels were slightly deranged (133mEq/L) on the day of
admission but on the day of reaction were normal (136mEq/L) while for
seizure to develop a level much below (125 mEq/L) is required.16
DISCUSSION
5. Sr. Mg levels (1.7mg/dl) are also on both days within normal range so can not
be the cause of seizure.
6. Sr. Ca levels were also normal on day of reaction. (9.0 mg/dl)
7. No history of Head Trauma Or Accident given by patient.
8. No signs and symptoms of CNS infection like throbbing headache, neck
stiffness etc. given by patient so Meningitis can be ruled out.
9. No History Of Any Poison Consumption.
10. Seizure Potential Of All Fluoroquinolones Is Well Known Also The Seizures
Occurred Within 10 Min. Of Starting Of Levofloxacin I.V. 17
A
SERIOUSNESS OF REACTION :
Reaction was SERIOUS as it prolonged hospitalisation.
OUTCOME :
Patient RECOVERED after stopping of drug.
DIAGNOSIS :
LEVOFLOXACIN INDUCED SEIZURES
18
CAUSALITY ASSESSMENT
According to WHO CAUSALITY assessment scale …..
PROBABLEBecause…
A) REASONABLE DRUG-EVENT TEMPORAL RELATION.
B) UNLIKELY CAUSED BY OTHER DRUGS/DISEASE.
C) DE-CHALLENGE RESPONSE POSITIVE.
19
HOW DO THEY INDUCE SEIZURES ?
1. Seizures have been reported following spinal injections of
Tetracaine, a local anaesthetic.
2. Monoamine Oxidase Inhibitors decrease the reuptake of
monoamines, increase the brain monoamine levels, and decrease the
threshold for seizures.
3. Dopamine-blocking drugs (Antipsychotics And Antidepressants)
enhance seizures.
4. Antidepressants also block the seizure-inhibiting effects of GABA
by antagonizing the GABA receptor.
5. Antidepressants are potent inhibitors of chloride influx into the
neurons, whereas anticonvulsant agents such as diazepam enhance it.
22
HOW DO THEY INDUCE SEIZURES ?
1. Chloroquine inhibits glutamate dehydrogenase activity and reduces
the concentration of inhibitory neurotransmitter GABA.
2. A nonspecific effect on centrally located neurons, related to its
membrane stabilizing effects by Beta Blockers.
3. A possible mechanism of epileptogenic effect is via the blocking of
GABA's effect when the Beta-lactam ring binds to GABA receptors.
4. Caffeine, Cocaine, Theophylline are simulants of CNS by which they
decrease threshold of seizures.
5. Anti Diabetic Agents cause epilepsy by causing hypoglycaemia.23
HOW DO THEY INDUCE SEIZURES ?
1. Salicylate uncouples oxidative phosphorylation from electron
transport and leads to depletion of body stores of glucose.
2. Generalized seizures occur in 1% to 4% of patients during
Interferon-alpha Therapy. Possible mechanism is exposure of the
cerebral cortex to interferon-alpha, possibly through a breach of
the blood-brain barrier.
3. Morphine can induce seizures in high doses in neonates and infants.
This may be due to an immature blood-brain barrier allowing a
greater penetration of the drug into the central nervous system
24
HOW DO THEY INDUCE SEIZURES ?
1. The epileptogenic effect of Radiologic Contrast Media seems to
result from direct action of these substances on the cerebral
cortex.
2. Diuretics, Proton Pump Inhibitors, Antimicrobials, and Anticancer
drugs, may cause hypomagnesemia, potentially leading to seizures
3. Pethidine is metabolized to Norpethidine, which has half the
analgesic potency of the parent compound but is twice as active as a
convulsant25
PATIENT RELATED RISK FACTORS
1. Family history of epilepsy or previous seizures.
2. Brain tumours, stroke, AIDS encephalopathy.
3. Breach of blood-brain barrier such as occurs in head injury and
meningitis
4. Psychiatric disorders
5. AGE of patient : The elderly and infants.
6. Systemic diseases affecting drug metabolism and excretion,
particularly those affecting renal and hepatic functions
7. High grade fever.26
FLUOROQUINOLONES
These are fluorinated quinolones.
The first quinolone, nalidixic acid, was isolated as a by-product of the
synthesis of chloroquine.
The quinolone antibiotics target bacterial DNA gyrase and
topoisomerase IV.
The Fluoroquinolones Are Potent Bactericidal Agents Against E. Coli
And Various Species Of Salmonella, Shigella, Enterobacter,
Campylobacter, And Neisseria.
Therapeutic Uses In – UTI, Prostatitis, STD, G.I. Infections, Resp.
Tract Infections, Bone Joint Soft Tissue Infections.28
LEVOFLOXACIN
Class – Fluroquinolone.
Origin – Quinolone. ( Nalidixic Acid… A Biproduct Of Chloroquine
Synthesis) .
Process – Fluorination.
Introduction – 1980s.
Generation – 2nd Generation Fluroquinolone.
Primary Activity – Gram Negative Bacteria29
SEIZURE INDUCING ACTION OF FLUOROQUINOLONES
Seizure inducing potential of fluoroquinolones is most probably
attributed to GABA inhibiting action of all fluoroquinolones.
Plasma concentration of THEOPHYLLINE, WARFARIN is increased
by fluoroquinolones due to inhibition of metabolism CNS toxicity can
occur due to concurrent use of Fluoroquinolone.
NSAIDs may enhance CNS toxicity seizures are reported. It acts
by enhancing GABA inhibiting action of Fluoroquinolones.
32
CONCLUSION The currently marketed quinolones are well tolerated, with safety profiles similar to
those of other antimicrobial classes.
Rare adverse effects attributed to some members of the quinolone family. More
likely to occur in select “susceptible” populations.
In some cases, the therapeutic value offered by a quinolone may outweigh its
potential risks.
Antibiotics clearly saves the life.
Poorly prescribing put patient into unnecessary risk, adverse reactions and
development of resistance to organisms Every time antibiotic is prescribed make
sure indication , dose and duration is proper.
Adjust or stop antibiotic if necessary.
Be specific to use of antibiotics.
33
REFERENCES
1. Carbon C (2001) comparison of side effects of levofloxacin versus other fluoroquinolones.
Chemotherapy 47(suppl 3):9–14 discussion 44–18
2. Christie MJ, wong K, ting RH, tam PY, sikaneta TG (2005) generalized seizure and toxic epidermal
necrolysis following levofloxacin exposure. Ann pharmacother 39(5):953–955
3. Kushner JM, peckman HJ, snyder CR (2001) seizures associated with fluoroquinolones. Ann
pharmacother 35(10):1194–1198
4. Bird SB, orr PG, mazzola JL, brush DE, boyer EW (2005) levofloxacin-related seizure activity in a
patient with alzheimer’s disease: assessment of potential risk factors. J clin psychopharmacol
25(3):287–288
5. Akahane K, kato M, takayama S (1993) involvement of inhibitory and excitatory neurotransmitters in
levofloxacin- and ciprofloxacin-induced convulsions in mice. 44(9)87–288
6. Levofloxacin, an optical isomer of ofloxacin, has attenuated epileptogenic activity in mice and inhibitory potency in gaba
receptor binding. Chemotherapy 40(6):412–417
7. Segev S, rehavi M, rubinstein E (1988) quinolones, theophylline, and diclofenac interactions with the
gamma-aminobutyric acid receptor. Antimicrob agents chemother 32(11):1624–162634
REFERENCES
8. Hori S, kizu J, kawamura M (2003) effects of anti-inflammatory drugs on convulsant activity of quinolones:
a comparative study of drug interaction between quinolones and anti-inflammatory drugs. J infect
chemother 9(4):314–320.
9. Shrivastava MP, makde SD, paranjpe BD (1997) interactionof ciprofloxacin with diclofenac and paracetamol
in relation to it’s epileptogenic effect. Indian J physiol pharmacol 41 (2):164–166.
10. Fuller MA, sajatovic M (2004) drug information handbook for psychiatry. Lexi-comp’s, Canada.
11. Association between oral fluoroquinolones and seizures: A self-controlled case series study neurology :86
may 03 (2016) 1708-1715.
12. Safety Concerns With Fluoroquinolone Ann Pharmacother Nov 2007 41: 1859-1866.
13. Safety Of Newer Parenteral Antibiotics Clinical infectious diseases, sept 01 2005 41: s293-s305.
14. Generalized Seizure And Toxic Epidermal Necrolysis Following Levofloxacin Exposure, Ann Pharmacother
Nov (2010) 39: 953-955.
15. Bachmann KA, Lewis JD, Fuller MA Et Al (2004) Drug Interactions Hand Book. Lexi-comp’s, Canada35
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