Question:

What is the mechanism by which the fluoroquinolone antibiotics (e.g., ciprofloxacin, gemifloxacin, levofloxacin, moxifloxacin) can increase a patient's risk for developing a seizure or worsen epilepsy?

Answer:

The fluoroquinolone antibiotics are commonly used in clinical practice for a number of conditions but most frequently are used to treat upper and lower respiratory tract infections (e.g., bacterial sinusitis, nosocomial and community acquired pneumonia), prostatitis and urinary tract infections (both pyelonephritis and cystitis).^1-5  Several fluoroquinolone antibiotics have been taken off the market, but those that remain include, ciprofloxacin (Cipro®), gemifloxacin (Factive®), levofloxacin (Levaquin®), moxifloxacin (Avelox®), norfloxacin (Noroxin®), and ofloxacin (Floxin®).^1-5  Many of the above medical conditions can occur in a wide group of patients including those patients already taking medications that have been associated with causing seizures or in patients who already have an underlying seizure disorder or epilepsy.  While the overall incidence of central nervous system (CNS) side effects is low (1-4%), convulsive seizures have been reported in patients taking fluoroquinolones, especially if they are also taking nonsteroidal antiinflammatory drugs (NSAIDs).^6-8   As a result, the Food and Drug Administration (FDA) approved product package inserts currently warn healthcare providers about the risk for various CNS side effects (tremors, restlessness, anxiety, confusion, paranoia, insomnia, etc.) as well as an increased risk for seizures.^1-5,8

What effect do fluoroquinolone antibiotics have on the CNS to cause these side effects?
Considering all of the signs and symptoms mentioned in the manufacturers' warnings, the answer is multifactorial.  One contributing factor is the ability of fluoroquinolones to modulate the activity of the gamma-aminobutyric acid (GABA)-A receptor.^9-11  GABA-A receptors, found in the CNS, are most commonly made up of a combination of 5 protein subunits (2-alpha, 2-beta, and 1-gamma).^12,13  When present, the major inhibitory neurotransmitter GABA will bind to the alpha subunit on the GABA-A receptor and allow negatively charged extracellular chloride ions to diffuse into the neuron.^12,13  This results in the neuron being slightly hyperpolarized (or have a greater negative resting membrane) and thus being inhibited from some stimulation.^12,13  Glutamate is the main excitatory neurotransmitter in the CNS and thus has the opposite effect of GABA.  Therefore, the CNS maintains a balance between the excitatory and inhibitory activities of the neurons by creating a balance between these two systems.  However, when the binding of GABA to the GABA-A receptor is blocked the neuron may become less polarized (i.e. the threshold for neuronal activation is decreased thereby increasing the risk of that neuron to fire an action potential resulting in the propagation of neuronal impulses in the brain, especially if glutamate is present).  If these neuronal impulses occur at too great a rate or are not coordinated for balanced brain activity within the hippocampus and cortex regions of the brain, then increased CNS stimulation can occur.  This can manifest clinically as the symptoms mentioned previously, including seizures.  In addition, changes in activity-dependent plasticity in these regions of the brain can also predispose patients to seizures.  Fluoroquinolones are known to modulate the biologic activity of these two CNS controls.^9-11,14 

As it relates to the influence of GABA-A receptor activity, the fluoroquinolones are known to non-competitively inhibit the activity of the neurotransmitter, GABA, thus decreasing the activation threshold needed for that neuron to generate an impulse.⁹  It does appear that each of the fluoroquinolone antibiotics do this to a different degree with ofloxacin and levofloxacin being the least likely and norfloxacin, enoxacin and ciprofloxacin being more likely to inhibit GABA-A receptor function.^9,14

What role do NSAIDs have in the predisposition for developing seizures while also taking a fluoroquinolone antibiotic?
Interestingly, the presence of an NSAID or NSAID metabolite can significantly augment this effect and result in an even greater inhibition of GABA-A receptor activity.  It is, however, important to note that majority of this effect is related to an NSAID that is only available outside of the United States called fenbufen (Afiancen®, Bifene®, Cincopal®, Cinopal®, Lederfen®, Reugast®).^9-11,14  It appears that the metabolite of fenbufen, 4-biphenylacetic acid (BPAA), augments the ability of the fluoroquinolone to inhibit GABA binding to the GABA-A receptor.^9-11,14  It is important to note that BPPA itself does not inhibit GABA binding to the GABA-A receptor, but rather when BPAA and the fluoroquinolone come in close proximity they interact in such a way that it results in the ability of the fluoroquinolone antibiotic to inhibit GABA binding to a greater degree than by itself.  It is possible that the interaction between a fluoroquinolone antibiotic and BPAA causes some other biologic effect that influences the activity of the GABA-A receptor.  In fact, there is some evidence that some fluoroquinolones (mainly enoxacin and norfloxacin) can increase the activity of nuclear activator protein 1 (AP-1) DNA- and cyclic AMP responsive elements (CRE)-binding activities in both the hippocampus and cerebral cortex.¹⁴  It has been suggested that increased activity of AP-1 mediated gene expression is important for activity-dependent plasticity in these regions of the brain and thus contribute to the increased risk for seizures.¹⁴  Even though fenbufen has been the main NSAID implicated in this adverse drug reaction, other NSAIDs such as indomethacin, ketoprofen, naproxen, ibuprofen have also been shown to augment fluoroquinolone induced GABA-A receptor inhibition in animal studies.⁹ 

While the data most strongly implicate certain fluoroquinolone antibiotics and NSAIDs, CNS side effects and seizures have been reported with many of the fluoroquinolones, including the ones currently on the market.^1-5  This is the reason that the product package inserts for the fluoroquinolone antibiotics not only list the above as potential side effects, but also describe the drug interaction with NSAIDs.^1-5  As such, until further evidence suggests otherwise, it would be prudent, especially from a medical legal perspective, for healthcare providers to avoid the use of fluoroquinolones with or without NSAIDs in patients who are at greater risk for seizures (e.g., history of epilepsy, severe cerebral arteriosclerosis) or those with a lower seizure threshold (e.g., patients on medications known to do this, renal dysfunction). 

(PW Pharmacother Newsl 2009;1(33):1-5.) ©2009 Pharmacology Weekly, Inc.