The U.S. Food and Drug Administration is requiring safety labeling changes for a class of antibiotics called
fluoroquinolones to strengthen the warnings about the risks serious blood sugar
disturbances.
Taking fluoroquinolones, a class of antibiotics
commonly used to treat pneumonia and urinary tract infections, may increase the
risk of blood sugar disturbances in individuals with diabetes.
FDA-approved fluoroquinolones include
levofloxacin (Levaquin), ciprofloxacin (Cipro), ciprofloxacin extended-release
tablets, moxifloxacin (Avelox), ofloxacin, gemifloxacin (Factive) and
delafloxacin (Baxdela).
There are more than 60 generic
versions of fluoroquinolones.
The FDA first added a Boxed Warning
to fluoroquinolones in July 2008 for the increased risk of tendinitis
and tendon rupture.
In February 2011, the risk of
worsening symptoms for those with myasthenia gravis was added to the
Boxed Warning.
In August 2013, the agency
required updates to the labeling to describe the potential for irreversible
peripheral neuropathy (serious nerve damage).
In 2016, the FDA enhanced warnings about the
association of fluoroquinolones with disabling and potentially permanent side
effects involving tendons, muscles, joints, nerves and the central nervous
system.
Because the risk of these serious
side effects generally outweighs the benefits for patients with acute bacterial
sinusitis, acute bacterial exacerbation of chronic bronchitis and uncomplicated
urinary tract infections, the FDA determined that fluoroquinolones should be
reserved for use in patients with these conditions who have no alternative
treatment options.
TABLE.1 Antibiotics and hypergycemia/hypogycemia
|
Drugs
|
Cases of hyperglycemia per
1000 patient
|
|
Moxifloxacin
|
6.9 cases
|
|
Levofloxacin
|
3.9 cases
|
|
Macrolide
|
1.6 cases
|
|
Drugs
|
Cases of hyporglycemia per
1000 patient
|
|
Moxifloxacin
|
10 cases
|
|
Levofloxacin
|
9.3 cases
|
|
Macrolide
|
3.7 cases
|
The primary theory of
fluoroquinolone-associated hypoglycemia is twofold, consisting of both
pharmacokinetic and pharmacodynamic effects.
The pharmacokinetic mechanism
involves drug–drug interactions, while the pharmacodynamic mechanism comprises
the possibility of enhanced pancreatic β-cell stimulation and subsequent
increased insulin release.
Kirchheiner and co-workers investigated
genetic polymorphisms of the cytochrome P-450 (CYP) isoenzyme system and their
effect on the activity of oral antihyperglycemic medications.
They found that CYP2C9 is the primary
isoenzyme pathway responsible for metabolizing glyburide, glimepiride, and
glipizide, though other pathways may play a minor role in the metabolism of
these drugs.
Other antihyperglycemic medications
metabolized by CYP isoenzyme systems include nateglinide (CYP2C9), repaglinide
(CYP2C8), pioglitazone (CYP2C8 and CYP3A4), and rosiglitazone (CYP2C9 and
CYP2C8).
Genetic polymorphisms in CYP2C8 and
CYP2C9 may alter the clearance of these drugs from the body in certain
individuals with altered genotypes of these isoenzymes.
Theoretically, concomitant use of a
drug that is a substrate or an inhibitor of a CYP pathway by someone with an
altered genetic polymorphism of that same CYP isoenzyme could result in
increased serum drug concentrations, resulting in an enhanced hypoglycemic
effect of the oral antihyperglycemic drug.
The proposed pharmacodynamic
mechanism by which the fluoroquinolones induce glycemic abnormalities is not
completely understood.
Increase of insulin release from the
islet cells of the pancreas has been reported as the most likely mechanism for
fluoroquinolone-induced hypoglycemia.
Adenosine
triphosphate (ATP)-sensitive potassium channels are involved in insulin
secretion.
When these channels are blocked, the
membrane of the β-cells is depolarized, allowing calcium to enter the cell through
the voltage-dependent calcium channels.
Insulin granules then exit the β-cells,
and blood glucose is reduced.
The ATP-sensitive potassium channels
of the islet cells are inhibited by the fluoroquinolones.
Due to this inhibition, insulin
secretion is increased, and hypoglycemia can ensue.
Saraya and his co-workers studied
the effect of levofloxacin, gatifloxacin, and temafloxacin on insulin secretion
and ATP-sensitive potassium-channel activity in rat pancreatic islet cells.
Only small increases in insulin
secretion occurred with levofloxacin, while insulin secretion increased
significantly with gatifloxacin and temafloxacin.
Levofloxacin slightly reduced potassium-channel
activity, while gatifloxacin and temafloxacin markedly inhibited
potassium-channel activity.
On a cellular level, eight subunits
(four Kir6.2 and four SUR1) comprise the ATP-sensitive potassium channel of the
pancreatic β-cell.
Saraya and his co-workers found that
levofloxacin, gatifloxacin, and temafloxacin inhibit the Kir6.2 subunits of
pancreatic β-cells.
Gatifloxacin and temafloxacin
appeared to have greater inhibitory potential than did levofloxacin on the
Kir6.2 subunit, which may explain why more cases of hypoglycemia have been
reported with gatifloxacin than with levofloxacin.
Under normal conditions, the body can
compensate for a decrease in blood
glucose levels through physiological
mechanisms.
Normally, a decrease in blood glucose
levels causes the pancreas to decrease its insulin secretion and glycogenolysis
to increase in the liver.
Glucose is produced endogenously from
lactate, glycerol, and amino acids.
Malnourished patients, such as the
elderly, may not have sufficient glycogen reserves to mobilize in response to
the hypoglycemia caused by fluoroquinolones.
This inability to appropriately
compensate, along with decreases in renal function in elderly patients, may
cause higher drug levels or decreased drug clearance.
This may explain why
fluoroquinolone-induced hypoglycemia is most frequently described in older
patients.
