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August 2007
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Elizabeth Dodds Ashley
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During the past several weeks, there have been two health alerts issued by
the FDA regarding the safe use of antiinfective agents. In each case, these
alerts led to some confusion among health care professionals. A description of
these warnings and some of the details behind the alerts are outlined below.
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Aerosolized colistimethate
sodium
On June 28, 2007, the FDA issued a public health advisory regarding the use
of inhaled colistimethate and its possible association with the death of a
patient. Although absorption of colistimethate is minimal when administered via
this route, the patient developed multi-organ failure and ultimately died from
what appeared to be systemic colistin toxicity.
What had occurred in this patient who was prescribed a therapy that,
although not FDA–approved for administration by this route, is routinely
used in the cystic fibrosis population? The patient had been prescribed
aerosolized colistimethate to be administered at home via nebulizer. The
medication the patient received from the pharmacy was a premixed, ready-to-use
supply of colistimethate. Within hours of the first treatment, the patient
developed respiratory distress that progressed during the next several days.
Nineteen days later, the patient died of multi-organ failure.
This case of pulmonary toxicity, followed by what appeared to be systemic
toxicity due to colistin, is likely linked to administration of a colistin
preparation with a higher than normal concentration of a more toxic formulation
of the drug.
In the United States, there are two commercially available preparations of
colistin: colistin sulfate and colistimethate sodium. The former is considered
the more toxic preparation and is only available for oral administration as
part of gastrointestinal tract decontamination regimens.
Colistimethate sodium (polymyxin E) is an inactive prodrug of colistin. It
is the preparation available for IV administration. When mixed with water,
colistimethate undergoes spontaneous hydrolysis to two distinct forms of the
active drug colistin (polymyxin E1 and polymyxin E2). One of these products,
polymixin E1, is toxic to lung tissue and can actually cause sufficient damage
to allow increased systemic absorption of the active drug form. This appears to
be what occurred in the patient cited in the FDA advisory.
Why was this particular patient exposed to higher than normal concentrations
of polymixin E1? Unlike many initially feared, this was not a case of
contaminated pharmacy compounding, as has occurred in recent years with
steroids and other injectible products. This is actually a normally occurring
process and would be expected when colistimethate is prepared more than 24
hours prior to its intended use. At most inpatient treatment facilities, it is
protocol to discard any unused colistimethate within 24 hours of admixture.
When used in the outpatient setting, premixing the medication is a
convenient option for many patients. However, this practice results in a more
toxic preparation given to patients. For any clinician who is using aerosolized
colistin in the outpatient setting, it is important to ensure that the
medication supply is not being compounded in advance.
The FDA advisory statement offers the following advice for health care
professionals:
- Health care professionals using aerosolized colistimethate need to be aware
of the potential toxicity arising from the polymyxin E1 metabolite.
- To avoid this toxicity, colistimethate should be administered promptly
after being mixed.
- Patients should be advised not to use premixed, ready-to-use formulation of
colistimethate. Also, any vials they have already purchased should be
discarded.
This case serves as a careful reminder that as aerosolization of
antimicrobials becomes more common in clinical practice, we must carefully
monitor the safety of the agents being used.
Coadministration of
ceftriaxone, calcium
On July 5, 2007, the FDA issued a warning via the MedWatch alert system
regarding toxicity associated with co-administration of IV ceftriaxone
(Rocephin, Roche) and calcium-containing products. The letter, written by Roche
representatives, outlines changes to the prescribing information for
ceftriaxone in regards to calcium products. In the warning section, the
following statements were added:
- Ceftriaxone must not be mixed or administered simultaneously with
calcium-containing solutions or products, even via different infusion lines.
- Calcium-containing solutions or products must not be administered within 48
hours of last administration of ceftriaxone.
- Cases of fatal reactions with calcium-ceftriaxone precipitates in lungs and
kidneys in both term and preterm neonates have been described. In some cases,
the infusion lines and times of administration of ceftriaxone and
calcium-containing solutions differed.
These changes were prompted following five neonatal deaths during the past
decade related to calcium-ceftriaxone precipitates in the lungs and kidneys of
affected patients.
This alert led to many questions by practitioners regarding exactly which
formulations of calcium were involved. Given the high frequency with which
ceftriaxone is administered, particularly during respiratory infection season,
the inability to administer any calcium within 48 hours of ceftriaxone
presented a logistical difficulty in many institutions.
Further clarification was provided by Roche in a letter dated July 12, 2007.
This letter clarifies many important considerations regarding the risk for this
event. First and foremost is the patient population affected. All of the
patients were neonates. There does not appear to be any similar risk observed
in adult patients receiving ceftriaxone. The risk appears to be highest for
neonatal patients with hyperbilirubinemia.
The letter also provides clarification for the 48-hour period of risk for
administration of calcium-containing products. Although the revised prescribing
information identifies all calcium-containing products and specifically states
that the reaction is noted with differing administration routes, the reaction
has not been reported in association with oral preparations of calcium.
In summary, use of ceftriaxone and concomitant calcium-containing products
in the neonatal population is certainly a patient-safety concern. There are
not, however, similar problems when calcium is administered to an adult patient
receiving ceftriaxone therapy. Calcium and calcium-containing solutions should
not be used as a diluent or co-infused with ceftriaxone for injection.
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