During the summer, many hospitals were faced with an erythromycin eye
ointment shortage. When trying to find a replacement product, many were
surprised to find that there are no other FDA-approved drug therapy options for
ophthalmia neonatorum prophylaxis. This poses a challenge for clinicians who
must choose a safe, efficacious alternative for a practice that has been around
for decades.
Dr. Carl Siegmund Franz Credé, the German gynecologist and
obstetrician, first introduced prophylaxis for ophthalmia neonatorum in 1881,
by cleansing the infant’s eyes and instilling silver nitrate solution 2%
in the conjunctival sac after birth. This therapy has since been proven
effective in preventing opthalmia neonatorum, conjuncitivitis in the newborn,
the most common gonococcal infection in neonates. Fewer data are available
regarding efficacy of this approach for prophylaxis against Chlamydia
trachomatis.
Silver nitrate has since fallen out of favor due to its adverse effects
of chemical conjunctivitis and argyria, a bluish discoloration of the eyes and
surrounding skin. Topical preparations can be used for ophthalmia neonatorum
prophylaxis, but treatment requires systemic antibiotics. Clinical symptoms of
gonococcal ophthalmia neonatorum are usually mild but can quickly progress to
corneal scarring and, in severe cases, subsequent blindness.
Therefore, prophylaxis has been identified as the preferred method to
address this infection. Although rare, the devastating consequences in the
small number of infected children warrant a comprehensive prophylactic
approach. In the United States today, the only available FDA-approved
medication for ophthalmia neonatorum prophylaxis is erythromycin ophthalmic
ointment 0.5%. The CDC’s 2006 Sexually Transmitted Disease (STD)
Treatment Guidelines recommend instilling the ointment into both eyes of
every neonate immediately after delivery. This guidance has subsequently been
adopted as mandate in many states.
CDC addresses shortage
In late August, the CDC’s Division of STD Prevention issued a
statement in conjunction with the FDA regarding the shortage of erythromycin
ophthalmic ointment 0.5% due to a combination of events. Akorn Consolidated
Midland and Wilson discontinued production of erythromycin ointment. Fougera
sold the rights for erythromycin ophthalmic ointment to Fera Pharmaceuticals,
which then experienced production delays. At the time, Fougera was the only
producer of 1g tubes of the ointment, the preferred package for opthalmia
neonatorum prophylaxis. All of these factors led to an increased demand on
Bausch & Lomb.
There are two FDA-approved indications for erythromycin ophthalmic
ointment 0.5%: prophylaxis of ophthalmia neonatorum caused by N. gonorrhoeae
or C. trachomatis and superficial ocular infections involving the
conjunctiva and/or cornea caused by susceptible organisms. Only the latter
condition has FDA-approved commercially available alternatives in the United
States. So which medication options are there for health care providers to
prevent ophthalmia neonatorum if erythromycin ophthalmic ointment is not
available?
One of the initial proposed solutions was to use bulk supplies of the
erythromycin ointment that remained commercially available and draw up aliquots
in sterile glass syringes. However, this was rejected because of concern of
contamination and potential medication errors. Several alternative medications
were considered by individual institutions; however, many of these were
problematic.
FDA recommendations
As far as medications to avoid, the FDA specifically recommends against
the use of betadine (povidone iodine) due to the risk of serious harm with
medication errors that may possibly occur if there was confusion with the
detergent formulation. Additionally, although silver nitrate solution 1% was
recommended for ophthalmia neonatorum prophylaxis in the CDC’s 2002
STD Treatment Guidelines, the product is not available in the
United States because of previously mentioned toxicities. Tetracycline
ophthalmic ointment 1% is an effective treatment option but is also not
commercially available. Health care providers are thus faced with the
difficulty of choosing appropriate alternatives for this potentially
eyesight-threatening condition that is caused by an increasingly resistant
organism.
First, it should be noted that all of the following suggested
alternatives to erythromycin ophthalmic ointment 0.5% are not FDA approved for
ophthalmia neonatorum prophylaxis, nor is there efficacy data regarding their
usage for this indication. The FDA, however, stated that the recommendations
are based upon pharmacology and gonococcal microbiologic sensitivity data. All
of the alternative prophylaxis options are recommended for infants delivered
vaginally and by cesarean section.
Azithromycin ophthalmic solution 1% (AzaSite, Inspire Pharmaceuticals)
is recommended as the preferred alternative therapy option when erythromycin
ophthalmic ointment 0.5% is not available. The recommended dose is one to two
drops in the conjunctival sac of each eye, without touching the applicator tip
to the eye. Difficulty in instilling a solution as opposed to ointment should
be handled by one person holding the infant’s eye lid open and a second
person administering the medication.
In situations in which neither erythromycin ophthalmic ointment nor the
alternative azithromycin ophthalmic solution is available, the FDA recommends
the following therapy options: gentamicin ophthalmic ointment 0.3% (Gentak,
Akorn) or tobramycin ophthalmic ointment 3% (Tobrex, Alcon Laboratories).
Of interest, case reports from 11 states have associated adverse events
with gentamicin ophthalmic ointment. The reports have described lid swelling
and dermatitis several days after administration. Most cases were not serious
and did not require treatment, but a few severe cases involved skin blistering.
No cases have been reported to affect the conjunctiva, orbital contents or
cornea; all cases resolved without complications or treatment. Gentamicin
ophthalmic ointment is still considered a potential alternative option when
erythromycin ophthalmic ointment and azithromycin ophthalmic solutions are not
available.
A last-line option would be a fluoroquinolone ophthalmic ointment such
as ciprofloxacin ophthalmic ointment 0.3% (Ciloxan, Alcon Laboratories), but
due to the high rates of N. gonorrhoeae resistance to fluoroquinolones,
this is a less appropriate choice. Fluoroquinolone resistance to N.
gonorrhoeae has been a growing problem over the past several years. There
were 336,742 cases of gonorrhea reported in 2008 in the United States, making
it the second most frequently reported infectious disease after chlamydia.
Emergence of resistance
Due to the emergence of resistance to fluoroquinolones in rates of more
than 25% in certain United States cities, in 2007, the CDC issued an update to
its 2006 STD Guidelines, recommending against the use of drugs
from this class to treat N. gonorrhoeae infections. The 2007 Annual
Report for the CDC’s Gonococcal Isolate Surveillance Project (GISP)
reported a 16.1% rate of total isolate intermediate resistance or resistance to
ciprofloxacin. Several regions and cities demonstrated alarming increases rates
of resistance, such as Las Vegas’ rise from 8.7% resistant isolates in
2006 to 18.7% in 2007. Consequently, cephalosporin-based regimens are the
first-line recommendation for treatment of gonococcal infections, with
ceftriaxone as a treatment choice for all types of N. gonorrhoeae
infection.
The rate of gonorrhea cases remained relatively stable for the last
decade. Of concern, resistance rates continue to rise while there is a lack of
new prospective therapy options for N. gonorrhoeae infections. This
stresses the importance of preventing the spread of N. gonorrhoeae to
neonates. To ensure that the most effective available prophylaxis option for
ophthalmia neonatorum caused by N. gonorrhoeae is available for this
indication, the FDA currently recommends reserving the use of erythromycin
ophthalmic ointment for ophthalmia neonatorum prophylaxis and using alternative
agents for superficial ocular infections involving the conjunctiva and/or
cornea caused by susceptible organisms.
Although initial estimates were that supplies of erythromycin ophthalmic
ointment would return to sustainable levels in early 2010, the supply remains
very limited. Many centers that developed initial contingency plans in the
summer are now being forced to select alternate agents. Additionally, it is
important for infectious diseases practitioners to know that these practice
changes have been occurring as we continue to track the epidemiology of these
infections.
Elizabeth Rightmier, PharmD, is a pharmacy practice resident at the
University of Rochester Medical Center in Rochester, N.Y.