D’andrea L1, Montemagni M2,
Celenza G3, Iorio R3, Costagliola
C2.
- Department of Public Health, University of Naples Federico II, 80131,
Naples, Italy
- Department of Neurosciences,
Reproductive and Dentistry Sciences, University of Naples Federico II,
80131, Naples, Italy
- Department of Biotechnological and Applied Clinical Sciences,
University of Aquila, 67100, Aquila, Italy
Corresponding author : Marina Montemagni, MD
Department of Neurosciences, Reproductive and Dentistry Sciences,
University of Naples Federico II, Naples, Italy. Via Sergio Pansini 15,
80131, Naples, Italy
Email:marinamontemagni91@gmail.com
Phone: +393200294414
ORCID 0000-0002-7981-3383
The authors declare no conflict of interest.
Keywords : Benzalkonium chloride, BAC, OSD, toxicity, glaucoma,
neuroinflammation.
Word count: 1001
Figure count: 1
Commentary
Benzalkonium chloride (BAC) is a quaternary ammonium compound introduced
in 1935 and widely used as a skin and surface disinfectant and
preservative in many household cleaning and personal care products. Due
to its antimicrobial activity against many common pathogens, BAC is also
employed as a preservative in several multidose eyedrops at
concentrations varying from 0.004% to 0.02%. The success and longevity
of BAC are attributable to its undeniable antibacterial efficacy and,
not least, its low production cost 1.
As a cationic surfactant, it has an amphipathic nature, and it expresses
the antimicrobial activity denaturing proteins and disrupting
cytoplasmatic membranes. BAC is also used as an excipient to stabilize
poor water-soluble drugs and as a penetration enhancer of active
compounds through ocular membranes. Indeed, it is believed that BAC can
solubilize the intercellular junctions in corneal epithelium, enhancing
drug delivery 2.
Although anecdotal reports have been circulating in the last years about
the adjuvant effect of BAC as an enhancer of the prostaglandin analogues
efficacy, recent studies have demonstrated that BAC does not change the
pharmacokinetics of the active ingredients. In fact, many studies on
glaucomatous patients show a similar intraocular pressure (IOP)
reduction in patients receiving BAC-containing and preservative-free
formulations. Pellinen and Lokkilla compared corneal penetration of
0.01% BAC preserved and preservative-free tafluprost in rabbit aqueous
humor after topical administration. No statistically significant
difference in the mean concentration over time was recorded (the maximum
drug concentration was 4.50 ng/mL for preservative-free tafluprost and
3.99 ng/mL for 0.01% BAC-preserved tafluprost, and the time to maximum
drug concentration was 45 min for both)3. This finding
demonstrated that BAC is far from an ideal penetration enhancer.
Eye drops containing BAC are associated with some adverse events,
particularly when used chronically, like in glaucomatous patients. The
European Medicine Agency (EMA) suggests to avoid preservatives in
glaucomatous patients, especially in whose with pre-existing Ocular
Surface Disease (OSD) or in those developing dry eye or ocular
irritation over time.
The development of OSD in glaucomatous patients depends primarily on
BAC, which affects lipid layer and tears film stability. Moreover, it
decreases tear break-up time (TBUT), induces apoptosis of conjunctival
cells with a breakdown of corneal epithelial junctions and loss of
superficial epithelial cells. It is not surprising that patients treated
with IOP-lowering eye drops show a higher percentage of OSD compared to
the general elderly population (59% vs 15%). A positive
correlation with the number of BAC-preserved eyes and drops used was
observed4. OSD causes significant morbidity and
influences treatment compliance, quality of life, and surgical
outcomes5. On the other hand, it is not surprising
that topical adverse effects represent a source of poor adherence and a
common reason for drop-out in clinical situations and clinical trials,
representing an important barrier to the effective management of
IOP6. Long-term use of topical eye drops rich in
preservatives can modify eye surfaces, compromising the success rate of
trabeculectomy. In most cases, the failure of glaucoma surgery
originates from a fibroblastic conjunctival response to inflammation at
the bleb level, which occurs in the early postoperative months. A
significant relationship between the number of drugs used, duration of
treatment, inflammatory cell and fibroblast infiltration in the
conjunctiva, and the risk of failure of filtering surgery has also been
found5.
Topically instilled BAC acts not only on superficial structures but also
reaches deeper tissues, such as trabecular meshwork and optic nerve
areas, with a greater impact in case of long exposure (inflammatory cell
infiltration and Müller glial cell activation), as demonstrated by
Brignole-Baudouin et al. though the use of mass spectrometry imaging and
immunological analyses 7. Thus, BAC exposure could
worsen glaucoma and, through its capacity to accumulate in the
trabecular meshwork, can cause changes similar to those found in the
ocular outflow pathway of glaucomatous patients. Detrimental BAC’s
effects could result in progressive loss of efficacy of IOP-lowering
compounds. Moreover, the presence of this preservative along the optic
nerve could be a sight-threatening issue: BAC side effects could account
for the percentage of glaucomatous patients whose disease progress
despite a good IOP control 7.
Stevens et al. showed that short-term BAC administration induces
inflammation in the anterior segment 8. When a
pro-inflammatory stimulus arises during injury or disease, astrocytes,
Müller cells, and microglia become activated and produce cytokines and
chemokines. This recruits blood-derived immune cells to the retina,
which causes amplification of the inflammatory response in the retina.
Thus, glaucomatous insult or elevation of IOP triggers the responses of
microglia, astrocytes, and Müller cells to participate in the process of
neuroinflammation. Glaucomatous patients present inflammatory
dysfunction of the retinal ganglion cell layer (RGC) and the optic nerve
head. BAC enhances inflammatory response both at the level of the ocular
surface and along all the visual pathways 7.
Mitochondrial oxidative stress has been reported to promote OSD. In
addition, RGC is a highly vulnerable neuronal cell type with reference
to mitochondrial dysfunction. In this sense, BAC has also been shown to
induce mitochondrial oxidative stress and detrimental effects on
mitochondrial function OSD due to topical preservatives in eye drops is
just the tip of the iceberg and the visible consequence of iatrogenic
inflammation induced by BAC9.
Lastly, it is important to consider also the effect of BAC on the
efficacy of antibiotic therapy. Many studies have shown that the
exposure to BAC is linked in promoting antibiotic resistance in
environmental bacteria and human pathogenic bacteria10.
In conclusion, clinical and experimental evidence demonstrates that BAC
causes instability of the tear layer, loss of goblet cells, apoptosis,
subclinical neuroinflammation and antibiotic resistance (Figure 1).
These findings strongly suggest avoiding the use of this preservative in
eye drops. At present, topical formulations containing alternative
preservatives (i.e., Polyquad, Purite, SofZia, GenAqua) and
preservative-free formulations which exhibit a similar efficacy of eye
drop containing BAC with a considerable low grade of ocular toxicity are
available. Considering the validity of the alternative formulations, it
is unreasonable to persist in using such toxic compounds and, perhaps it
is time for a moratorium on the use of BAC in eye drops.