Antibiotics and cytotoxicity

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Friday, 17 November 2023

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Eye infections

Choosing the right antibiotic in eye infections: which criteria to refer to.

Choosing the right antibiotic

Choosing the right antibiotic in eye infections requires careful consultation with a doctor: what are the criteria to refer to.

The Respondent

Dr. Carlos Cólliga of the Clinica Rementería in Madrid is an ophthalmologist with a specific specialisation in microbiology and infectious diseases of the eye, as well as ocular surface diseases such as dry eye syndrome.

We therefore asked him a few questions about proper antibiotic therapy.

When dealing with an eye infection, what are the criteria to follow in the'use of the best antibiotic?

An antibiotic drug appropriate for the treatment of eye infections must fulfil several essential characteristics.

First of all, it must have a broad spectrum of antibiotic activity to cover all possible aetiological agents causing the infection.

Secondly, the antibiotic of choice should have a low antibiotic resistance rate in order to avoid both any complications that may arise from the infection and the need to change therapy, perform further tests, etc.

Thirdly, a good antibiotic for the treatment of eye infections, especially those affecting the ocular surface (which are the majority) must have a good tolerance profile, a good safety profile and low toxicity to the ocular surface, as antibiotic therapy sometimes has to be prolonged for several weeks or longer.

Could you point us to any molecules that meet these criteria?

In this regard the netilmicin stands out as a broad-spectrum antibiotic for both Gram-positive and Gram-negative bacteria, and with a very low, almost non-existent rate of antibiotic resistance for the micro-organisms most frequently isolated in ocular infections.

It is an aminoglycoside antibiotic with concentration-dependent bactericidal activity, with a good pharmacotherapeutic PK/PD (pharmacokinetic/pharmacodynamic ratio) profile and a maximum Cmax/MIC (MIC: Minimum Inhibitory Concentration) concentration higher than 10, which is essential for its efficacy and high post-antibiotic effect.

For which disorders is it important that the antibiotics used are not toxic to the ocular surface?

All those pathologies in which the integrity of the ocular surface is compromised, such as chronic conjunctivitis, chronic ocular allergies, dry eye syndrome, when wearing contact lenses, muco-cutaneous pathologies (pathologies affecting the skin and mucous membranes with ampullary vesicular lesions, usually bilateral and of autoimmune aetiology - such as pemphigoid), chronic use of topical hypotensive drugs, etc.

In all these cases, antibiotic treatment that respects the integrity of the ocular surface is absolutely necessary.

In these cases, in particular, it is even more important to use an antibiotic with a low toxicity precisely because of the pre-existing damage that many of these patients present at the level of their ocular surface and the potential complications due to the use of drugs that increase epithelial toxicity, as well as to ensure adequate tolerance to the antibiotic and high adherence to therapy for the treatment of the infection.

Which antibiotic do you consider most toxic?

The toxicity of antibiotics depends very much on the time of use and the concentration, as well as the dosage.

Among the aminoglycosides, both gentamicin and tobramycin reported high toxicity on keratocytes and cells in other districts, such as the renal tubule epithelium, and were therefore nephrotoxic.

In this regard, netilmicin is less toxic than tobramycin at the level of the renal tubule epithelium, as has been shown in both animal models and clinical studies.1,2

In studies on the retinal toxicity of intravitreal injections of aminoglycosides, the most retinotoxic antibiotic was gentamicin, above tobramycin and netilmycin.3

With regard to fluoroquinolones, antibiotics widely used in ophthalmology, ofloxacin was found to be significantly more toxic than netilmycin, with a 50% inhibition of cell proliferation and corneal epithelium viability, whereas netilmycin has no toxic effect on the same cells, according to the same study.4

In which population should special attention be paid to cytotoxicity?

In general, we should be particularly cautious about prescribing antibiotics to fragile populations, such as children and the elderly, some of whom have a damaged or immature enzyme metabolism.

In conclusion, for the treatment of infections, drugs must be used that are safe at the minimum effective concentration, by the appropriate route of administration, for the necessary time without exceeding the minimum effective concentration, with the minimum rate of resistance5, with a sufficiently wide therapeutic range, with no or minimal toxicity to the body and, in the specific case of eye infections, to the eye.

In these situations, topical netilmicin in ointment form for the treatment of eye infections fulfils all these characteristics and is safe for administration in people of all ages.

On the subject of antibiotic therapy see also:

Netilmycin and the eye

We also list the studies in the literature on the use of Netilmicin in ophthalmology.

MICROBIOLOGY STUDIES
1) Invest. Ophthalmol. Vis. Sci. 2015; 56(7):283
Netilmycin for antibiotic prophylaxis before cataract surgery
Papa V, Cannatella C, Blanco AR, Santocono M

2) Curr Eye Res. 2016 May;41(5):581-9.
Surveillance of the Activity of Aminoglycosides and Fluoroquinolones Against Ophthalmic Pathogens from Europe in 2010-2011
Sanfilippo CM, Morrissey I, Janes R, Morris TW

3) Curr Eye Res. 2013 Aug;38(8):811-6.
Susceptibility of methicillin-resistant Staphylococci clinical isolates to netilmycin and other antibiotics commonly used in ophthalmic therapy.
Blanco AR, Sudano Roccaro A, Spoto CG, Papa V

4) Taiwan Journal Ophtahl. 2010; 40(6): 354-358.
What should be the antibiotic preference in bacterial conjunctivitis treatment?
Eser I, Akçal A, Çömez AT, Kömür B, Özbey N, Otkun MT

5) Investigative Ophthalmology & Visual Science 2009; 50(13): 2664
Antibacterial Activity of Netilmicin and Netilmicin/Dexamethasone Fixed Combination Against the Most Common Ocular Isolates
Blanco A, Mezzatesta M, Gona F, Sudano Roccaro A, Mazzone MG, Stefani S

6) Rev. Mex. Oftalmol; Enero-Febrero 2009; 83(1):1-5
Susceptibilidad a netilmicina en 400 cepas bacterianas aisladas de infecciones oculares
Vanzzini de R V, Alcantara-Castro M, Flores V

7) Medical Microbiology 2008; Vol. 23 (4)
2777 cultures on conjunctivitis (whose nature is not determined): epidemiological survey in the course of 7 years of observation
Giardini F, Protti R, Bay A, Grandi G, Pollino C, Murisciano R, Grosso A

8) Ophthalmologica. 1997;211(Suppl 1):15-24.
Antibiotic sensitivity of recent clinical isolates from patients with ocular infections.
Ooishi M, Miyao M

9) Chemotherapy. 2001 Mar-Apr;47(2):117-22.
Netilmicin: in vitro activity, time-kill evaluation and postantibiotic effect on microorganisms isolated from ocular infections.
Bonfiglio G, Scuderi AC, Russo G

CYTOTOXICITY STUDIES
10) Cornea. 2006 Jan;25(1):85-90.
In vitro effects of fluoroquinolone and aminoglycoside antibiotics on human keratocytes.
Leonardi A, Papa V, Fregona I, Russo P, De Franchis G, Milazzo G

11) Cornea. 2005 Aug;24(6):710-6.
In vivo toxicity of netilmycin and ofloxacin on intact and mechanically damaged eyes of rabbit.
Marino C, Paladino GM, Scuderi AC, Trombetta F, Mugridge K, Enea V

12) J Ocul Pharmacol Ther. 2003 Dec;19(6):535-45.
Effect ofloxacin and netilmycin on human corneal and conjunctival cells in vitro.
Papa V, Leonardi A, Getuli C, Pacelli V, Russo P, Milazzo G

13) Cornea. 2003 Jul;22(5):468-72.
In vitro toxicity of netilmycin and ofloxacin on corneal epithelial cells.
Scuderi AC, Paladino GM, Marino C, Trombetta F

PHARMACOKINETIC STUDIES
14) Investigative Ophthalmology & Visual Science May 2007, Vol.48, 4276.
Netilmicin Ocular Distribution of Three Different Ophthalmic Preparations: Eyedrops, Hydrogel and Ointment
Mazzone M, Civiale C, Mattei E, Blanco AR

15) Cornea. 2002 Jan;21(1):48-50.
Residence Time of Netilmicin in Tears
Scuderi AC, De Lazzari A, Miano F, Zola P

CLINICAL STUDIES
16) Journal of Cataract Refractive Surgery 2016 in press
Ocular flora and their antibiotic susceptibility. An observational study in patients undergoing cataract surgery in Italy
Papa V, Blanco AR, Santocono M

17) Eur J Ophthalmol. 2008;18(4):512-6.
Effect of topical netilmicin on the reduction of bacterial flora on the human conjunctiva
Aslan O, Teberik K, Yucel M, Gur N, Karakoc AE.

18) Cornea. 2002;21(1):43-7.
Treatment of Acute Bacterial Conjunctivitis With Topical Netilmicin.
Papa V, Aragona P, Scuderi AC, Blanco AR, Zola P, Di Bella A, Santocono M, Milazzo G.

19) Int J Clin Pharmacol Ther. 1999 May;37(5):243-8.
Topical netilmycin compared with tobramycin in the treatment of external ocular infection.
Milazzo G, Papa V, Carstocea B, Chercota G, Rodica P, Gafencu O, Santocono M.

CLINICAL STUDIES - Focus Paediatrics
20) Bulletin of Ophthalmology 1996; YEAR 75 - No. 1:3-6
Netilmycin: efficacy in dacryocystitis and bacterial conjunctivitis in children
Pullerone S, Piozzi E

21) Bulletin of Ophthalmology 1994; YEAR 73 - No. 5:739-742
The use of netilmicin eye drops in paediatric eye infections
Papparella AM, De Girolamo N, Piroli C

22) Bulletin of Ophthalmology 1994; YEAR 73 - No. 1:1-3
Netilmycin in congenital nasolacrimal duct obstructions
Nucci P

23) Bulletin of Ophthalmology 1993: YEAR 72 suppl. 5:691-699
Clinical efficacy of netilmicin in topical application in bacterial conjunctivitis in early childhood
Ricci B, Caprilli A, Zonghi E, Longo P, Lepore D

Bibliografia

1. Dahlager JI. The effect of netilmycin and other aminoglycosides on renal
function. A survey of the literature on the nephrotoxicity of netilmycin. Scand J
Infect Dis Suppl. 1980;Suppl 23:96-102. PMID: 7010549.

2. R.J. Szot, G. McCormick, M. Chung, B. Christie, E. Weinberg, E. Schwartz,
Comparative toxicity of netilmycin and tobramycin in dogs, Toxicology and
Applied Pharmacology, Volume 55, Issue 1, 1980.
3. D'Amico DJ, Caspers-Velu L, Libert J, Shanks E, Schrooyen M, Hanninen LA,
Kenyon KR. Comparative toxicity of intravitreal aminoglycoside antibiotics. Am J
Ophthalmol. 1985 Aug 15;100(2):264-75. doi: 10.1016/0002-9394(85)90792-5.
PMID: 4025468.

4. Papa V, Leonardi A, Getuli C, Pacelli V, Russo P, Milazzo G. Effect of ofloxacin
and netilmicin on human corneal and conjunctival cells in vitro. J Ocul
Pharmacol Ther. 2003 Dec;19(6):535-45. doi: 10.1089/108076803322660459.
PMID: 14733711.

5. Milazzo G, Papa V, Carstocea B, Chercota G, Rodica P, Gafencu O, Santocono
M. Topical netilmycin compared with tobramycin in the treatment of external
ocular infection. Int J Clin Pharmacol Ther. 1999 May;37(5):243-8. PMID:
10363623.