Ординатура / Офтальмология / Английские материалы / Ophthalmic Drugs Diagnostic and Therapeutic Uses 5th edition_Hopkins, Pearson_2007

CONTACT LENS SOLUTIONS 177

179

SECTION III

Therapeutic drugs and their uses

Chapter 12

Drugs for the treatment of infections

The term ‘anti-infective’ covers a wide group of agents that are effective against a variety of infections (e.g. viruses, rickettsiae, bacteria, fungi and protozoa). The mechanism of action of these agents varies greatly and, to some extent, will depend on the organism on which the particular agent acts. In the majority of cases, however, some competitive inhibition of a biochemical process is involved. As a result, the concentration level of the antibacterial (and hence the dose) are fundamental to the success or otherwise of antibacterial treatments. Minimum inhibitory concentrations (MICs) are often published for the common anti-infective drugs. These values will vary according to the infecting organism, the MIC for a strain of methicillin-resistant Staphylococcus aureus is considerably higher than that for normal Staph. aureus.

When it comes to treating ophthalmic infections, there are many more factors to take into consideration. The locus of infection will determine not only the route of administration but also the prognosis. Infections of the anterior eye will respond better to treatment than those further back. The level of inflammation and tear flow will similarly affect the absorption of anti-infective agents.

ANTIBACTERIALS

As with most ophthalmic drugs, the antibacterials used on the eye were originally developed for systemic use. However, in the main, it is the ones that have no, or very restricted, systemic use that are most popular for the treatment of the eye. Even fusidic acid, which has extensive use in dermatological preparations for the topical treatment of skin infections, has little systemic use, although tablets and suspension are available.

Although some antibacterials are marketed as simple ophthalmic preparations, containing just one active ingredient, many preparations contain either a combination of antibacterials or a steroid and antibacterial. A table of the steroid/antibiotic preparations is included at the end of Chapter 13.

180 OPHTHALMIC DRUGS

The absence of a product at the end of a section indicates that there is no currently available, commercially produced formulation. This does not mean that the compound is not used in ophthalmic treatment, as some specialist hospitals produce their own individual preparations.

Antibacterials can be divided into the following groups:

•beta-lactams

•tetracyclines

•macrolides

•chloramphenicols

•fluoroquinolones

•aminoglycosides

•sulfonamides

•miscellaneous agents.

BETA-LACTAMS

These agents are so called because of the presence of a beta lactam ring in their chemical structure. They all produce their effect by interfering with the synthesis of the cell wall by binding to certain enzymes in the cell membrane that are responsible for the building of the cell wall, producing morphological changes in the bacteria they affect. Long filamentous cells are produced, which fail to divide. Lysis of cells can occur due to the antibacterial action of some autolysins which normally only function during cell division. They can be divided into two main groups: the penicillins and cephalosporins.

Penicillins The principal agent in this group is penicillin, the original antibiotic. Although penicillin is still extensively used in systemic medicine, several synthetic derivatives have been developed with broader spectrums (e.g. amoxicillin and ampicillin) whereas others are resistant to penicillinase (e.g. flucloxacillin). Some newer penicillins even have anti-pseudomonal activity (e.g. piperacillin). They all share the danger of inducing a possible fatal anaphylaxis in certain, susceptible patients.

Resistance to penicillins can be caused by difficulty of the compound penetrating to the site of action. Penicillins pass across the ocular barriers very poorly and products containing them are rarely used in the treatment of ocular infections.

TETRACYCLINES

Tetracyclines are a group of broad-spectrum antibiotics that include chlortetracycline, demethylchlortetracycline, oxytetracycline, tetracycline and minocycline. There is little to choose between them with the exception of minocycline, which has a broader spectrum and more specific indications. Although the rest of the members of the group are quite similar, cross resistance between them does not necessarily occur.

182 OPHTHALMIC DRUGS

chloramphenicol is effective, there are many ocular pathogens such as Corynebacterium spp, E. coli, Haemophilus spp and streptococci. It has been recommended for the routine treatment of ophthalmia neonatorum (Pierce et al 1982). Its effect against chlamydiae has led to its use in trachoma, although its usefulness for this condition is probably in the treatment of the secondary infections that are responsible for many of the adverse effects of the infection. However, it is not effective against most strains of Ps. aeruginosa and Serratia marcescens. The bacteriostatic action of chloramphenicol is due to the inhibition of protein synthesis by interaction with the bacterial ribosomes. It penetrates easily into the cell by a process of facilitated diffusion. Resistance to chloramphenicol is brought about by the production of inactivating enzymes (chloramphenicol acetyltransferase).

One of the reasons for the popularity of chloramphenicol as an ophthalmic antibacterial is that it is rarely used systemically and thus there is little chance of cross-resistance developing. In a study of 738 patients, only 6% of the organisms cultured were resistant to chloramphenicol. This resistance rate was lower than for any other of the antibiotics tested (Seal et al 1982), although much higher resistance rates (e.g. 30.9%) against chloramphenicol have been reported (Mahajan 1983).

Apart from its employment in the treatment of life-threatening conditions such as typhoid, salmonella infections and bacterial meningitis, the systemic use of chloramphenicol is very restricted today because of the possibility of aplastic anaemia producing agranulocytosis. From systemic treatment, the incidence is about 1 in 50 000 patients and from topical use, the incidence is much lower. Trope et al (1979) failed to find systemic absorption after drops were administered every 2 hours for 5–7 days. This has not prevented a reluctance by some clinicians to use chloramphenicol. However McGhee (1996) points out that the theoretical risk of a fatal blood dyscrasia is about the same order as that of fatal penicillin anaphylaxis. He concludes that there is no evidence to suggest that children are more susceptible than adults. Decisions not to use chloramphenicol because of its possible toxicity must take in consideration the increased costs of treatment and the problems that will arise from the overuse of other antibiotics that should be retained for infections that are refractory to chloramphenicol. Chloramphenicol remains the first-line treatment for minor infections such as bacterial infections. Titcomb (1997) has reviewed the evidence for the link between chloramphenicol and aplastic anaemia and found the case unproven.

Apart from the uncertain potential to cause this rare blood dyscrasia, chloramphenicol is an excellent topical antibiotic, although topical use can sometimes lead to irritation. It is available as a 0.5% solution or a 1% eye ointment. Intramuscular injections have been recommended for the treatment of trachoma (Chastain & Newton 1954). Chloramphenicol has a high lipid solubility and in a study on ovine eyes (Ismail & Morton 1987) was found to be retained in the cornea at higher levels than the aqueous humour. Ointments gave consistently higher levels in both the cornea and aqueous humour. Solutions of chloramphenicol are not stable at room temperature and must be stored between 2 and 8°C.

DRUGS FOR THE TREATMENT OF INFECTIONS 183

184 OPHTHALMIC DRUGS

Ciprofloxacin As a result of these studies, an ophthalmic form of ciprofloxacin has been introduced as a 0.3% solution. Absorption into ocular tissues is good, leading to aqueous humour levels that exceed the MIC of many ocular pathogens. It also produced least experimental damage to rabbit corneae. Tear levels are also maintained above MICs for many bacteria up to 4 hours after instillation in healthy individuals (Limberg & Bugge 1994). Whether the same levels would be maintained in eyes in which tear production and drainage is raised due to inflammation is open to question. It has been shown to be as effective as tobramycin in the treatment of bacterial conjunctivitis (Leibowitz 1991a) and a safe and effective treatment of bacterial keratitis caused by a wide variety of bacteria, both Gram-positive and Gram-negative (Leibowitz 1991b). The majority of the former were either staphylococci (including MRSA) or streptococci; Ps. aeruginosa was the predominant Gram-negative bacterium.

In the treatment of bacterial conjunctivitis, ciprofloxacin has proved to be as valuable a drug as chloramphenicol in terms of efficacy and safety (Power et al 1993). It demonstrates a definite postantibiotic suppression, which is more marked than for the other fluoroquinolones (Fuhr 1995) and was found to be more effective than rifampicin in the treatment of bacterial conjunctivitis and blepharitis (Adenis et al 1995) It is also more effective than tobramycin and another fluoroquinolone, norfloxacin, in the treatment of experimental pseudomonal keratitis in rabbits (Reidy et al 1991). It has the advantage of not causing aplastic anaemia but, as the occurrence of this effect is very rare from ophthalmic application, this might not be sufficient reason for using the newer drug routinely as a first treatment for conjunctivitis.

Preparations

Ofloxacin In the past, ofloxacin was used in the treatment of chlamydia conjunctivitis (Zhang et al 1995). It is now marketed for the treatment of external ocular infections. It has similar antibacterial properties to ciprofloxacin.

Preparations

BAK, benzalkonium chloride

186 OPHTHALMIC DRUGS

Preparations

* With gramicidin 25 units and polymixin B sulphate 5000 units BAK, benzalkonium chloride

NS – generic product, preservative not stated

Framycetin Framycetin is produced by certain strains of Streptomyces fradiae or

Streptomyces decaris.

Framycetin is an isomer of neomycin and is used extensively as a topical antibiotic in general. Neomycin is a mixture of three substances – neomycin A, neomycin B and neomycin C. In fact, neomycin A is an inactive breakdown product of the other two and is normally present at a concentration of 10–15%. Framycetin is otherwise known as neomycin B and preparations contain not more than 3% neomycin C and not more than 1% neomycin A. It has a broad spectrum of activity against Grampositive and Gram-negative bacteria. It is effective against a greater range of bacteria than penicillin or streptomycin, e.g. Proteus vulgaris,

E.coli, H. influenzae and Klebsiella spp.

Like all antibiotics, resistance can develop with continued indiscrimi-

nate use, but this tends to develop more slowly than to other antibiotics. There is a cross-resistance between neomycin and framycetin and other aminoglycoside antibiotics.

Neomycin and framycetin are poorly absorbed from the alimentary tract. For this reason neomycin can be used to suppress normal intestinal bacteria prior to alimentary surgery. It is well absorbed from injection but produces toxic reactions, especially to the kidneys and ears. Framycetin has similar toxicity. Because of the poor systemic absorption and the toxicity, neomycin and framycetin are principally used for topical application. Framycetin is used on gauze dressings, in skin creams, nebulizers and eye preparations.

Preparations

BAK, benzalkonium chloride

DRUGS FOR THE TREATMENT OF INFECTIONS 187

Gentamicin Gentamicin is another aminoglycoside antibiotic with the same toxic effects as neomycin. It is one of the more effective agents in this group and will kill many strains of Ps. aeruginosa. It is the treatment of choice for this organism (Seal et al 1982), although resistant strains of Pseudomonas have been found (Insler et al 1985). Gentamicin is given by injection for serious systemic infections when the nature of the invading organism is not known, and therefore it should be kept for serious infections of the eye where other antibacterial agents are ineffective. The large number of topical gentamicin preparations available has resulted in gentamicinresistant Pseudomonas infections, probably because gentamicin has been used for the treatment of trivial infections such as conjunctivitis.

Absorption across the corneal epithelium is very poor. Hillman et al (1979) found that after application of gentamicin by drops very little appeared in the aqueous humour. Subconjunctival injection produced effective corneal concentrations in 2 hours and these were maintained for 24 hours. Better anterior eye levels were obtained using transcorneal and transscleral iontophoresis in rabbits (Grossman et al 1990). If a deep infection of the eye occurs, it is best treated by a slow intravitreal injection. Michelson & Nozik (1979) investigated the use of an implantable osmotic minipump for the administration of gentamicin for the treatment of experimental endophthalmitis in rabbits.

Reversible cellular oedema has been reported in the corneal endothelium following anterior chamber injection (Lavine et al 1979). Systemic injection will not give rise to sufficient ocular levels because of its poor ability to cross the blood/aqueous barrier. It is usually applied as a 0.3% solution but more concentrated solutions have been recommended for the treatment of bacterial corneal ulcers (Chaudhuri & Godfrey 1982). An intense dosing schedule has been suggested in order to achieve high initial levels in the cornea (Glasser et al 1985). Loading doses consisting of one drop every minute for 5 min produced significant levels in the cornea of rabbits.

Gentamicin is a very toxic compound and, like other aminoglycosides, can cause damage to the ears and kidneys. Both parts of the ears are affected and so ataxia due to vestibular damage and deafness from cochlear damage are the results of toxic doses. Hypersensitivity reactions can occur after local use and patients who are sensitized to one aminoglycoside, will react to others.

Preparations

BAK, benzalkonium chloride