Mukesh Patel BSc (Hons) Pharmacol, BSc (Hons) Optom, MCOptom Ocular side effects of systemic drugs
Part 5 – Antimicrobial agents
This series of articles on ocular side
the diseases caused by them, e.g. rhinoviruses effects of drugs considers all the
familiar to optometrists, particularly the very cause colds; picornaviruses are minute RNA major classes of drugs sequentially,
common acute infective conjunctivitis. The viruses (PICO + RNA + VIRUS). Viruses cannot system by system. The first four
latter, although usually minor, can be caused exist independently, but can only live and articles concentrated on
replicate within living cells of the host.
cardiovascular drugs. This article
adenoviruses or streptococci (haemophilus in Protozoa are unicellular organisms which are covers infections by various
notorious for causing disease in the tropics.
microbes, their treatment and the
Plasmodium species (see later) cause malaria, ocular complications of these
usually parasites, but can occasionally live as treatments.
saprophytes or commensals. There are several millions of lost man hours every year. Malaria Several types of bacteria and viruses live on disease. Bacteria and viruses are the most mosquito (the Culex mosquito is the insect and in our bodies, particularly on the skin and widely known; bacteria can be sub-divided vector for the transmission of yellow fever).
into gram positive and gram negative bacteria passages and the lining of the gut) without according to how they stain with the gram causing any adverse effects. In fact, the stain, a dye used to make them viewable with commensal bacteria in the ileum are of benefit Worms can also cause disease, e.g Filariasis in helping prevent virulent organisms from The much smaller organisms called viruses flourishing and digest extrinsic matter.
are only visible under the electron microscope.
They consist of a core of nucleic acid (either volvulus, which leads to so-called ‘river DNA or RNA) surrounded by protein; they are blindness’ (onchocerciasis) in North Africa. classified into DNA and RNA viruses, according (Figures 1 and 2). These infections have very to which nucleic acid they contain. Further bacterial infections for the first time. diverse clinical features, and can be life- subdivision depends on their morphology or An antibiotic is defined as a substanceproduced by one living organism, which is harmful or lethal to another (micro) organism.
The term antimicrobial agent has a broader meaning and includes synthetic drugs, e.g.
sulphonamides as well as anti-protozoal agentssuch as suramin.
There are several groups of ‘antibiotics’ and classification by their mechanisms of action isthe most useful. This is presented below: • Agents which attack the bacterial cell wall, e.g. penicillins, cephalosporins, bacitracin(CICATRIN), miconazole (DAKTARIN) • Antimetabolites which inactivate specific Brief classification of bacteria showing just a few examples;
the organisms named in red are gram-positive, and those in blue, gram-negative
Figure 2
Brief classification of pathogenic organisms other than bacteria; this diagram is not a comprehensive representation of
parasitology, but rather attempts to illustrate the basic principles involved

Clavulanic acid is a ‘suicide’ inhibitor of beta-lactamase produced by a wide range of gram positive and gram negative organisms. It • Nucleic acid analogues, e.g. vidarabine, is an example of a molecule which can bind to d) Drug allergy: Allergic reactions to penicillin beta-lactamases and inactivate them, thus • Inhibitors of protein synthesis, e.g.
preventing the destruction of beta-lactam administered in susceptible patients, and antibiotics which are substrates for these any physician prescribing penicillin always enzymes. It is called a ‘suicide’ drug because asks if the patient has taken it before and it is inactivated during its action. Clavulanic acid has been combined with amoxycillin as an causing a misreading of the genetic code, oral preparation (AUGMENTIN). Amoxycillin plus clavulanate is effective in vitro and in vivo for beta-lactamase-producing strains of (G-6-PD) deficiency develop haemolysis if Staphylococci, H. influenzae, gonnococci, and certain drugs (including chloramphenicol) • Other enzyme inhibitors e.g. ciprofloxacin are administered. This is of relevance to the optometrist in that these patients may Choosing an optimal
antimicrobial agent
Ocular side effects
individual antibiotics are more effective against a particular organism than others, e.g.
The use of antibiotics is extremely widespread chloramphenicol (CHLOROMYCETIN) is the drug pharmacokinetic factors and host factors.
in terms of the actual numbers of prescriptions of first choice in Haemophilus influenzae meningitis, and the drug of second choice in indiscriminately) by general practitioners.
Bactericidal drugs kill the organism, while Considering this fact, the frequency of reports amoxycillin (AMOXIL). In identifying the best bacteriostatic ones only inhibit their growth.
of ocular toxicity is relatively small. However, drug for a particular situation, efficacy against It is not advisable to combine a bactericidal the actual number of side effects reported is drug with a bacteriostatic one as this results still very large, and it is important to interpret penetration of the drug into the relevant reports or published letters in perspective.
tissue, lack of toxicity in effective dosages andother factors need to be taken into Penicillins
The Minimum Inhibitory Concentration (MIC) Certain individuals have an intrinsic propensity Optimal selection of antimicrobial agents of an antibiotic is the smallest strength of to developing a severe allergic reaction to for the therapy of infectious diseases is a drug which will prevent replication or cause penicillin. This takes the form of swelling of death of organisms. The MIC, and preferably the eyelids and conjunctiva occurring as part clinical judgement and detailed knowledge of multiples of it, must be achieved at the site of pharmacological and microbiological factors infection for effective eradication of an angioneurotic oedema3. This condition, also known as anaphylactic shock in its severe characteristics of absorption, distribution, form, is life-threatening due to the possibility practitioner with an infection, a specimen of metabolism and excretion of the drug. The of cardiovascular collapse or laryngeal oedema tissue (or biological media, e.g. sputum, urine, route of administration, oral, parenteral, (obstructing the airway). It is due to a Type I nasal, rectal or sublingual, is also important.
or immediate-type hypersensitivity reaction spectrum antibiotic to cover a wide range of possible causative bacteria. This is called substances from mast cells activated by IgE.
empirical antibiotic therapy. When the actual Parenteral hydrocortisone or adrenaline may bacterium responsible has been identified by be necessary to prevent severe shock or even the laboratory, the best antibiotic against that antimicrobial agent. Reduced immunity, as death. Doctors always ask about past allergy organism is substituted. This later specific to penicillin before prescribing a drug of this therapy is called definitive antimicrobial certain antibiotics. Pus, which consists of Extensive use of antibiotics has resulted in phagocytes, protein, debris and fibrin, has Stevens-Johnson syndrome is a severe Type III dermatological reaction to certain drugs, most microorganisms. For instance, some decades (e.g. streptomycin), resulting in reduced ago, penicillin G (benzylpenicillin) was very exudative conjunctivitis and keratitis may be effective against Staphylococcus aureus. But followed by conjunctival shrinkage and the dry metabolism and renal excretion of drugs is eye syndrome. Stevens-Johnson syndrome due translocation, conjugation and transduction, poorly developed in the newborn. A similar to amoxycillin (AMOXIL) has been reported by have led to development of strains of S.
situation exists in elderly patients, and in Davidson and Windebank5 among others.
aureus, which can produce penicillinase, an patients with compromised hepatic or renal Penicillins also occasionally cause a dose enzyme which destroys penicillin G. Penicillins function. For the latter, a quick look at the resistant to penicillinase-producing bacteria convulsions, respiratory embarrassment (due inappropriate choice of drug. Tetracyclines to suppression of the medullary respiratory development, e.g. flucloxacillin (FLOXAPEN), neuromuscular blockade6. In the eyes, these ‘resistance race’, bacteria are always one step neuritis, drug-induced myopia or strabismus development of better antibiotics will continue c) Pregnancy: Administration of streptomycin due to blockade of terminals of oculomotor, Quinolones
orthophosphate. The volume of distribution and is effective against sensitive strains of of the tetracyclines is comparatively larger sequestration of the drug in some tissues.
indicated in a variety of systemic infections Crystalline deposits probably of a metabolite erythematosus, in these cases in much higher including urinary tract infections (UTI), of tetracycline, have also been observed in doses, and it is in this capacity that it may certain types of pneumonia and sinusitis.
maculopathy. Excretion of chloroquine is slow levofloxacin, when given orally, penetrates the interesting ocular side effect of tetracycline is vitreous posteriorly. The study was performed probably seen very rarely. The efficacy of to elucidate the possible efficacy of the drug tetracycline in acne is believed to be via a decrease in the fatty acid content of sebum.
with chloroquine, a baseline eye examination implications on the possibility of ocular side The question arises as to whether there is any including VA, visual fields, ophthalmoscopy effect of prolonged therapy with this drug on and colour vision appraisal, should be carried the lipid layer of the tear film produced by Tetracyclines
the secretion of the meibomian glands.
This small group of antibiotics includestetracycline (ACHROMYCIN), minocycline Cephalosporins
(MINOCIN) and oxytetracycline (OXYTET). They This is a large group of antibiotics with the inhibit bacterial protein synthesis. They are same mechanism of action as the penicillins, particularly useful in the long-term treatment of rosacea and acne vulgaris, but are also used formation (Table 1). This effect leads to entry in other infectious conditions, notably urinary of water into the bacterial cell by osmosis resulting in rupture of the bacterium.
Cephaloridine administered systemically has headaches and bilateral visual loss secondary tetracycline and isotretinoin (ROACCUTANE) for semisynthetic derivative of cephamycin c and is resistant to breakdown by beta-lactamases out. Six-monthly monitoring is recommended (see above). It is indicated for the therapy of Lee’s8 report was regarding a 14-year old infections. Exfoliative dermatitis associated dermatologist. The patient was at one time with the use of cefoxitin was reported by pigment stippling of the RPE may occur.
treated with isotretinoin 40mg per day and Kannangara et al11. As with penicillin, this can Blurred vision may also be reported.
tetracycline 500mg per day. Over three weeks, affect the eyes and the periorbital skin. This Chloroquine retinotoxicity is popularly known the patient noticed decreased visual function to cause bull’s eye maculopathy (Figure 3).
in both eyes. All other findings were negative cefoxitin at a dosage of 1.0g intramuscularly This consists of a central bright red circular at this stage. Later, visual field testing area, surrounded by a concentric lighter, revealed an inferonasal defect in the right eye, (infection of bone) of the calcaneum.
circular region which, in turn, is surrounded and a superior paracentral defect in the left by a further bright hyperpigmented area. Generic name
Trade name
intracranial pressure (ICP) and the patient underwent optic nerve sheath decompression amiodarone, an antiarrhythmic agent13. In of the left eye, followed one month later by contrast to chloroquine retinopathy, this is optic nerve sheath decompression of the right eye. Patients on one of the tetracyclines who treatment. It appears that the drug itself is headache, nausea and vomiting, diplopia or tetracycline can lead to discolouration of Chloroquine
trypanosomiasis (sleeping sickness), and is various body sites including skin, nails, bone, Chloroquine (NIVAQUINE) is an antimalarial also currently being investigated for the drug which attacks the asexual erythrocytic treatment of various neoplasms. It can lead to therapy has been reviewed recently9. They forms of the malaria parasite or plasmodium, many different adverse effects which vary in found that pigmentation of the skin and oral i.e. it is a schizonticide. The mechanism of intensity and frequency with the nutritional mucosa is reversible on withdrawal of the this effect is unknown, but the latest theory status of the patient, and reactions are more drug; however, although eye pigmentation is severe in malnourished patients. The adverse less common, it is usually irreversible. Scleral Plasmodium to a toxic product by inhibiting effects of suramin on the visual mechanism pigmentation (specifically) consisting of a its binding to a histidine-rich protein12 blue-grey 3-5mm band starting at the limbus (plasmodium is a unicellular protozoan).
due to this drug has also been reported10.
There are four species of Plasmodium, namely Staining of developing bones, teeth, nails so-called G-protein, which is an important P. ovale and P. falciparum, each causing a intermediary in the cascade reaction which therapy is well known. In these tissues, the chelation of tetracycline is with calcium prolongs remissions between P. vivax attacks chromophore into millions of molecules of the developed countries, antibiotics and other 3. Crews, SJ (1977) Ocular adverse reactions conversion of the 11-cis condition in the dark antibacterial agents are very commonly used; these are also used frequently in those third 4. Patel, M (2002) Understanding disease: world countries which can afford them, but in medicine and surgery for the optometrist.
A vortex keratopathy similar to that seen these countries, the antiprotozoal agents and with chloroquine, amiodarone (CORDARONE X) antihelminthic drugs also constitute a large and procainamide (PRONESTYL), may also be proportion of drugs used. What is more, in these regions, many of these drugs are freely Tryparsamide
This drug is also used in trypanosomiasis.
As a result, ocular effects reported from Ocular side effects of tryparsamide are more antimicrobial drug use are numerous. For the neurotoxicity of antibacterial agents.
severe and common than other side effects.
Constriction of the visual fields followed by 7. Herbert, EN, Pearce, IA, McGalliard, J, described above and their early detection so neuritis resulting in blindness if therapy is not discontinued early. ‘Shimmering’ or serious consequences ensue, and secondly to ‘dazzling’ of vision occurs in nearly 10% of help this process by looking into the more interesting but perhaps less serious side 8. Lee, AG (1995) Pseudotumor cerebri after effects (such as the deposition of tetracycline amoebiasis and giardiasis, other protozoal infections. One patient has been reported to experience oculogyric crises while taking this practitioners reading this article, it is hoped Incidence, prevention and management.
that the scale of the problem not only of Anti-tuberculous drugs
ocular, but perhaps even more so of systemic 10. Fraunfelder, FT and Randall, JA (1997) Streptomycin is used in the therapy of several side effects of antimicrobial agents, would Minocycline-induced scleral pigmentation.
conditions, particularly tuberculosis (where make him/her reconsider their prescribing two or more drugs to which the organism is policies for infectious diseases. It should be 11. Kannangara, DW, Smith, B and Cohen, K reiterated here that before prescribing any drug, a doctor should, as a matter of routine, cefoxitin therapy. Arch. Intern. Med.
endocarditis. Goode et al17 have studied the balance the possibility of side-effects against abolition of the vestibuloocular reflex (VOR) the potential consequences of the malady, if Srivastava, J, Pandey, KC and Chauhan, VS reversible (it is not in man). Streptomycin is reputed to be toxic to the hair cells in the detoxification inhibition by chloroquine.
vestibule. Ethambutol (MYAMBUTOL) is active other generally untreatable infections like Lassa fever (which is rife in Nigeria), the need ethambutol have been reported, most being for antimicrobial agents will continue to reversible. However, some irreversible effects increase and, consequently, the incidence of ocular and other side effects is also likely to rise. A reappraisal of prescribing practices is coupling of rhodopsin to transducin.
neuritis, patients on ethambutol should be instructed on home testing of visual acuity ocular side effects and drug interactions 15mg/kg/day, screening of the patient every About the author
3rd Edition. Lea and Febiger, Philadelphia.
Mukesh Patel is a practising optometrist with 16. Kirkham, G and Gott, J (1986) Oculogyric crisis associated with metronidazole.
to treat tuberculosis. It often leads to optic neuritis19 but this can be prevented by daily pharmaceutical company. His special interest is in clinical cardiovascular pharmacology, Fuchs, AF (2001) Visual influences on the and he lectures on various topics from time to reported to lead to production of antinuclear vestibuloocular reflex in the chicken.
systemic lupus erythematosus (SLE), and even References
18.Sivakumaran, P, Harrison, AC, Marschner, 1. Ball, AP, Geddes, AM, Davey, PG, Farrell, ID and Brookes, GR (1980) Clavulanic acid RIMACTANE) or its metabolite in tears has and Amoxycillin: a clinical, bacteriological been reported to cause orange discolouration 19. To, TQ and Townsend, JC (2000) Ocular Conclusion
Although certain drugs are obviously required more often in certain parts of the world, the 20.Lyons, RW (1979) Orange contact lenses

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