Ординатура / Офтальмология / Английские материалы / Clinical Ocular Pharmacology 5th edition_Bartlett, Jaanus_2008

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172 CHAPTER 10 Ocular Hypotensive Drugs

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Humans are constantly exposed to a variety of microorganisms, including bacteria, viruses, and fungi. In most cases these microorganisms do not produce infection because the skin and mucous membrane surfaces provide effective barriers against invasion. A few microorganisms, however, can invade directly through these barriers, and others can cause infection if introduced into the body through lesions from surgery or trauma. If microorganisms penetrate the body’s outer barriers, the immune system usually deals with them quite effectively. However, some microorganisms possess special properties that allow them to overcome this system. In addition, patients’ immune systems do not always function optimally, allowing microorganisms that would normally not pose a problem to cause an infectious disease. When the immune system is depressed, the term immunocompromised is used.Two of the many situations that can cause immunocompromise are the use of drugs, such as corticosteroids that depress the immune response, and infection with human immunodeficiency virus (HIV), which causes acquired immunodeficiency syndrome (AIDS).

Many different compounds have been used to assist the body’s immune system in killing microorganisms. An especially important property of an anti-infective drug is selective toxicity. The drug must be more toxic for the microorganism than for the host. An ideal anti-infective drug kills microorganisms while causing minimal or no adverse reaction in the host.

Each of the major categories of microorganisms that cause disease (bacteria, viruses, and fungi) has a unique physical structure and metabolism. The differences between the categories are so broad that drugs that are toxic for organisms in one category are usually not active against members of the other two categories. Thus antiinfective drugs are classified as being antibacterial, antiviral, or antifungal.

An anti-infective drug is usually not active against all species of microorganisms within a category. The species against which a drug shows intrinsic activity is referred to as the drug’s spectrum of activity. A narrow-spectrum anti-infective drug is active against only a few species,

whereas a broad-spectrum drug is active against a wide variety of species. Knowledge of a drug’s spectrum of activity is useful in determining clinical applications for the drug.

As anti-infective drugs are used to treat diseases, microorganisms evolve various strategies to resist them. Resistance occurs when a microorganism that was originally in an anti-infective drug’s spectrum of activity is no longer susceptible to the drug. Resistance limits the usefulness of an anti-infective drug. Knowledge of the resistance patterns in the geographic area where the patient resides can help to determine an initial drug to treat an infection. Using this type of information, the drug choice is considered empiric. When information on the specific resistance pattern of the microorganism that is causing the infection is available, this determines whether the microorganism is susceptible to the initial drug or whether another drug would be better for treatment of the infection.

This chapter describes the mechanisms of action, spectra of activity, resistances, indications, and potential side effects for each of the major antibacterial, antiviral, and antifungal drugs.Antiprotozoal drugs of interest in ocular pharmacotherapy are also discussed.

GUIDELINES FOR EFFECTIVE

ANTIMICROBIAL THERAPY

The clinical process of selecting an anti-infective drug for the treatment of disease can be complex, and many factors must be considered (Box 11-1). First, the patient’s history, symptoms, and signs need to be evaluated to establish a tentative infectious diagnosis, and then a “best guess” regarding the causative microorganism(s) is made.

An anti-infective agent (or combination of agents) can then be selected and empiric therapy planned.

Samples of tissue or body fluids may be obtained for laboratory culture and identification so that the clinician’s “guess”can be confirmed and susceptibility of the isolated microorganisms(s) to anti-infective drugs can be assessed.

Because laboratory identification and susceptibility

176 CHAPTER 11 Anti-Infective Drugs

Box 11-1 Guidelines for Effective Antimicrobial Therapy

Establish accurate clinical and laboratory diagnosis Select anti-infective drug to which the microorganism

is sensitive

Select least toxic anti-infective drug

Establish adequate drug levels at site of infection Select optimum route(s) of administration

Use appropriate dosage regimen

Prescribe drug for appropriate length of time Augment drug therapy with physical procedures Educate patient

testing requires several days, the clinician often must initiate empiric anti-infective therapy before this process is complete.

After the clinician has selected a drug for use, he or she needs to determine which route(s) of administration will best ensure a therapeutic concentration at the site of infection. For different types of ocular infection, topical application, oral administration, intramuscular injection, intravenous injection, intravitreal injection, or a combination of routes may be appropriate (Table 11-1).

Topical instillation of anti-infective drugs is usually the preferred mode for local therapy of ocular infections. Solution formulations are typically chosen over ointments for adults, particularly for use during waking hours, because ointments tend to blur vision after application. Ointments, on the other hand, are often preferred for infants and young children because of prolonged contact

time between the drug and eye and the resistance to tear washout.

When planning antibiotic therapy, the clinician should also estimate the length of time of drug administration. An appropriate period eradicates the microorganisms while minimizing adverse events. Excessive use of antiinfective drugs can cause hypersensitivity or toxicity reactions. In addition, using an antibacterial drug longer than necessary to eradicate the microorganism or using it inappropriately facilitates the development of resistant strains of bacteria.The risk of superinfection, which is an overgrowth of microorganisms that are usually held in check by the body’s normal flora, also exists with the use of any antibacterial drug, especially with excessive use of multiple antibacterial drugs.

Another factor to consider in developing a treatment plan is to determine which physical procedures might augment the drug therapy. Such procedures can be especially useful when appreciable quantities of purulent exudate or necrotic tissue are present and must be removed from the site of infection. As an example, the application of hot compresses and lid scrubs to improve circulation and to remove crusting deposits on the lids and lashes is especially useful in the treatment of lid infections with staphylococci.

Educating the patient about his or her disease and the use of the anti-infective drug that is being prescribed is essential for effective therapy. The right drug with the right route of administration cannot be effective unless the patient uses or takes the medication appropriately.

When a patient with an ocular disease fails to respond to anti-infective therapy even though an appropriate treatment plan was developed and followed, a variety of explanations are possible. Box 11-2 outlines these explanations.

ANTIBACTERIAL DRUGS

Bacteria That Cause Ocular Infections

Bacteria are a diverse group of single-celled microorganisms that, in most cases, can produce their own energy and cellular components. The largest division of bacteria can be subdivided using microscopic morphology: Gram stain

Box 11-2 Reasons for Antimicrobial Failure

Inaccurate diagnosis Resistant microorganism

Inadequate drug dosage (amount, frequency, or duration)

Inadequate supplemental physical procedures Inadequate patient immune system response Patient noncompliance

reaction, shape of the cells, and arrangement of the cells. Of the many bacterial species, only a few are pathogenic in humans. Table 11-2 shows the most common pathogenic bacteria and the infections they cause.

Gram-positive spherical bacteria (cocci) arranged in clusters are staphylococci. Staphylococcus epidermidis is found normally on the skin and mucous membranes in high numbers. However, it can cause an infection if an opportunity such as a skin abrasion occurs.Staphylococcus aureus is also found on the skin and mucous membranes but in lower numbers than S. epidermidis. It is a much more virulent pathogen and usually causes more serious disease. About half the ocular infections that occur are caused by staphylococci.

The streptococci are the other group of gram-positive cocci that cause ocular infections; morphologically, they are arranged in chains. This group includes Streptococcus pneumoniae (morphologically seen as diplococci), which causes corneal ulcers and pediatric conjunctivitis.

Gram-negative cocci that cause infections include

Neisseria gonorrhoeae,which causes gonorrhea.Neisseria gonorrhoeae initially causes hyperpurulent conjunctivitis but can quickly invade the cornea and the rest of the eye.

Two types of gram-negative rods cause eye infections. Haemophilus influenzae causes infections in early childhood, with otitis media and conjunctivitis often seen concurrently. The enteric gram-negative rods include

Escherichia coli, Serratia marcescens, Proteus, and

Pseudomonas aeruginosa. These bacteria are typically found in the intestinal tract and commonly cause urinary tract infections. In the eye they can cause corneal ulcers.

In addition, several groups of bacteria with unique structural morphology or metabolism can cause ocular disease. Chlamydia lacks the ability to produce sufficient energy to grow independently and mimics viruses in that it must grow and multiply inside other living cells. Chlamydia trachomatis is transmitted by finger-to-eye or fomite-to-eye in the case of trachoma or by selfcontamination from a genital infection in the case of inclusion conjunctivitis.

The spirochetes, which have a special morphology consisting of flexible spirals, include Treponema pallidum, which can cause syphilis. Possible syphilitic eye disease findings include interstitial keratitis, uveitis, pigmentary retinopathy, vitritis, retinal vascular sheathing, and papillitis.

Bacterial Resistance

As antibiotics are used to treat infections, bacteria evolve various strategies to resist them. Resistance occurs when bacteria that were initially susceptible to an antibiotic become resistant to the action of the drug. Bacteria become resistant through one or more of the following mechanisms: (1) producing an enzyme capable of destroying or inactivating the antibiotic, (2) altering the

target site receptor for the antibiotic so as to reduce or block its binding, and/or (3) preventing the entry of the antibiotic into the bacterial cell and/or actively transporting the antibiotic out of the bacterial cell.

Exposure to antibiotics does not, in itself, cause bacteria to become drug resistant. Changes in bacteria that facilitate resistance occur naturally as a result of mutation (i.e., change in the chromosomal DNA) or as a result of the bacteria receiving extrachromosomal DNA in the form of a plasmid from other bacteria. Exposure to an antibiotic simply selects for strains of the organism that have become resistant through these natural processes. Misuse of antibiotics (e.g., prescribing them for nonbacterial infections) increases the rate at which this selection occurs.

Resistant mutants are more likely to arise after exposure of a bacterial subpopulation to repeated sublethal doses of an antibiotic. Thus antibiotics should not be used intermittently. Patients should be educated about using or taking antibiotics according to the dosage schedule and should use or take the entire amount of antibiotic prescribed. Sublethal exposure can also occur during

tapering of an antibiotic. Thus antibiotics are not tapered but are discontinued abruptly while at the therapeutic level.

As bacteria become drug resistant, new drugs must be isolated or developed in the laboratory. Unfortunately, bacterial resistance is developing faster than the development of new antibiotics; thus choosing an effective antibiotic for treating a serious bacterial infection is becoming more difficult.

Because of bacterial drug resistance, information about a pathogen’s pattern of resistance/susceptibility is essential when choosing an antibacterial agent. Several laboratory tests are used to determine resistance/susceptibility of a bacterial pathogen. In these in vitro tests, an organism is generally considered susceptible if the concentration of antibiotic necessary to inhibit its growth is lower than the concentration potentially attainable in body fluids, particularly blood.

In a common type of susceptibility testing, serial dilutions of the antibacterial drug are inoculated with the bacteria to determine a minimal inhibitory concentration (MIC), which is the lowest concentration of the drug that

produces no apparent bacterial growth. The MIC is then compared with the concentration of the antibacterial drug typically attainable in the blood. If the MIC of the bacteria is higher than the attainable blood level, the bacteria are resistant to the drug. If the MIC is lower than the blood level, the bacteria are susceptible to the drug. Because the results of in vitro tests correlate closely with in vivo results, culture and susceptibility testing should be requested when a systemic antibiotic is needed to treat the infection.

To evaluate the clinical significance of resistance to an antibiotic that is to be used topically, it is helpful to quantify the level of resistance as low level or high level. Lowlevel in vitro resistance seen when the MIC is just slightly above the level attainable in the blood may not necessarily translate into clinical treatment failure because the tissue levels that can be achieved with topical dosing may be much higher than those typically achieved after systemic dosing. By contrast, high-level resistance seen when the MIC is significantly higher than the levels achievable with systemic dosing is more likely to be associated with treatment failure because the MIC of the isolate may not be achievable even with a topical route of delivery.

Relationship Between Bacterial Structure

and Antibacterial Drug Action

Several differences exist between bacterial and human cells, and these differences form the basis for selective toxicity of the antibacterial drugs (Figure 11-1). First, bacteria have a unique outermost layer, a cell wall that is not found in any human cell. A specific layer within the cell wall, called the peptidoglycan, is necessary for the bacterium’s structural integrity; without it the bacterium lyses and dies. Several antibacterial drugs act by inhibiting synthesis of the cell wall, specifically the peptidoglycan.

DNA

Peptidoglycan of Cell Wall

Cell Membrane

Cell Wall

Ribosomes

Figure 11-1 Morphology of a bacterial cell.

A second way in which bacterial and human cells may differ involves their cell membranes. However, because membranes of both cells are so similar, only a few compounds have been found that can selectively disrupt bacterial cell membranes while leaving those of the human cells intact.

A third difference between bacterial and human cells involves their ribosomes. Bacterial ribosomes are neither the same size nor have the same composition as human ribosomes. Thus drugs that bind more to bacterial than to human ribosomes can inhibit bacterial protein synthesis and have a selective toxicity for these cells.

A fourth difference between bacterial and human cells involves specific biosynthetic pathways. Bacterial cells usually synthesize their own folic acid, whereas humans receive folic acid preformed in their food. Thus drugs that can inhibit folic acid synthesis are selectively toxic for bacteria.

A fifth difference between bacterial and human cells involves the enzymes DNA gyrase and topoisomerase IV. These enzymes are involved in bacterial DNA synthesis and are responsible for cutting and resealing DNA strands to prevent excessive supercoiling. Because human cells lack these enzymes, drugs that inhibit the enzymes are specifically active against bacteria.

Drugs Affecting Cell Wall Synthesis

Antibacterial drugs that affect cell wall synthesis include two large families, the penicillins and cephalosporins, and two individual drugs, bacitracin and vancomycin.

Penicillins

Pharmacology

All penicillins contain a common nucleus composed of a thiazolidine ring and a β-lactam ring connected to a side chain. An intact β-lactam ring is necessary for biologic activity, but the side chain primarily determines the antibacterial spectrum, susceptibility to destruction by gastric acid and β-lactamase enzymes, and pharmacokinetic properties.

The penicillins act by inhibiting synthesis of the bacterial cell wall. The rigid cell wall structure is due to peptidoglycan, which is a mucopeptide made up of linear polysaccharide chains cross-linked by peptide bonds. Penicillins inhibit the enzymes called transpeptidases that create the peptide cross-linkage, and this leads to an incomplete cell wall structure. The enzymes are located beneath the cell wall and are also known as “penicillinbinding proteins.” Penicillins exert their bactericidal effect most strongly on actively dividing cells that are synthesizing new cell walls.

The basic penicillin nucleus has been and continues to be chemically modified to produce penicillins with unique advantages. Based on their spectra of antibacterial activity and their clinical applications, the penicillins can be divided into four categories (Table 11-3).