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

Clinical Uses

Penicillins Effective Against Gram-Positive Bacteria. The two most important drugs in this category are penicillin G and penicillin V. Penicillin G is not stabile in gastric acid and is administered parenterally. Penicillin V, which is not inactivated by gastric acid, can be given orally.

A major mechanism of acquired resistance to the penicillins is bacterial production of enzymes called β-lactamases. These enzymes hydrolyze the penicillin β-lactam ring that is necessary for its activity. β-Lactamases with a strong proclivity for penicillins are called penicillinases. Because most strains of Staphylococcus aureus and many strains of Staphylococcus epidermidis produce penicillinase, penicillins G and V are not effective against these gram-positive bacteria.

Some streptococci have developed a different mechanism of acquired resistance to penicillin drugs. These bacteria have altered transpeptidases (also known as penicillin-binding proteins) that no longer bind penicillin, and thus peptidoglycan synthesis is not disrupted. This mechanism of resistance is found in Streptococcus pneumoniae. Estimates of penicillin-resistant S. pneumoniae in the United States range from 25% to 66%, including strains recovered from ocular and periocular infections. Many isolates of penicillin-resistant S. pneumoniae also are resistant to the cephalosporins, macrolides, and the older fluoroquinolones. Use of alternative antibiotics such as vancomycin is necessary for infections caused by penicillin-resistant isolates.

In addition to S. pneumoniae, the viridans group of streptococci is also developing resistance to penicillin through the same mechanism, altered penicillin-binding proteins. In contrast, resistance has not developed in Streptococcus pyogenes, and both penicillins G and V are antibiotics of choice for systemic infections caused by this organism.

Gram-negative Neisseria gonorrhoeae is within the spectrum of activity for penicillin G, but many strains of this organism produce penicillinase. Because antibiotic therapy is typically taken before bacterial susceptibilities are known, recommended drugs for treatment of gonococcal infections include the cephalosporins, ceftriaxone and cefixime, which are not inactivated by gonococcal penicillinase.

Because Treponema pallidum is sensitive to penicillin G, this antibiotic is the drug of choice for treatment of syphilis and syphilitic eye disease (see Table 11-1). Syphilitic eye disease can include interstitial keratitis (stromal inflammation and vascularization), episcleritis, scleritis, nongranulomatous or granulomatous iritis, iris papules (collections of dilated capillaries in the iris), chorioretinitis, papillitis, retinal vasculitis, and exudative retinal detachment. Probenecid can be added to procaine penicillin to decrease excretion of the penicillin by the kidneys, thus causing an increase in penicillin plasma levels. Penicillins are not used for the treatment of minor ocular infections such as blepharitis and conjunctivitis

because of the high incidence of allergic reactions when the drug is administered topically.

Penicillins Resistant to Penicillinase. Modification of the penicillin structure produced a group of drugs including methicillin, oxacillin, cloxacillin, dicloxacillin, and nafcillin that are not susceptible to staphylococcal penicillinase.Their appropriate use is in the treatment of infections caused by strains of Staphylococcus aureus and

Staphylococcus epidermidis that produce penicillinase. These include most strains isolated from hospital settings and the general community.

As this category of penicillins was used for treatment, S. aureus and S. epidermidis became resistant to them through the production of altered penicillin-binding proteins. These strains of staphylococci are called “methicillin resistant,” which denotes resistance not only to all penicillinase-resistant penicillins but to all penicillin drugs. Methicillin-resistant staphylococci have become a major problem in treatment because they are also resistant to the cephalosporins, aminoglycosides, and macrolides. For this reason vancomycin, a more toxic antibiotic, is the drug of choice for these organisms.

Penicillins resistant to penicillinase can be used to treat ocular infections. An internal hordeolum, which is an infection of a meibomian gland typically with staphylococci, can be treated with oral dicloxacillin when the hordeolum is severe or not resolving with more conservative treatment.

Orbital cellulitis is an infection of the orbital contents posterior to the orbital septum. Streptococci and staphylococci are common bacterial isolates. Many regimens exist for empiric treatment of this disease, but no regimen has been tested in clinical trials. Intravenous nafcillin can be used as initial therapy for orbital cellulitis, especially when a staphylococcal infection is suspected or known (see Table 11-1).

Penicillins With Extended Spectra of Activity. Further modification of the basic penicillin structure produced ampicillin and amoxicillin with broader spectra of activity than the original penicillins. One important organism included in the spectra of these antibiotics is Haemophilus influenzae. These antibiotics are used to treat otitis media and respiratory infections in children.

A disadvantage of ampicillin and amoxicillin is that they are inactivated by penicillinase, and more strains of H. influenzae are becoming resistant through penicillinase (β-lactamase) production.The addition of a β-lactamase inhibitor such as clavulanate (clavulanic acid) or sulbactam to a penicillin preparation can protect the penicillin component because these chemicals irreversibly inactivate bacterial β-lactamases.

Amoxicillin/clavulanate and ampicillin/sulbactam are useful for treating lower respiratory infections, otitis media, and sinusitis caused by β-lactamase–producing strains of H. influenzae (see Table 11-3). They are also

182 CHAPTER 11 Anti-Infective Drugs

useful for treating skin infections caused by penicillinaseproducing strains of Staphylococcus aureus and for urinary tract infections caused by β-lactamase–producing strains of Escherichia coli, Klebsiella sp., and Enterobacter sp. Penicillin-susceptible Streptococcus pneumoniae responds to this drug combination, but penicillin-resistant S. pneumoniae does not because its resistance is not due to production of a penicillinase.

Amoxicillin/clavulanate given orally and ampicillin/ sulbactam given intravenously are useful for treating ocular infections suspected or caused by penicillinaseproducing strains of Staphylococcus aureus and Staphylococcus epidermidis, penicillin-susceptible strains of Streptococcus pneumoniae, and β-lactamase–producing strains of H. influenzae. These infections include orbital cellulitis, preseptal cellulitis, and dacryocystitis (see Table 11-1).

Preseptal cellulitis is an infection anterior to the orbital septum in the connective tissue of the lid and anterior periorbital tissues. Staphylococcus aureus, Streptococcus pyogenes, and, in children less than 5 years of age, H. influenzae are often isolated. In mild preseptal cellulitis oral amoxicillin/clavulanate can be prescribed, whereas in a more serious infection of the lids, ampicillin/sulbactam can be used intravenously (see Table 11-1).

Dacryocystitis occurs when the lacrimal drainage system is blocked and bacteria from the tears infect the lacrimal sac. Bacterial etiology includes staphylococci,

Streptococcus pneumoniae, and H. influenzae in children, all of which are susceptible to oral amoxicillin/ clavulanate. More serious infections require intravenous administration of ampicillin/sulbactam. This bacterial infection needs to be treated before nasolacrimal duct irrigation, probing, or surgery is performed.

In about 2% to 4% of full-term newborns, the membrane over the valve of Hasner at the nasal end of the duct has not perforated. This causes a recurrent conjunctivitis and sometimes a dacryocystitis. Because spontaneous opening frequently occurs 1 to 2 months after birth, management is typically not aggressive.Warm compresses, massage from the canaliculi down over the lacrimal sac, and a topical antibiotic, if mucopurulent discharge is present, are usually prescribed for initial treatment (see Table 11-1).

Penicillins With Antipseudomonal Activity. The chief advantage of the antipseudomonal penicillins, carbenicillin, mezlocillin, piperacillin, and ticarcillin, is that they act against Pseudomonas aeruginosa and certain Proteus and Enterobacter species not susceptible to most other penicillins. Patients with septicemia, burn infections, pneumonia, severe urinary tract disease, and meningitis caused by these organisms have often dramatically improved after use of these drugs, often in combination with an aminoglycoside. The drugs are also useful for serious ocular infections caused by gram-negative bacteria, especially P. aeruginosa. Ticarcillin or piperacillin have

been used along with an aminoglycoside for the topical treatment of bacterial corneal ulcers caused by gram-negative rods, including P. aeruginosa.

Side Effects

The major adverse reactions to the penicillins are hypersensitivity responses. Manifestations of hypersensitivity include urticaria, angioedema, and anaphylaxis (type I reaction); hemolytic anemia (type II reaction); interstitial nephritis, vasculitis, and serum sickness (type III reaction); and contact dermatitis or Stevens-Johnson syndrome (type IV reaction). A maculopapular rash occurs late in the treatment course of 2% to 3% of patients receiving a penicillin drug. Once a patient has had a hypersensitivity response to a penicillin, it is probable, but not certain, that a reaction will occur with exposure to the same penicillin or to any other penicillin. Intradermal skin tests can predict whether a patient is at risk for developing a hypersensitivity reaction to the penicillins. If the results are positive, penicillins should generally be avoided.

Penicillins can cause local effects such as pain, induration, and tenderness at the site of an intramuscular injection. Administration of penicillin intravenously can also cause burning or phlebitis. Hematologic toxicity produced by penicillins is rare, but various types of dyscrasias such as leukopenia, granulocytopenia, abnormal platelet aggregation, and anemia have been reported.

Adverse effects of the penicillins on the central nervous system include headache, dizziness, somnolence, confusion, tremor, and seizures. The penicillins can also adversely affect the liver, as evidenced by elevated liver enzymes and bilirubin, and the kidney, as evidenced by elevated blood urea nitrogen and creatinine.

Penicillins alter the normal bacterial flora in areas of the body, including the respiratory and intestinal tracts. Patients taking oral penicillins may experience nausea, vomiting, or diarrhea. This is usually of little clinical significance because the normal microflora reestablishes itself quickly after cessation of therapy. However, serious superinfection with resistant organisms such as Pseudomonas, Proteus, or Candida can follow long-term therapy with any penicillin. Superinfection with Clostridium difficile can lead to potentially fatal pseudomembranous colitis.

Very infrequently and unpredictably, penicillins can cause oral contraceptives to fail. For maximal protection, a barrier contraceptive method should be used routinely while taking a short course of a penicillin and for at least 7 days afterward.

Penicillin use may be related to breast cancer development. However, more research is needed to determine whether the relationship is causal.

Contraindications

Because penicillins and cephalosporins have a common chemical structure, cross-allergies occur with these drugs. Thus before initiating therapy with a penicillin,

careful inquiry should be made concerning previous hypersensitivity reactions to any penicillin or cephalosporin.

Cephalosporins

Pharmacology

Like the penicillins, cephalosporins contain a β-lactam ring that is necessary for antimicrobial activity. However, a six-member dihydrothiazine ring replaces the fivemember thiazolidine ring characteristic of the penicillins.

Penicillins and cephalosporins have similar mechanisms of action. They both interfere with the terminal step in bacterial cell wall formation by preventing proper cross-linking of the peptidoglycan.

An important mechanism of acquired resistance to cephalosporins is drug inactivation by β-lactamases to which the cephalosporins have variable susceptibility. For example, the β-lactamases produced by S. aureus are considered true penicillinases and do not affect the cephalosporins. Thus the cephalosporins are usually active against penicillinase-producing S. aureus. In contrast, gram-negative bacteria produce β-lactamases that inactivate many of the cephalosporins.

Adding different side chains extensively modified the parent cephalosporin compound and created a whole family of cephalosporin antibiotics. For the sake of convenience, these drugs are considered as first-, second-, third-, or fourth-generation compounds based on their spectra of bacterial activity and their clinical uses (Table 11-4).

Clinical Uses

First-Generation Cephalosporins. First-generation cephalosporins include cephradine, cephalexin, cefadroxil, and cefazolin (see Table 11-4). All act effectively against gram-positive bacteria (e.g., methicillin-sensitive

Staphylococcus aureus, Streptococcus pyogenes, peni- cillin-sensitive Streptococcus pneumoniae) but have relatively modest activity against gram-negative bacteria.

Cefazolin is used in combination with gentamicin or tobramycin to treat bacterial corneal ulcers as part of a broad-spectrum approach (see Table 11-1). Cefazolin is used because its spectrum of activity encompasses the gram-positive cocci, including penicillinase-producing staphylococci. However, there is increasing concern about treating corneal ulcers with cefazolin because more penicillin-resistant Streptococcus pneumoniae and viridans streptococci are being isolated from corneal infections. Cefazolin is administered topically as fortified eyedrops that are prepared by diluting high concentration products intended for parenteral use.

Second-Generation Cephalosporins. Second-generation cephalosporins include cefaclor, cefprozil, cefuroxime, cefoxitin, and cefotetan (see Table 11-4). Drugs in this group have increased activity against certain gramnegative pathogens (e.g., H. influenzae), and cefoxitin and cefotetan are effective against bowel anaerobes.

Cefaclor is used to treat bacterial infections of the middle ear, lung, and urinary tract. Oral cefaclor can also be used to treat mild preseptal cellulitis. Parenteral administration of cefuroxime along with ampicillin/sulbactam is a recommended treatment for severe or unresponsive preseptal cellulitis (see Table 11-1). However, with the increase of penicillin-resistant isolates of Streptococcus pneumoniae, the effectiveness of empirically treating this condition with β-lactam drugs needs to be carefully considered.

Third-Generation Cephalosporins. Third-generation cephalosporins include cefixime, cefdinir, cefotaxime, ceftriaxone, and ceftazidime (see Table 11-4). These drugs are somewhat less active against gram-positive cocci but are much more active against enteric gram-negative bacteria. The primary advantage of ceftazidime when compared with the other currently available third-generation cephalosporins is its excellent activity against gram-nega- tive bacteria, including P. aeruginosa. Ceftazidime is used as an alternative for topical and intravitreal amikacin, an aminoglycoside, to cover gram-negative organisms, including P. aeruginosa, in the treatment of endophthalmitis (see Table 11-1). Ceftazidime or ceftriaxone combined with nafcillin can be used to treat orbital cellulitis. Ceftriaxone combined with vancomycin can be used to treat moderate to severe preseptal cellulitis.

With a nationwide distribution of penicillinase-producing N. gonorrhoeae, a recommended regimen for treating gonococcal infections, including gonococcal conjunctivitis, is intramuscular ceftriaxone, a third-generation cephalosporin (see Table 11-1). Intramuscular or intravenous ceftriaxone is also the recommended treatment for gonococcal ophthalmia neonatorum. Cefixime, another third-generation cephalosporin, has been recommended for treatment of gonorrhea and is advantageous because it can be administered orally.

Fourth-Generation Cephalosporins. The fourth-generation cephalosporin, cefepime, has an extended spectrum of activity against both gram-positive (e.g., methicillinsensitive S. aureus) and gram-negative organisms (e.g., Pseudomonas).

Side Effects

As with the penicillins, hypersensitivity reactions are the most common systemic adverse events caused by cephalosporins. Maculopapular rash, urticaria, fever, bronchospasm, and anaphylaxis have been associated with the use of cephalosporins. Because the molecular structure of the penicillins and the first-generation cephalosporins are similar, there is a risk in patients who are allergic to penicillin to manifest allergic cross-reactions when prescribed any of this group of cephalosporins. In contrast, the risk of cross-reactivity between the penicillins and the second-, third-, and fourth-generation cephalosporins has been overestimated, and patients with a previous allergic

reaction to penicillin may be able to safely take these cephalosporins.

Like penicillins, cephalosporins alter the normal microflora of the intestinal tract and can cause anorexia, nausea, vomiting, and diarrhea. In some cases the diarrhea can become severe enough to warrant discontinuation of the drug. Antibiotic-associated pseudomembranous colitis due to C. difficile can also occur with the cephalosporins. This condition should be considered in the differential diagnosis of diarrhea associated with cephalosporin use.

Overgrowth of resistant organisms such as Acinetobacter, Candida, and enterococci can occur after

long-term use of the cephalosporins. If therapy is prolonged, the patient should be closely monitored for signs of superinfection, especially if he or she is severely ill or if invasive devices such as catheters have been used.

Cephalosporins can also destroy certain components of the intestinal microflora, and a vitamin K deficiency leading to bleeding episodes can result. Administration of vitamin K can reverse this bleeding.

Administration of cephalosporins can lead to reversible renal impairment. When a cephalosporin and an aminoglycoside are administered concomitantly, an additive nephrotoxicity can occur. This reaction is most

likely to occur in the elderly and in patients with decreased renal function.

Cefaclor has been associated with a high incidence of adverse joint and skin reactions. This unusual serum sickness–like reaction appears to be due to an inherited defect in the body’s handling of cefaclor metabolic products.

Cephalosporin use may be related to breast cancer. However, more research is needed to determine whether the relationship is causal.

Contraindications

The cephalosporins are contraindicated in patients with known allergies or intolerances to any of the cephalosporins. Because the penicillins and cephalosporins have a common chemical structure, cross-allergies occur with these drugs. Thus before initiating therapy with a cephalosporin, careful inquiry should be made concerning previous hypersensitivity reactions to the other drugs. Because a secondary vitamin K deficiency can develop with cephalosporin use, the cephalosporins are contraindicated in patients with hemophilia. Cefaclor is also contraindicated in any patient with previous drug-related joint and skin reactions.

Bacitracin

Pharmacology

Bacitracin inhibits bacterial cell wall synthesis by inhibiting the movement of a precursor of peptidoglycan through the cell membrane from the cytoplasm to the cell wall. Most gram-positive bacteria such as staphylococci and streptococci are susceptible to bacitracin. Although this drug is active against Neisseria, most other gram-negative bacteria are resistant.

Clinical Uses

Bacitracin is seldom used parenterally because renal necrosis has been reported after systemic use. Bacitracin is primarily used topically to treat skin and mucous membrane infections caused by gram-positive bacteria because only a few of these bacteria have become resistant to it.

Bacitracin is available in topical preparations either as a single-entity product or as a component of fixedcombination products. Because bacitracin is unstable in solution, it is available only in ointment form. The rationale for combining drugs containing bacitracin along with other antibacterial agents, such as neomycin and polymyxin B, is that by judicious selection, combinations can be produced with complementary antibacterial spectra covering most of the common pathogens. The antibacterial spectrum of bacitracin is mostly gram positive and the spectrum of polymyxin B is gram negative. The spectrum of neomycin includes many gram-negative organisms.Thus bacitracin complements either of the other two drugs. Topical fixed-combination ointments containing

bacitracin are effective for a variety of dermatologic infections such as ulcers and impetigo. Topical combination products are also available as over-the-counter preparations to treat minor skin cuts and abrasions.

Topical ophthalmic preparations containing bacitracin (Tables 11-5, 11-6, and 11-7) are effective for treatment of superficial eye infections. Bacitracin is especially useful for treating staphylococcal blepharitis, because most staphylococci remain sensitive to this antibiotic (see Table 11-1).

Side Effects

Hypersensitivity reactions, usually presenting as contact dermatitis, are rare but can occur with topically applied bacitracin.

Contraindications

Bacitracin is contraindicated in patients with known hypersensitivity or intolerance to the drug.

Vancomycin

Pharmacology

Like the other drugs discussed in this section, vancomycin acts by inhibiting biosynthesis of the bacterial cell wall, specifically the mucopeptide portion of the peptidoglycan. It is highly active against the gram-positive cocci, staphylococci and streptococci, and C. difficile.

Clinical Uses

Because of its potential toxicity, vancomycin is reserved for serious infections in which less toxic antibiotics are ineffective or not tolerated. Generally, vancomycin is administered intravenously because of poor intestinal absorption. It is the drug of choice for treating infections caused by methicillin-resistant staphylococci and penicillinresistant Streptococcus pneumoniae. Vancomycin has been used to treat enterococcal infections because of their resistance to the β-lactam antibiotics, but most enterococci are now also resistant to vancomycin. Oral administration of vancomycin is important for treatment of some gastrointestinal infections such as pseudomembranous colitis caused by C. difficile.

Methicillin-resistant strains of Staphylococcus aureus and S. epidermidis and penicillin-resistant Streptococcus pneumoniae have been isolated from ocular infections. Therefore treatment of ocular infections caused by these organisms might require use of vancomycin for resolution. Vancomycin is also recommended for empiric intravitreal and topical therapy in bacterial endophthalmitis and for parenteral therapy in moderate to severe preseptal cellulitis (see Table 11-1).

Side Effects

The use of intravenous vancomycin in prolonged therapy, in concomitant or sequential use with other ototoxic or nephrotoxic drugs, or in patients with impaired renal function has caused permanent deafness and

fatal uremia. Thus hearing and renal function should be monitored frequently when administering systemic vancomycin.

If vancomycin is needed in a topical form to treat an eye infection, a highly concentrated solution intended for intravenous injection can be diluted. Because this concentrated solution is acidic, dilution with artificial tears or a buffer increases patient comfort.

Contraindications

Vancomycin is contraindicated in patients with known hypersensitivity or intolerance to the drug.

Drugs Affecting the Cell Membrane

Antibacterial drugs that affect the bacterial cell membrane include polymyxin B and gramicidin.

Polymyxin B

Pharmacology

Of the large number of compounds that affect the bacterial cell membrane, only a few have sufficient selective toxicity to be therapeutically useful. Polymyxin B is a cationic detergent or surfactant that interacts with the phospholipids of the cell membrane, thus disrupting the osmotic integrity of the cell. This increases the bacterial cell’s permeability and causes cell death. Polymyxin B acts selectively on gram-negative bacteria, including

P. aeruginosa.

Clinical Uses

Polymyxin B is not used systemically because of its neurotoxicity and nephrotoxicity. Topically, it is used in combination with other antibacterial drugs or steroids to prevent and treat skin infections and external otitis.

Ocular polymyxin B is commercially available in combination with other antibiotics (see Table 11-6) or with steroids (see Table 11-7) to treat infections of the lids and conjunctiva. It is also used to prevent infection when the conjunctiva or cornea is compromised or when a steroid is used.

Side Effects

Adverse reactions to topical application of polymyxin B include irritation and allergic reactions of the eyelids and conjunctiva but are infrequent and typically mild. However, when administered by subconjunctival injection, polymyxin B can cause pain, chemosis, and tissue necrosis.

Contraindications

Polymyxin B is contraindicated in patients with known hypersensitivity or intolerance to the drug.

Gramicidin

Like polymyxin B, gramicidin changes permeability characteristics of the cell membrane, thus killing the cell. However, in contrast to polymyxin B, gramicidin is effective against gram-positive bacteria. It replaces bacitracin in some fixed-combination antibacterial solutions used topically for ocular infections (see Table 11-6).

Drugs Affecting Protein Synthesis

Antibacterial drugs that affect bacterial protein synthesis include the aminoglycosides, tetracyclines, macrolides, and the single drug chloramphenicol.

Aminoglycosides

Aminoglycosides include gentamicin, tobramycin, neomycin, and amikacin.

Pharmacology

Aminoglycosides inhibit bacterial protein synthesis by binding to the 30S subunit of the bacterial ribosome. Consequences of this interaction include inhibition of bacterial protein synthesis and incorrectly reading the genetic code.

Aminoglycosides are bactericidal against a broad spectrum of bacteria, including Staphylococcus aureus, and many strains of gram-negative bacteria, including

P. aeruginosa, Proteus, Klebsiella, E. coli, Enterobacter, and Serratia. They are inactive against anaerobes and poorly active against streptococci, enterococci, and methi- cillin-resistant S. aureus. In contrast to gentamicin, tobramycin, and amikacin, neomycin is not effective against P. aeruginosa. An important attribute of the aminoglycosides is their ability to achieve an additive or synergistic effect against most aerobic gram-negative bacilli and gram-positive cocci when combined with β-lactam antibiotics. There is a similar effect against gram-positive cocci when aminoglycosides are combined with vancomycin.

Gram-negative bacilli show widespread resistance to the aminoglycosides because the bacilli produce enzymes that inactivate the drugs. Gram-negative bacilli produce many different aminoglycoside-inactivating enzymes, with some enzymes inactivating certain drugs but not others. Thus knowledge of general resistance patterns is helpful only in the initial selection of an

aminoglycoside. The specific sensitivity to each drug must be determined for the individual pathogen.

Aminoglycosides are poorly absorbed from the gastrointestinal tract, so when used systemically they must be given parenterally. Note that penicillins or cephalosporins can inactivate aminoglycosides if mixed together in the same solution for injection or for topical application; each drug must be administered separately. If topical fortified cefazolin and fortified tobramycin are used to treat a corneal ulcer, each should be prepared and administered in a separate bottle.

Clinical Uses

Neomycin. Neomycin is the oldest aminoglycoside. It is available for oral, topical, and parenteral administration, but there are almost no indications for oral and parenteral use.

The most common form of neomycin administration is topical. The drug is available in combination with other antibiotics and steroids in numerous ophthalmic, otic, and dermatologic preparations designed to treat a variety of skin and mucous membrane infections (seeTables 11-6 and 11-7). Topical ocular application of neomycin can result in

sensitization to the drug, which leads to contact dermatitis in approximately 4% of patients. Therefore routine use of topical preparations containing neomycin is not recommended, and other drugs or combinations (e.g., bacitracin– polymyxin B) should generally be substituted.

Gentamicin. Gentamicin is widely used in the treatment of severe infections. Uses include septicemia, neonatal sepsis, neonatal meningitis, biliary tract infection, pyelonephritis, prostatitis, and endocarditis. Gentamicin is frequently used for empiric therapy in presumed gramnegative bacillary infections before the identification and susceptibility of the causative organism are known. Patients with cystic fibrosis and those in intensive care units often have Pseudomonas infections and are typically treated with gentamicin.

Topical dermatologic preparations of gentamicin are commonly used for the treatment of infected burns. Topical ophthalmic gentamicin (see Table 11-5) is used to treat a variety of bacterial infections of the external eye and adnexa (e.g., conjunctivitis, blepharitis, and keratoconjunctivitis).

Gentamicin is used for the initial treatment of bacterial corneal ulcers, but the commercially available strength of ophthalmic gentamicin solution is considered inadequate. Consequently, solutions containing fortified concentrations are prepared from sterile products intended for parenteral use. Empiric therapy with fortified gentamicin drops along with a penicillinase-resistant cephalosporin (e.g., cefazolin) is useful until the causative organism and susceptibility are known. An initial loading dose (one drop every minute for 5 minutes) rapidly increases the antibiotic concentrations in the cornea. Drops can then be applied every hour, with the first antibacterial applied on the hour and the second on the half hour. Gentamicin, sometimes in combination with a penicillin having antipseudomonal activity (e.g., ticarcillin), is a specific treatment for P. aeruginosa corneal ulcers.

Tobramycin. The antibacterial activity and pharmacokinetic properties of tobramycin resemble those of gentamicin, and the therapeutic uses of tobramycin are essentially identical to those for gentamicin. Although some bacteria are resistant to both gentamicin and tobramycin, it is unpredictable in individual strains. Amikacin is usually effective for infections caused by organisms resistant to both gentamicin and tobramycin.

Tobramycin is available as a topical ophthalmic solution and an ointment (see Table 11-5). Tobramycin is also prepared as a topical fortified solution for the treatment of corneal ulcers and is used in place of fortified gentamicin using the same dosage schedule (see Table 11-1).

Amikacin. Amikacin was the first semisynthetic aminoglycoside to be marketed. Because a chemical modification present in amikacin protects the molecule from many aminoglycoside-inactivating enzymes, it has become the preferred drug for treatment of gram-negative bacillary infections in which resistance to both gentamicin and tobramycin is encountered. At the clinical level, however, evidence is lacking that amikacin is more efficacious than gentamicin or tobramycin for infections caused by susceptible organisms. Because amikacin is active in vitro against many gram-negative bacilli that are resistant to other aminoglycosides and because amikacin is less toxic when injected intravitreally, it has become a primary antibiotic, along with vancomycin, for treatment of bacterial endophthalmitis (see Table 11-1).

Side Effects

Neurotoxicity manifested as auditory and vestibular ototoxicity can occur in patients treated systemically with any of the aminoglycosides. High concentrations of aminoglycosides that can accumulate in the kidney and urine correlate with the potential for these drugs to cause nephrotoxicity. Usually, discontinuing the drug can reverse early changes. Because the incidence and severity of nephrotoxicity and ototoxicity relate directly to aminoglycoside concentration in the body and to the

length of drug exposure, these antibiotics should be used only when less toxic antibiotics are not effective. Systemic gentamicin can also cause a rare visually related side effect: pseudotumor cerebri with secondary papilledema.

Side effects produced by topical gentamicin or tobramycin are uncommon but can include corneal and conjunctival toxicity. Punctate epithelial erosions, delayed reepithelialization, and corneal ulceration characterize this corneal toxicity, whereas chemosis, hyperemia, and necrosis characterize conjunctival toxicity. Allergic reactions to topical gentamicin occur infrequently, but approximately 50% of patients who are allergic to neomycin are also allergic to gentamicin.

Retinal damage in the form of macular infarction has occurred after intravitreal administration of gentamicin. Because amikacin is less toxic when injected intravitreally, the current recommendation for treatment of postoperative endophthalmitis is intravitreal amikacin (or ceftazidime) for gram-negative coverage.

Contraindications

The aminoglycosides are contraindicated in patients with hypersensitivity or intolerance to any drug within the family.

Tetracyclines

The tetracyclines are a family of drugs that can be divided into three groups based on differences in pharmacokinetics: short acting, intermediate acting, and long acting (Table 11-8).

Doxycycline is the preferred tetracycline because it is better absorbed and distributed than the others.

Table 11-8

Tetracyclines: Classes and Oral Doses

190 CHAPTER 11 Anti-Infective Drugs

Doxycycline also requires only twice-a-day dosing and can be taken with foods, both of which encourage patient compliance.

Pharmacology

Tetracyclines inhibit bacterial protein synthesis by binding to the 30S subunit of the ribosome, thus blocking the attachment of aminoacyl-tRNA to the receptor site on the messenger RNA–ribosome complex.

Although tetracyclines have been widely used antibiotics, their clinical usefulness has declined because of increased bacterial resistance. The resistance is due to a decrease in the bacterial drug concentration caused by an active drug efflux mechanism developed by the bacterial cells.

Clinical Uses

Although the clinical usefulness of tetracyclines is limited for most of the common microbial pathogens, they remain drugs of choice (or very effective alternative therapy) for a wide variety of infections caused by less common pathogens. These include brucellosis; rickettsial infections such as Rocky Mountain spotted fever, typhus, and Q fever; Mycoplasma pneumonia; cholera; plague; Ureaplasma urethritis; Chlamydia infections; and Lyme disease. Oral doxycycline, 100 mg orally twice a day for 7 days, is a recommended treatment for chlamydial sexually transmitted disease.

In adults with chlamydial ocular infections such as inclusion conjunctivitis or trachoma, treatment with oral doxycycline or tetracycline is a recommended strategy (see Table 11-1). In community-based programs to control trachoma, topical tetracycline ointment administered twice daily on an intermittent schedule (5 consecutive days each month for 6 months) can be useful. However, incomplete cure and subsequent disease transmission can result. In contrast, oral treatment with tetracycline or doxycycline cures trachoma.

A fixed-combination ointment containing oxytetracycline and polymyxin B is available for topical ocular use (see Table 11-6). The Centers for Disease Control and Prevention recommends ophthalmic ointments containing a tetracycline or erythromycin as an effective alternative to silver nitrate for prophylaxis of gonococcal ophthalmia neonatorum. A major advantage of using an antibiotic ointment such as oxytetracycline–polymyxin B is that it does not cause the chemical conjunctivitis typically produced by silver nitrate.

Oral tetracycline or doxycycline can be an effective therapy for noninfectious conditions involving the eye such as acne rosacea and meibomianitis. When patients with acne rosacea or meibomianitis receive oral tetracycline, two changes occur: amelioration of the symptoms and reduction of free fatty acids in the surface sebum. Free fatty acids are released from sebum by bacterial lipases and are irritating as well as inflammatory. Tetracycline causes a significant decrease in lipase

production in sensitive or resistant S. epidermidis without necessarily affecting bacterial growth. Although some patients can discontinue medication without recurrence of symptoms,others must continue on low-dose maintenance for extended periods.

Oral tetracycline has been effective for recalcitrant (i.e., resistant to corticosteroid therapy) cases of nontuberculous phlyctenular keratoconjunctivitis. The manner in which systemic tetracycline affects the ocular flora or alters the immune response remains unclear.

Tetracycline and doxycycline are metalloproteinase inhibitors and when given orally can block the action of corneal collagenases. Either may be effective for resolving noninfected corneal ulcers or “corneal melting’’ in which progressive necrosis of stromal tissue occurs despite the absence of a positive culture. Similarly, the anticollagenolytic activity of tetracycline or doxycycline can prove clinically useful in treating persistent corneal epithelial defects.

Side Effects

A photosensitivity reaction, which manifests as an exaggerated sunburn, is common in patients receiving any tetracycline drug. Hypersensitivity reactions to tetracyclines including anaphylaxis, urticaria, periorbital edema, and morbilliform rashes can occur but are uncommon.

At the usual dosage levels, all tetracyclines have relatively low toxicity, but oral administration can produce varying degrees of gastrointestinal irritation. Anorexia, heartburn, nausea, vomiting, flatulence, and diarrhea commonly occur. Although not usually disabling, these reactions can become severe enough to require discontinuation or interruption of therapy. When diarrhea persists or becomes severe, pseudomembranous colitis caused by C. difficile must be considered.

The administration of tetracycline with food can ameliorate its irritative effects, but food can adversely affect the drug’s absorption. In contrast, the absorption of doxycycline is only slightly affected by the presence of food, including dairy products. Because all tetracyclines can form complexes with divalent cations, the absorption of any tetracycline is markedly decreased when administered with iron-containing tonics or antacids containing calcium, magnesium, or aluminum. Sodium bicarbonate also adversely affects tetracycline absorption.

Most tetracyclines can cause azotemia in patients with impaired renal function. The only tetracycline recommended for use in such patients is doxycycline because it exits the body mainly via the intestinal tract rather than through the kidneys.

Tetracyclines are attracted to embryonic and growing bone tissues. A tetracycline–calcium orthophosphate complex is formed that temporarily depresses bone growth. Tetracyclines can also cause changes in both deciduous and permanent teeth during the time of tooth development; these changes include dysgenesis, staining, and an increased tendency to caries. Discoloration may be progressive and can vary from yellowish brown to dark gray. Because of