Article Date: 7/1/2008

THE BUGS VS. THE DRUGS: A Guide to Antibiotics
anti-infectives

THE BUGS VS. THE DRUGS: A Guide to Antibiotics

To best treat ocular conditions, have a working knowledge of the straight antibiotics and bacterial resistance.

KAREN PUCHALSKI, O.D.,
Plantation, Fla.

It's essential you obtain education or refresh yourself on the role of the straight antibiotics, the five types in this drug category and the antibiotic resistance issue, so you can ensure you provide your patients with the most appropriate care.

The role of antibiotics

For our purposes, antibiotics are ophthalmic "pesticides" designed to kill "bugs," or various forms of bacteria. We not only prescribe them to patients who have ocular infections, such as bacterial keratitis, but as an antibacterial prophylaxis pre- and post-cataract surgery or when the patient presents with an ocular anomaly, such as a corneal or conjunctival abrasion.

Antibiotics eradicate antigenic bacteria by either directly killing them (bactericidal) or halting their reproduction (bacteriostatic). In addition, antibiotics are selective to the type of bacteria present in the body. This means they can distinguish between a bacteria's cell make up vs. normal cells in our body.

Some broad-spectrum antibiotics, however, act on the antigen present as well as on our body's normal flora. This situation stimulates the rise of secondary infections, such as a diffuse keratitis, after treating a severe localized bacterial corneal ulcer. For this reason, target antibiotic therapy for the appropriate bacteria present.

We commonly treat bacterial keratitis with fluoroquinolone antibiotics.

Typically, antibiotics target specific features in bacterial composition in order to effect their action. They act based on their ability to fight gram-positive and/or gram-negative bacteria. Therefore, to select the best antibiotic class to stop an infection, identify the specific feature(s) in the composition of the offending bacteria. Do this by culturing the organism to see what species to which it belongs. Then, use the medical literature to determine its sensitivity and resistance to antibiotics. For example, all mycoplasma species (spp.) lack a cell wall. Therefore, prescribing antibiotic therapy that aims at inhibiting cell-wall synthesis is ineffective against this particular organism.

Antibiotics can cause minor hypersensitivity reactions, such as itching, tearing redness, mucopurulent discharge, conjunctivitis and, in rare cases, life-threatening anaphylactic responses.1 As a result, prior to prescribing a particular ophthalmic antibiotic solution or ointment, ask the patient if he has any allergies to these drugs.

Because many physicians use antibiotics not only therapeutically, but also prophylactically, this can promote bacterial resistance to the chosen antibiotic.2 (I'll discuss resistance later in greater detail.)

Aminoglycosides

The aminoglycosides are comprised of gentamicin (topical ophthalmic solution and ointment), tobramycin (topical ophthalmic solution and ointment) and neomycin (ointment).3

This class of antibiotic works by inhibiting bacterial protein synthesis.4 In the past, the function of aminoglycosides was to treat severe infections from aerobic gram-negative bacilli, especially pseudomonas aeruginosa, some mycobacteria enterococci, and staphylococcus aureus infections, such as blepharitis, blepharoconjunctivitis and endogenous endophthalmitis. Some enterobacteriaceae spp. have become highly resistant to the aminoglycosides, which is why physicians now use the aminoglycosides in combination with beta-lactam antibiotics.

Aminogylcosides have a post-antibiotic effect. This means they continue to kill without additional dosing. Aminoglycosides are concentration dependent, meaning that in higher doses, they have more of a bactericidal effect.4

We mainly use aminoglycosides to treat blepharitis, conjunctivitis and bacterial keratitis. Due to local toxicity, however, this class of drugs is difficult for patients to use. Typically, we prescribe these drugs t.i.d. to q.i.d. per day. The amount may vary, however, depending on the severity of the disease.

Prescribe tobramycin solution or ointment in children older than two months of age and gentamicin solution or ointment in children older than age six.3

Prescribe neomycin, however, as a combination medication in adults, as researchers have yet to establish its safety in children.3 A combination medication would include neomycin, polymyxin B, and bacitracin together.3

This purulent bacterial conjunctivitis indicates a need for broad-spectrum antibiotic therapy.

Macrolides

The macrolides are comprised of erythromycin ointment and azithromycin ophthalmic solution. These antibiotics bind to the ribosomal subunit of the bacteria and inhibit its synthesis.5 Macrolide antibiotics are bacteriostatic.5

Erythromycin is effective against gram-positive bacteria, such as group A beta hemolytic streptococcus pneumoniae and some gram-negative bacteria, such as neisseria meningitides and bordetella pertussis.5 Prescribe this drug to patients of any age group — even newborns.3,5 You can also prescribe it as a second line therapy against neonatal neisseria gonorhorreae.5 Other common indications: blepharitis, conjunctivitis and bacterial infection prophylaxis. Of note: Staphylococcal resistance may occur with erythromycin.5 Side effects from topical administration may include itching, tearing, redness, mucopurulent discharge and conjunctivitis.1 Azithromycin is effective against bacterial conjunctivitis associated with H. influenzae, S. aureus, streptococcus mitis and streptococcus pneumoniae.5 It works well in children older than age one.6

Some adverse effects if used longer than needed: ocular irritation, burning, or stinging. Less commonly reported symptoms include corneal erosion, dry eyes, ocular discharge and punctate keratitis

Polypeptides

This category of antibiotics inhibit cell wall synthesis.7 Polypeptide antibiotics are comprised of bacitracin and polymixin B sulfate.

Bacitracin, a commonly used topical ointment, inhibits cell-wall synthesis in gram-positive bacteria, such as S. aureus, streptococcus pneumoniae and H. influenzae.6

Prescribe Bacitracin ointment for eyelid infections, such as blepharitis, or ectropion/entropion. Prescribe it for adult use only.6 Adverse effects: prolonged healing time and overgrowth of resistant bacteria present.6

Polymyxin B sulfate ophthalmic solution binds to and disrupts the bacteria's cell membrane.7 Some practitioners use it therapeutically to treat eyelid infections, such as blepharitis and entropion/ectropion, for its multi-drug resistant effect on gram-negative bacteria, such as H. influenzae, streptococcus pneumoniae and P. aeruginosa.6,7 Polymyxin B is an ingredient in many combination medications, such as polysporin, trimethoprim and neomycin.3

Sulfonamides

Sulfonamides are another bacteriostatic antibiotic group which block cell metabolism by inhibiting the enzymes needed in the production of folic acid.8 The cell needs folic acid to synthesize nucleic acids. Nucleic acids are essential building blocks of Deoxyribonucleic acid (DNA) and Ribonucleic Acid (RNA). In its absence, cells are unable to divide. DNA contains a genetic code, which the body uses in the development and functioning of all cellular activity. Without this code, organisms would cease to exist.

This class of drugs is mainly effective against gram-negative bacteria, such as pneumocystis carinii, and some gram-positive bacteria, such as S. aureus as well as toxoplasma.8,9 P. aeruginosa and S. aureus, however, are typically resistant.8

Sulfacetamide sodium is an ophthalmic solution and ointment for conjunctivitis and blepharitis.3 Prescribe this drug to children two months of age or older.3

Ophthalmic Antibiotics
AMINOGLYCOSIDES:
• Gentac 0.3%; Sterile Ophthalmic Solution (Akorn)
• Tobrex (Alcon)
• Neosporin neomycin and polymyxin B sulfates and bacitracin zinc ophthalmic ointment, USP (Burroughs Wellcome Inc.)

MACROLIDES:
• Ilotycin erythromycin ophthalmic ointment, USP (Eli Lilly & Co)
• Azasite azithromycin ophthalmic solution 1% (Inspire)

POLYPEPTIDES:
• AK-Tracin (Akorn, inc.)
• Ocu-Tracin (Ocumed Inc.)
• Polytrim trimethoprim sulfate and polymixin B sulfate ophthalmic solution (Allergan)

SULFONAMIDE:
• Bleph-10 sulfacetamide sodium ophthalmic solution, USP 10% (Allergan)

FLUOROQUINOLONES:
• Chibroxin norfloxacin ophthalmic solution, sterile (Merck)
• Ciloxan ciprofloxacin HCL ophthalmic solution 0.3% as Base (Alcon)
• Ciloxan ciprofloxacin hydrochloride ophthalmic ointment, 0.3% as Base (Alcon)
• Ocuflox ofloxacin ophthalmic solution 0.3% (Allergan)
• Iquix levofloxacin ophthalmic solution 1.5% (Vistakon Pharmaceuticals)
• Vigamox moxifloxacin hydrochloride ophthalmic solution 0.5% as base (Alcon)
• Zymar gatifloxacin ophthalmic solution 0.3% (Allergan)

Some side effects to topical sulfonamides: hypersensitivity reactions and mucopurulent discharge.

Adverse effects to all sulfonamides occur if the patient is allergic to sulfur-based products. One of the more serious adverse reactions is Stevens-Johnson syndrome, in which people get blisters around the mouth, eyes or anus.10 As a result, ask the patient if he has any sulfa allergies before prescribing these drugs.

Another important adverse effect of all sulfonamides is kernicterus in newborns.9 Kernicterus is brain damage caused by excessive jaundice.11 Therefore, don't prescribe any sulfonamides to pregnant patients, and only prescribe them to children older than two months of age.3

Fluoroquinolones

This last group of antibiotics is unique in that it we not only use these drugs to treat conjunctivitis and blepharitis but more serious conditions, such as bacterial keratitis. Fluoroquinolones inhibit DNA gyrase, which affects the bacterial DNA replication process, making these drugs exceptionally bactericidal.

They are protective against aerobic gram-negative organisms, such as H. influenzae, P. aeruginosa, neisseria gonorrhoea and chlamydia.12

Although two separate mutations are necessary for resistance to develop, prescribing drugs from this category in less than sublethal doses can result in resistance. Prescribe any fluoroquinolone in children older than age one.3

The fluoroquinolones:

Nalidixic acid and cinoxicin. Physicians administer nalidixic acid and cinoxacin orally. Eyecare practitioners don't commonly prescribe the ophthalmic forms of these drugs, due to their now limited ability to fight bacteria and bacteria's growing resistance to them.

Norfloxacin, ciprofloxacin and ofloxacin. Prescribe norfloxacin ophthalmic solution for the treatment of bacterial infections, such as conjunctivitis, as it's effective against organisms, such as S. aureus, P. aeruginosa and H. influenza. Adverse reactions to this drug: burning, conjunctival hyperemia, chemosis, photophobia and a bitter taste post application.13 Safety and efficacy is proven in children older than age one.13

Ciprofloxacin and ofloxacin — the former an ophthalmic solution and ointment, the latter a solution — are effective against H. influenzae, P. aeruginosa, S. aureus, staphylococcus epidermidis and Streptococcus pneumoniae and are FDA approved for the management of bacterial keratitis. Once again, prescribe this drug to children older than age one. The adverse reactions noted in ciprofloxacin are burning, crystalline deposits, lid-margin crusting, foreign body sensation, itching, conjunctival hyperemia, bad taste post instillation, corneal staining, keratopathy/keratitis, allergic reactions, lid edema, tearing, photophobia, corneal infiltrates, nausea and decreased vision.14 Ofloxacin adverse reactions: burning, stinging, redness, itching, chemical conjunctivitis/keratitis, periocular/facial edema, foreign body sensation, photophobia, blurred vision, tearing, dryness and eye pain.15

Levofloxacin ophthalmic solution. Its ability to treat bacterial conjunctivitis is enhanced by its increased gram-negative activity against bacteroides fragilis, chlamydia spp., mycoplasma pneumoniae and mycobacterium spp.16 Researchers have not tested this medication in children. As a result, it's only approved in adults older than age 18.16 Adverse reactions for the 1.5% drug include headache, a temporary taste change after post installation, decreased/blurred vision, diarrhea, heart burn, fever, infection, irritation/discomfort in the eye(s) that received the drop(s), eye infection, nausea, eye pain/discomfort and throat irritation.17

Moxifloxacin and gatifloxacin. This group is affective against gram-negative bacteria, such as P. aeruginosa, H. influenzae and enterobacteriaceae, and gram-positive bacteria, such as any species of staphylococcus and streptococcus pneumoniae.18 These drugs inhibit topoisomerase four, which breaks the double stranded DNA into two daughter cell strands.12 This is important in the replication process.18

Prescribe these drugs to treat bacterial conjunctivitis and keratoconjunctivitis.18 Something to keep in mind: Although these drugs aren't FDA approved to treat bacterial keratitis, many practitioners have used them off-label, as they've noted it's a clinically effective treatment for this condition.

Side effects of all fluoroquinolone antibiotics are considered mild, typically including ocular irritation, keratitis, chemosis and hyperemia.3 In addition, the fluoroquinolones have been known to cause cartilage damage in fetus.' Therefore, don't prescribe these drugs during pregnancy.12

The resistance issue

Methicillin resistant S. aureus (MRSA) is a common pathogen found in approximately 33% of patients.19

Originally, physicians used beta lactam antibiotics to inhibit penicillin-binding proteins. As each bacterial pathogen mutated, however, they possessed an enzyme known as beta-lactamase, which lysed the beta-lactam ring, rendering the drug ineffective. Researchers created methicillin to resist beta-lactamase and remain effective against S. aureus.19

Currently, methicillin resistance is growing due to a new altered penicillin-binding protein (PBP2a) that has decreased the susceptibility and inhibition of bacteria to methicillin. Also, a patient who has had a previous MRSA infection is at a high risk of developing another one.19 This has created great worry because resistance to all antibiotics makes this pathogen highly virulent and possibly lethal.

Further, medical professionals believe that MRSA infections are increasing due to antibiotic over prescribing and inappropriate tapering. As a result, unless you're positive that the patient has a bacterial infection or is at an increased risk for developing one, try the least evasive methods of treatment, such as artificial tears, before prescribing an antibiotic, and closely monitor the patient.

Researchers are conducting studies with new antibiotics that reputedly have excellent anti-MRSA activity. These drugs include linezolid, a streptogramin combo, daptomycin and tigecycline.19 The drug-development pipeline contains a number of drugs for MRSA infections, including enhanced glycopeptides (dalbavancin, oritavancin and telavancin) and anti-MRSA cephalosporins (ceftobiprole).20

Your patients rely on your expertise as an eyecare practitioner to provide them with the best and most appropriate care. By obtaining education or refreshing yourself on the straight antibiotics, the resistance issue and your patient's medical history, you possess the tools needed to safely and effectively treat their ocular condition. OM

Stay tuned for a feature article on anti-infective/steroid combination drugs in an upcoming issue.

  1. Ansari, I, Onyema, E. Severe generalized hypersensitivity reaction to topical neomycin after cataract surgery: a case report. Journal of Medical Case Reports. 2008 Feb; Vol 2.
  2. Frost, KJ. An overview of antibiotic therapy. Nurs Stand. 2007 Nov 7-13;22(9):51-7
  3. Heard, C. The Optometry Drug Guide: Informed Decision-Making at the Point of Care. 2006-2007.
  4. Edson, Randall S. MD; Terrell, Christine L. MD. The Aminoglycosides. Mayo Clinic Proceedings: Symposium On Antimicrobial Agents-Part 8: Vol 74(5), May 1999: 519-528.
  5. Alvarez-Elcoro, Salvador MD; Enzler, Mark J. MD. The Macrolides: Erythromycin, Clarithromycin, and Azithromycin. Mayo Clinic Proceedings: Symposium on Antimicrobial Agents- Part 9: Vol 74(6), June 1999: 613-634.
  6. Marlin, DS. Conjunctivitis, Bacterial. WebMD Emedicine. www.emedicine.com/OPH/topic88.htm. Accessed June 12, 2008.
  7. Tam, VH., Schilling, AN., Vo, G., et al. Pharmacodynamics of Polymyxin B against Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2005 Sep; 49(9):3624-30.
  8. Smilack, Jerry D. MD. Trimethoprim-Sulfamethoxazole. Mayo Clinic Proceedings: Symposium on Antimicrobial Agents: Vol 74(7), July 1999: 730-734.
  9. RxList The Internet Drug Index. Bleph 10 www.rxlist.com/cgi/generic/sulfacet_cp.htm. Accessed June 17. 2008.
  10. Chang, YS, Huang, FCh, Tseng SH, et al. Erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis: acute ocular manifestations, causes, and management. Cornea. 2007 Feb;26(2):123-9.
  11. Virginia Commonwealth University. Kernicterus Newborn Jaundice Online. www.kernicterus.org. Accessed June 12, 2008.
  12. Walker, RC. The Fluoroquinolones. Mayo Clinic Proceedings: Symposium on Antimicrobial Agents-Part 13: Vol 74(10), Oct 1999: 1030-1037.
  13. RxList. The Internet Drug Index. Chibroxin. www.rxlist.com/cgi/generic/norfloxacinopad.htm. Accessed June 17, 2008.
  14. RxList. The Internet Drug Index. Ciloxan Ophthalmic Solution www.rxlist.com/cgi/generic/ciloxansol_od.htm. Accessed June 18, 2008
  15. RxList The Internet Drug Index. Ocuflox. www.rxlist.com/cgi/generic/ocuflox_adhtm. Accessed June 18, 2008
  16. Ernst ME, Ernst EJ, Klepser ME. Levofloxacin and trovafloxacin: the next generation of fluoroquinolones? Am J Health Syst Pharm. 1997 Nov 15;54(22):2569-84.
  17. New Iquix. Consumer Brief Summary. www.vistakonpharmaceuticals.com/iquix/pdf/consumer-brief-summary.pdf. Accessed June 18, 2008)
  18. Mah FS. Fourth-generation fluroquinolones: new topical agents in the war on ocular bacterial infections. Curr Opin Ophthalmol. 2004 Aug;15(4):316-20.
  19. Edmunds MW. Clinal Challenges of Methicillin-Resistant Staphylococcus aureus (MRSA). WebMD. Medscape. www.medscape.com/viewarticle/522947. Accessed June 12, 2008.
  20. Loffler CA, MacDougall C. Update on prevalence and treatment of methicillan-resistant Staphyloccocus aureaus infections. Expert Rev Anti Infect Ther. 2007 Dec;5(6):961-81.
Dr. Puchalski is currently finishing her residency in primary care/ocular disease at Nova Southeastern University. She plans to join a private practice in south Florida. E-mail her at kpuchals@nova.edu.


Optometric Management, Issue: July 2008