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I. The age of Modern Medicine A. Alexander Fleming is considered to be the father of modern medicine 1. He discovered penicillin more than 70 years ago (1928) is considered to be one of the most significant medical breakthroughs of the twentieth century 2. Prior to Penicillin, the # 1 war-time killer was infection 3. This marked a new era in modern medicine 4. Within 4 yrs of its release, resistance to penicillin began popping up and grew at an alarming rate B. By the mid-1940s and early 1950s streptomycin, chloramphenicol, and tetracycline had been discovered and the age of antibiotic therapy was underway 1. These new antibiotics were very effective against a number of different pathogens including Gram-(+) and gram (-) bacteria, intracellular parasites, and tuberculosis 2. The mass production of antimicrobials provided a temporary advantage in the struggle with microorganisms 3. Despite these rapid advances resistance quickly followed II. How Resistance Develops A. Bacterial become resistant when a mutation occurs in the DNA that protects the bacteria from a chemical B. Mutation is only significant if the bacteria colony is exposed to the drug “Survival of the fittest” dictates survival occurs in only those capable of mutating A. For any given bacterial population, random mutations will arise 1. With strong external selection pressures these mutations will be favored resulting in resistant bacteria 2. American Academy of Microbiology: 17.8 million pounds of antibiotics are used in animals each year, Human exposure of these antibiotics is significant B. One significant problem is that antibiotics are used extensively topically, systemically, Agriculturally as a growth stimulant III. Staphylococcus Aureus A. Common bacteria usually found on the skin or in the nose B. Can cause a range of illnesses from minor skin infections such as pimples, impetigo, boils, cellulitis and abscesses…To life-threatening diseases such as pneumonia, meningitis, endocarditis, and septicemia C. There are many different types of staphylococcus aureus IV. Methicillin Resistant Staphylococcus Aures (MRSA) A. MRSA is a particular strain of staphylococcus aureus that does not respond to many antibiotics B. Methicillin was an antibiotic used many years ago to treat patients with Staphylococcus aureus infections 1. It is now no longer used except as a means of identifying this particular type of antibiotic resistance C. 1st outbreak identified in 1960 ‘s D. Predominantly seen in hospitals, chronic care facilities and parenteral drug abusers 1. The prevalence of MRSA isolates in hospitals in the US has risen steadily, such that now about ¼ nosocomial isolates are methicillin resistant E. Community-acquired MRSA is becoming a significant problem, with the prevalence of MRSA among community isolates expected to reach as high as 25% in the next decade F. About 1/3 of people carry MRSA on their skin or in their nose without knowing it 1. Most people who carry MRSA in this way don’t go on to develop an infection G. Risk Factors for MRSA 1. Proloned hospital stays 2. Prior surgery 3. Seriously ill in intensive care 4. Immunocompromised H. 2005: Deaths from MRSA Surpassed AIDS: In 2005, AIDS killed 17,011 Americans CDC reports > 90,000 get the potentially deadly "superbug" infections annually 1. Recent JAMA surveillance study, only about ¼ of MRSA infections involved hospitalized patients, More than half were in the health care system V. Ocular Involvement of MRSA A. 13 Cases of MRSA Following Refractive Surgery 1. Multicenter, retrospective chart review of 13 cases of MRSA keratitis following refractive surgery 2. 9 were either healthcare workers or exposed to a hospital surgical setting 3. 7 pts were prescribed 3rd generation FQ, 1 pt prescribed tobramycin, 1 pt was prescribed erythromycin and 3 were prescribed a 4th generation FQ B. Ocular MRSA Northern California: July 1, 1998 and July 31, 2006: 12.6% increase in ocular MRSA 1. Most cases were mild and nonsight threatening 2. 78% had MRSA blepharoconjunctivitis 3. 4.6% with had keratitis, 2.4% with endophthalmitis 4. 100% of the isolates were sensitive to vancomycin 5. 93.2% sensitive to tetracycline and 63.6% were sensitive to bacitracin. 6. Ciprofloxacin and erythromycin were essentially ineffective with sensitivities of 14.8% C. Bascom Palmer Study: Retrospective, cross-sectional study evaluating the resistance trends for patients presenting with bacterial conjunctivitis from 1994 to 2003. 1. 1254 culture (+) pathogens were recovered from 2408 consecutive conjunctival s sabs (52.1%) 2. Gram (+) pathogens accounted for 52.2% of culture-positive isolates 3. S aureus was the most frequent isolate overall (n = 471; 37.6%) in pts > 6 years 4. Staphylococcus aureus overall: 37.6%, 47.8% in people > 8 y/o 5. MRSA showed a significant increase in the 10-year period (4.4%-42.9%) VI. Tracking Resistance in U.S. Today (TRUST) A. FDA initiated program in 1996 with the introduction of levofloxacin for systemic use Surveillance for new systemically administered antibiotics so the infectious disease community has access to data from national surveillance programs that can put local findings of antibiotic resistance in perspective 1. In vitro susceptibility testing is performed by an independent central laboratory on isolates submitted annually by 200 or more clinical laboratories across all 50 states 2. Ocular isolates periodically have been submitted for testing in the TRUST program, but no national surveillance program systematically has tracked in vitro susceptibility in ocular isolates 3. Ocular Trust: Expansion of the TRUST program to include an ocular-specific substudy that annually will monitor in vitro susceptibility of pathogens isolated from ocular infections 4. Ocular TRUST is the only nationwide surveillance program to monitor antimicrobial susceptibility in prospectively collected ocular isolates VII. The Arsenal of Antibiotic Therapy for Ophthalmic Use A. The Fluoroquinolones 1. The first safe broad-spectrum ophthalmic agents 2. Revolutionized treatment of severe corneal infections 3. Excellent safety profile 4. 1st released for ophthalmic use in early 1990’s 5. Represented an important break-through for clinicians 6. For the 1st time strong commercially available antibiotics available to treat bacterial conjunctivitis and ulcerative keratitis 7. The BIG problem with the fluoroquinolones has been bacterial resistance resistance to cipro, oflox, levoflox a. 1993 – 5.8% resistance (2 yrs after release of fluoroquinolones) b. 1997 – 35% bacterial resistance c. 2001 – 100% resistance to staph aureus isolates cultured in endophthalmitis B. 4th Generation Fluoroquinolones: developed to address the issues of resistance and to allow for broader coverage for both gram (+) and gram (-) organisms. They also provide much better gram (+) coverage C. Fluoroquinolone structure 1. Improved in vitro activity of 4th-generation fluoroquinolones against Grampositives is due to the 8-methoxy group ( not present in the 3rd-generation) 2. Mechanism of Action: Fluoroquinolones: Cause lethal breaks in the bacterial chromosome at their target site 3. 4th-generation FQs are dual binding: DNA gyrase AND topo IV in both Gram-positives and Gram-negatives B. AzaSite: 1% topical azithromycin 1. Macrolide 2. Broad spectrum of action particularly against gram-positive organisms 3. It works by inhibiting protein synthesis 4. It is bacteriostatic and not bacteriacidal 5. Dosing for treating bacterial conjunctivitis: drop bid X 2 days, followed by 1 qd for 5 days 6. DuraSite®: The AzaSite™ Vehicle a. DuraSite is an advanced synthetic polymeric mucoadhesive matrix that stabilizes small molecules like azithromycin b. DuraSite® allows for a stable formulation of azithromycin and increase the bioavalability of azithromycin in tissue 7. Early studies have shown very good bacterial eradication rates of most common pathogens a. Haemophilus influenze: 92.7% bacterial eradication rate b. Sterp pneumoniae: 90.2 bacterial eradication rate c. Staph aureus: 82.5% eradication rate