4/12/2016

The Age of Modern Medicine

The Battle of Resistance: ™ Prior to , the # 1 war-time killer was infection Treating Infections in the Age ™ Began being mass produced in 1943 of Resistance ¾ Physicians were finally able to treat many diseases and childhood infections Mark T. Dunbar, O.D., F.A.A.O. ¾ This marked a new era in modern medicine Bascom Palmer Eye Institute ™ Within 4 yrs of its release, resistance to University of Miami, Miller School of Med penicillin began popping up and grew at an Miami, FL alarming rate

Mark Dunbar: Disclosure The Age of Modern Medicine

™ Optometry Advisory Board for: ™ By the mid-1940s and early 1950s streptomycin, chloramphenicol, and tetracycline had been ¾ Allergan discovered and the age of therapy was ¾ Carl Zeiss Meditec underway ¾ ArticDx ™ These new were very effective against a number of different pathogens including Gram-(+) ¾ Sucampo and gram (-) , intracellular parasites, and tuberculosis. ™ The mass production of antimicrobials provided a temporary advantage in the struggle with microorganisms ¾ Despite these rapid advances resistance quickly followed Mark Dunbar does not own stock in any of the above companies

The Age of Modern Medicine

™ is considered to be the father of modern medicine ¾ He discovered penicillin more How Resistance Develops than 70 years ago (1928)  Considered to be one of the most significant medical breakthroughs of the twentieth century ¾ Ernest Duchesne was the 1st to describe the antibiotic properties of Penicillium sp. 1897

1 4/12/2016

Factors Implicated in Growing Bacterial Resistance Rates of Antibiotic Resistance ™ Microbiological ™ Bacterial become resistant when a ¾ Antibiotic misuse mutation occurs in the DNA that ™ Environmental Factors protects the bacteria from a chemical ¾ Aging population ¾ Social behavior ¾ Mutation is only significant if the bacteria colony is exposed to the drug ¾ AIDS ¾ International travel ™ “Survival of the fittest” dictates ™ Technical Factors survival occurs in only those capable ¾ Increasing surgical of mutating intervention ¾ Organ replacement ¾ Life support systems

Resistant Bacteria Susceptibility of Multidrug-Resistant Bacteria ™ For any given bacterial population, ™ 256 bacterial strains isolated from 164 patients random mutations will arise undergoing intraocular surgery b/w 1/2002 10/2002 ™ With strong external selection pressures ™ 124 (76%) coagulase-negative Staphylococci these mutations will be favored resulting ™ High level of resistance to penicillin, aminoglycosides, macrolides, ciprofloxacin,ofloxacin in resistant bacteria ™ Gatifloxacin and moxifloxacin had the lowest ™ American Academy of Microbiology resistance frequency in the fluoroquinolones antibiotic group ¾ 17.8 million pounds of antibiotics are used ™ Newer-generation fluoroquinolones provide excellent in animals each year broad-spectrum coverage against bacterial flora ¾ Human exposure of these antibiotics is isolated from conj, despite the high % of multidrug- resistant bacteria significant Miño de Kaspar et al. AJO 2005

Widespread Resistance Bacterial Resistance to Older Antibiotics

100% The problem is…. 90% 80% 70% Antibiotics are used extensively 60% 50% ¾ Topically 40% 30% 20% ¾ Systemically 10% 0% ¾ Agriculturally as a growth PercentageBacteria of Resistant Oxacillin Amikacin Penicillin Ofloxacin Cefazolin Neomycin Mezlocillin (Imipenem) Gentamicin Norfloxacin Cefotaxime Tobramycin Cefuroxime Meropenem Ceftazidime Tetracycline stimulant Gatifloxacin Moxifloxacin Levofloxacin Azithromycin Ciprofloxacin (Minocycline) Erythromycin Antibiotic (Vancomycin)l ¾ Most significant use of fluoroquinolones Chloramphenicol Miño de Kaspar et al. AJO 2005

2 4/12/2016

Staphylococcus Aures MRSA Pharmacology

™ Methicillin was an antibiotic used Methicillin-Resistant many years ago to treat patients with Staphylococcus Aureus Staphylococcus aureus infections ™ It is now no longer used except as a means of identifying this particular type of antibiotic resistance

Staphylococcus Aureus MRSA

™ Common bacteria usually found on the skin ™ 1st outbreak identified in 1960 ‘s or in the nose ™ Can cause a range of illnesses from minor ™ Predominantly seen in hospitals, skin infections such as pimples, impetigo, chronic care facilities and parenteral boils, cellulitis and abscesses… drug abusers ™ To life-threatening diseases such as pneumonia, meningitis, endocarditis, and ™ The prevalence of MRSA isolates in septicemia hospitals in the US has risen steadily, ™ There are many different types of staphylococcus aureus such that now about ¼ nosocomial isolates are methicillin resistant

Staphylococcus Aures MRSA Pharmacology

™ MRSA is a particular strain of ™ Community-acquired MRSA is staphylococcus aureus that does not respond (is resistant) to many becoming a significant problem, with antibiotics the prevalence of MRSA among ™ S aureus was sensitive to penicillin community isolates expected to reach when the drug was 1st introduced, but as high as 25% in the next decade resistance developed almost immediately as the organism acquired a β-lactamase enzyme that was capable of inactivating drug

3 4/12/2016

Reasons for Rise of MRSA Risk Factors for MRSA

™ More powerful strains of MRSA ™ Proloned hospital stays developing ™ An increased number of very sick people in ™ Prior surgery hospital ™ Seriously ill in intensive care ™ More complex medical treatments ¾ The use of central lines and catheters ™ Immunocompromised ™ Patients move within and between hospitals more often ™ High workloads which result in less compliance with routine hand washing

Multi-Drug Resistant 2005: Deaths from Bacteria MRSA Surpassed AIDS ™ Emerging resistance of S aureus has also ™ In 2005, AIDS killed 17,011 Americans been demonstrated for streptomycin, tetracycline, chloramphenicol, ™ CDC reports > 90,000 get the potentially erythromycin and third-generation deadly "superbug" infections annually fluoroquinolones. T ™ Recent JAMA surveillance study, only ™ The topical 4th Generation about ¼ of MRSA infections involved fluoroquinolonesare are more potent hospitalized patients against MRSA than prior generation ¾ More than half were in the health care system fluoroquinolones  People who had recently had surgery or were on kidney ¾ They inhibit both DNA gyrase and dialysis topoisomerase IV, requiring two genetic  Open wounds and exposure to medical equipment are mutations for the bacteria to become resistant major ways the bug spreads.

MRSA MRSA Facts

™ About 1/3 of people carry MRSA on their ™ MRSA has evolved into a multitude of skin or in their nose without knowing it genetically distinct strains that vary ‘ ’ ™ These people are said to be carriers of widely in drug resistance, MRSA ¾ The bacteria are present on the body but transmissibility and virulence don’t cause any harm ¾ This is also referred to as being ‘colonised’ with MRSA ™ Most people who carry MRSA in this way don’t go on to develop an infection

4 4/12/2016

4th Gen FQ Resistant Bacterial MRSA Facts Keratitis after Refractive Surgery

Moshirfar M, J Cataract Refract Surg 2006; 32:515-518 ™ Non-healthcare workers are now just as likely as healthcare workers to 2 Cases of Bacterial Keratitis resistant to carry MRSA on the conjunctiva and 4th Gen FQ lid margin ™ 1st pt – Pseudomonas following PRK -> had been treated with Vigamox ™ 2nd pt – MRSA following LASIK treated with Zymar…and Vigamox ™ Culture susceptibilities resistance to both 4th Gen FQ

13 Cases of MRSA Following MRSA Fact Refractive Surgery

™ While CA-MRSA strains tend to be ™ Multicenter, retrospective chart less multi-drug resistant, some review of 13 cases of MRSA keratitis strains are associated with unusually following refractive surgery invasive infections of the eye and ¾ 9 were either healthcare workers or orbit exposed to a hospital surgical setting rd ¾ USA300 clone – CA-MRSA with the ™ 7 pts were prescribed 3 generation PVL virulence marker FQ, 1 pt prescribed tobramycin, 1 pt was prescribed erythromycin and 3 were prescribed a 4th generation FQ Solomon. Am J Ophthalmol. 2007.

Methicillin-Resistant Staphylococcus aureus Infectious Keratitis Following Refractive Surgery

™ A retrospective chart review of cases occurring between May 2002 and February 2005 in 10 referral cornea and refractive disease practices Ocular Involvement of Prophylactic Antibiotics Unknown, 1 (bilateral)/13 patients MRSA Tobramycin 1/13 patients 7.7% 7.7% Erythromycin 1/13 patients 7.7% Third-generation Fluoroquinolones Ciprofloxacin or ofloxacin 53.4% 23.1% 7/13 patients Fourth-generation Fluoroquinolones Gatifloxacin or moxifloxacin 3/13 patients Solomon. Am J Ophthalmol. 2007.

5 4/12/2016

Infectious Keratitis in Refractive Eye Care

™ Clinicians must be alert to the postop patient with signs and symptoms of Tracking Resistance possible post-LASIK and post-PRK infectious keratitis. ™ PRK: Corneal scrapings, cultures, and sensitivities of all cases of focal infiltrates ™ LASIK: Lifting the flap, scraping, culturing, and obtaining sensitivities on all cases of focal infiltrates

Precautions for Culture Positive Rates Healthcare Workers BPEI 2011-2013

™ Patients exposed to healthcare facilities who are at higher risk of infection from nosocomial MRSA, prophylactically treat blepharitis with lid hygiene and hot compresses preoperatively ™ Consider a nasal swab for MRSA carriage ™ Consider bacitracin or a fourth-generation fluoroquinolone or bacitracin for preoperative prophylaxis

Treatment of MRSA s/p Impact of Prior Therapy (59.8%)- LASIK Pathogen Recovery 2013*, N=338,

™ Irrigating under the flap with fortified vancomycin (50 mg/ml) ™ Antibiotics to include better coverage for MRSA-fortified vancomycin every 30 minutes, alternating with topical 4th Gen q 30 min

™ Bacitracin ointment or Neosporin • First and last quarter-2013, Significant differences, p=0.001 ointment to the eyelids qid • 64.7%-Monotherapy

6 4/12/2016

Presenting Monotherapy Choice Trends in Organism Group Frequency (%) N=119/184 (64.7%) Nonbacterial (N=417, 13.3%)

Yeast Mold Amoeba 10.9

7.1 7.5

4.4

3.1 3.8

2.9 1.4 1.6

2005‐2007 (n=2980) 2008‐2010 (N=2960) 2011‐2013 (N=3136)

Significant, decline in nonbacterial pathogens from 2005 to 2013, p=0.00016

Impact of Prior Therapy- Detection Time (N=153)

JAMA Ophthalmology 2015

™ ARMOR study was initiated in 2009 to survey antibiotic resistance among S. aureus, Co.NS, S. pneumoniae, H. influenzae, and Pseudomonas isolates from ocular infections

Update on Epidemiology and Anti-Microbial Resistance in South Florida ARMOR MOTT (N=142) 5% acan (N=43) 1% yeast (N=139) ™ A total of 3,237 ocular isolates were obtained from 72 centers 4% ¾ 1169 S aureus ¾ 992 CoNS gpos (N=1320) 42% ¾ 330 S pneumoniae gneg (N=1257) 40% ¾ 357 H influenzae ¾ 389 P aeruginosa) mold 8% ™ Methicillin resistance was found among 493 S aureus isolates (42.2%) and 493 CoNS isolates (49.7%) ™ Methicillin-resistant (MR) isolates had a high probability of concurrent Organism group-Distribution resistance to fluoroquinolones, aminoglycosides, or macrolides ™ There was “multidrug resistance” to at least 3 additional antibiotic Ocular Pathogens 2011-2013 classes was found in MR cases ™ All staphylococcal isolates were susceptible to vancomycin

7 4/12/2016

MRSA Trends

™ Staphylococcal isolates from elderly patients were more likely to be MR, as were S aureus isolates obtained from the southern United States

Trends in Infectious Keratitis

™ 73% of MRSA strains are resistant to multiple antibiotics ™ 23% of ALL staphylococci strains are resistant to at least 3 ocular antibiotics commonly used to treat

ARMOR: 5 Year Results

CONCLUSIONS: ™Resistance to 1 or more antibiotics is prevalent among ocular bacterial pathogens. ™Current resistance trends should be considered before initiating empiric treatment of common eye

8 4/12/2016

In vitro Susceptibility for Ophthalmic Antibiotics: Select/Common Ocular Drugs. Fluoroquinolones ™ The first safe broad-spectrum Antibiotic MSSA (%S) MRSA (%S) ophthalmic agents N=190 N=84 Cefazolin 100 0 ™ Revolutionized treatment of severe Erythromycin 98 43 corneal infections Gentamicin 100 85 ™ Very low sensitization rate Gatifloxacin 93 25 ™ Excellent safety profile Moxifloxacin 91 31 ™ Comfortable Trimethoprim 99 92 ™ No reports of systemic effects -sulfa

Fluoroquinolones

™ 1st released for ophthalmic use in early Our Arsenal of 1990’s Antimicrobial Therapy ™ Represented an important break- through for clinicians ™ For the 1st time strong commercially available antibiotics available to treat bacterial conjunctivitis and ulcerative keratitis ™ Broad spectrum including pseudomonas

The Arsenal Fluoroquinolones Ophthalmology July 1999; 106 (7): 1313-8 ™ Fluoroquinolones ™ Macrolides ™ The BIG problem with the ¾ Ciprofloxacin ¾ Erythromycin fluoroquinolones has been bacterial ¾ Levofloxacin ¾ Bacitracin resistance! ¾ Gatifloxacin ¾ Azithromycin ¾ 1993 – 5.8% resistance ¾ Moxifloxacin ™ Dihydrofolate  2 yrs after release of fluoroquinolones ™ Aminoglycosides reductase inhibitors ¾ 1997 – 35% bacterial resistance ¾ Tobramycin ¾ Trimethoprim ¾ 2001 – 100% resistance to staph aureus ¾ Gentamycin ™ Polypeptides isolates cultured in endophthalmitis ¾ Polymixin B  Resistance to cipro, oflox, levoflox

9 4/12/2016

Resistance to FQ’s Fluoroquinolones: Resistance Alexandrakis et al, Ophthalmology August 2000; 107: 1497-1502 9 yr period: 2920 cultures; 1468 (50%) recovered ™ In vitro tests that compare 1990 1998 moxifloxacin with other Bact Keratitis 196 137 fluoroquinolones suggest that moxifloxacin is Resistance to 11% Cipro 28 % Cipro Staph Aures and Oflox and Oflox less likely to ¾ Be affected by genetic mutations1,2 Resistance to 0% 0% 2,3 Pseudomonas ¾ Select for resistance Staph aures (27) 29% (32) 48% 1. Tankovic J, et al. J Antimicrob Chemother. 1999;43(suppl B):19-23. 2. Schedletzky H, et al. J Pseudomonas (51) 54% (32) 46% Antimicrob Chemother. 1999;43(suppl B):31-37. 3. Balfour JAB, Lamb HM. Drugs. 2000;59:115-139.

Resistance to FQ’s 4th Generation Goldstein et al. Ophthalmology July 1999; 106 (7): 1313-8 1053 Isolates from 825 Cases 1993 to 1997 Fluoroquinolones 1993 1997 ™Developed to address the issues of Bact Keratitis 284 75 resistance Resistance to 5.8% Cipro 35% Cipro ™Developed to allow for broader Staph Aures 4.7% Oflox 35% Oflox coverage for both gram (+) and gram Resistance to 51% 50% (-) organisms Strep ¾Better gram (+) coverage is needed as Gram + 81.8% 51.4% the growing trend towards more gram Gram - 18.2% 48.6% (+) infections

Widespread Decline in Susceptibility to Mechanism of Action: 3rd-Generation Fluoroquinolones Fluoroquinolones In Vitro Susceptibility of Staphylococcus aureus to 3rd-Generation Fluoroquinolones: Campbell Laboratory Survey ™Cause lethal breaks in the bacterial 100 chromosome at their target site 90 80 ™Targets of 3rd-generation FQs 70 60 ¾DNA gyrase in Gram-negatives 50 ¾Topo IV in Gram-positives 40 30 ™Targets of 4th-generation FQs are dual

Percentage Susceptible Percentage Keratitis 20 Endophthalmitis binding 10 Conjunctivitis/Blepharitis 0 ¾DNA gyrase AND topo IV in both 1993 1994 1995 1996 1997 1998 1999 2000 2001 Year Gram-positives and Gram-negatives Kowalski et al. Ophthal Clinics of N. America. 2003.

10 4/12/2016

3rd Generation FQ’s

Gatifloxacin and Moxifloxacin Comparison of In Vitro Efficacy

Fourth-Generation Fluoroquinolones Far More Effective Than Third-Generation Fluoroquinolones 4th Generation Isolates From Bacterial Endophthalmitis Resistant Fluoroquinolones to Ciprofloxacin, Ofloxacin, and Levofloxacin

Moxi CoagNeg Gati Staphylococcus (n = 10) S aureus (n = 8) Levo

Oflox

Cipro

0 10203040506070

Median MIC (μg/mL)

*CoagNeg = Coagulation Negative; Moxi = moxifloxacin; Gati = gatifloxacin; Levo = levofloxacin; Oflox = ofloxacin; Cipro = ciprofloxacin Mather et al. Am J Ophthalmol. 2002.

Fourth-Generation Fluoroquinolones More Effective Rate of Endophthalmitis: Third- vs Than Older-Generation Fluoroquinolones Fourth-Generation Fluoroquinolones

Staphylococcal Endophthalmitis Isolates More Susceptible to Fourth ™ A retrospective, cross-sectional (prevalence) study of Generation Fluoroquinolones than to Older Fluoroquinolones patients who had phacoemulsification at a university eye center over a 10-year period.

™ The main outcome measure was the occurrence of Gatifloxacin (n = 33) endophthalmitis after cataract surgery. Moxifloxacin (n = 33) ¾ Third-generation fluoroquinolones (ciprofloxacin, ofloxacin) were used as prophylactic antibiotics from January 1997 to August 2003. Ciprofloxacin (n = 33) ¾ Fourth-generation fluoroquinolones (gatifloxacin, moxifloxacin) were Levofloxacin used as prophylactic antibiotics from September 2003 to December (n = 23) 2007. Ofloxacin (n = 18) ™ A nosocomial infectious reporting database was used to 0 20406080100 report endophthalmitis occurrences.

In Vitro Susceptibility (Percentage Sensitive) ™ Prospectively collected data were retrospectively analyzed to establish endophthalmitis rates. Miller et al. Arch Ophthalmology. 2006. Jensen et al. J Cataract Refract Surg. 2008.

11 4/12/2016

Ten-Year Retrospective Comparison of Endophthalmitis after Cataract Surgery

P = .0011

0.197%

P = .040

0.1%

0.056%

0.015%

Ciprofloxacin/Ofloxacin Vigamox®/ZYMAR® Vigamox® ZYMAR® n = 16,710a n = 12,566b n = 5915b n = 6651b aDuring the period of 1997 to 2003. bDuring the period of 2003 to 2007. Jensen et al. J Cataract Refract Surg. 2008.

Four-Year Retrospective Comparison of Endophthalmitis after Cataract Surgery

7 Cases of Endophthalmitis out of 12,566 Cataract Surgeries (0.056%)

P = .040 0.1%

0.015% Endophthalmitis Rate Rate (%) Endophthalmitis

ZYMAR® Vigamox® n = 6651 n = 5915

The rate of 0.015% with Zymar® is the lowest rate of endophthalmitis ever recorded in cataract surgery patients using perioperative antibiotics.

Jensen et al. J Cataract Refract Surg. 2008.

Ophthalmic Solutions of Fourth- Generation Fluoroquinolones

ZYMAR® Vigamox® Besivance™ ZYMAXID™

Approval year 2003 2003 2009 2010

Indication Bacterial Bacterial Bacterial Bacterial conjunctivitis conjunctivitis conjunctivitis conjunctivitis

Active Gatifloxacin Moxifloxacin Besifloxacin Gatifloxacin Ingredient 0.3% 0.5% 0.6% 0.5%

Preservative 0.005% BAK No preservative 0.01% BAK 0.005% BAK

Package size/ 5 mL/132 mean 3 mL/82 mean 2.5 mL/83 mean 5 mLa mean drops drops per bottle drops per bottle drops per bottle

BAK = benzalkonium chloride. a Besivance™ mean drops not yet calculated.

Besivance™ [package insert]. 2009; Jensen and Fiscella. Am J Health Syst Pharm69. 2006; Vigamox® [package insert]. 2003; ZYMAR® [package insert]. 2004; ZYMAXID™ [package insert]. 2010.

12