Bacterial Resistance. Battle of the Bugs: Treating Infections in the Age of Resistance. How Resistance Develops 10/16/2009. The Age of Modern Medicine

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1 The Age of Modern Medicine Battle of the Bugs: Treating Infections in the Age of Resistance Mark T. Dunbar, O.D., F.A.A.O. Bascom Palmer Eye Institute University of Miami, Miller School of Med Miami, FL Alexander Fleming is considered to be the father of modern medicine He discovered penicillin more than 7 years ago (1928) Considered to be one of the most significant medical breakthroughs of the twentieth century Ernest Duchesne was the 1 st to describe the antibiotic properties of Penicillium sp The Age of Modern Medicine Prior to Penicillin, the # 1 war-time killer was infection Began being mass produced in 1943 Physicians were finally able to treat many diseases and childhood infections This marked a new era in modern medicine Within 4 yrs of its release, resistance to penicillin began popping up and grew at an alarming rate The Age of Modern Medicine By the mid-194s and early 195s streptomycin, chloramphenicol, and tetracycline had been discovered and the age of antibiotic therapy was underway These new antibiotics were very effective against a number of different pathogens including Gram-(+) and gram (-) bacteria, intracellular parasites, and tuberculosis. The mass production of antimicrobials provided a temporary advantage in the struggle with microorganisms Despite these rapid advances resistance quickly followed Bacterial Resistance How Resistance Develops Bacterial become resistant when a mutation occurs in the DNA that protects the bacteria from a chemical 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 1

2 Resistant Bacteria For any given bacterial population, random mutations will arise With strong external selection pressures these mutations will be favored resulting in resistant bacteria American Academy of Microbiology 17.8 million pounds of antibiotics are used in animals each year Human exposure of these antibiotics is significant Bacterial Resistance The problem is. Antibiotics are used extensively Topically Systemically Agriculturally as a growth stimulant Most significant use of fluoroquinolones Factors Implicated in Growing Rates of Antibiotic Resistance Microbiological Antibiotic misuse Environmental Factors Aging population Social behavior AIDS International travel Technical Factors Increasing surgical intervention Organ replacement Life support systems Susceptibility of Multidrug-Resistant Bacteria 256 bacterial strains isolated from 164 patients undergoing intraocular surgery b/w 1/22 1/ (76%) coagulase-negative Staphylococci High level of resistance to penicillin, aminoglycosides, macrolides, ciprofloxacin,ofloxacin Gatifloxacin and moxifloxacin had the lowest resistance frequency in the fluoroquinolones antibiotic group Newer-generation fluoroquinolones provide excellent broad-spectrum coverage against bacterial flora isolated from conj, despite the high % of multidrugresistant bacteria Miño de Kaspar et al. AJO 25 acteria Resistant Percentage of Ba 1% 9% 8% 7% 6% 5% 4% 3% 2% 1% % Mezlocillin Oxacillin Penicillin Widespread Resistance to Older Antibiotics Cefazolin Cefuroxime Cefotaxime Ceftazidime (Imipenem) Meropenem Amikacin Gentamicin Neomycin Tobramycin Antibiotic Azithromycin Erythromycin Ciprofloxacin Ofloxacin Norfloxacin Levofloxacin Gatifloxacin Moxifloxacin (Minocycline) Tetracycline Chloramphenicol (Vancomycin)l Methicillin-Resistant Staphylococcus Aureus Miño de Kaspar et al. AJO 25 2

3 Staphylococcus Aureus Common bacteria usually found on the skin or in the nose 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 There are many different types of staphylococcus aureus Staphylococcus Aures Pharmacology is a particular strain of staphylococcus aureus that does not respond (is resistant) to many antibiotics S aureus was sensitive to penicillin when the drug was 1 st introduced, but resistance developed almost immediately as the organism acquired a β-lactamase enzyme that was capable of inactivating drug Staphylococcus Aures Pharmacology Methicillin was an antibiotic used many years ago to treat patients with Staphylococcus aureus infections It is now no longer used except as a means of identifying this particular type of antibiotic resistance 1 st outbreak identified in 196 s Predominantly seen in hospitals, chronic care facilities and parenteral drug abusers The prevalence of isolates in hospitals in the US has risen steadily, such that now about ¼ nosocomial isolates are methicillin resistant Community-acquired is becoming a significant problem, with the prevalence of among community isolates expected to reach as high as 25% in the next decade Reasons for Rise of More powerful strains of developing An increased number of very sick people in hospital More complex medical treatments The use of central lines and catheters Patients move within and between hospitals more often High workloads which result in less compliance with routine hand washing 3

4 Multi-Drug Resistant Bacteria Emerging resistance of S aureus has also been demonstrated for streptomycin, tetracycline, chloramphenicol, erythromycin and third-generation fluoroquinolones. T The topical 4 th Generation fluoroquinolonesare are more potent against than prior generation fluoroquinolones They inhibit both DNA gyrase and topoisomerase IV, requiring two genetic mutations for the bacteria to become resistant About 1/3 of people carry on their skin or in their nose without knowing it These people are said to be carriers of The bacteria are present on the body but don t cause any harm This is also referred to as being colonised with Most people who carry in this way don t go on to develop an infection Risk Factors for Proloned hospital stays Prior surgery Seriously ill in intensive care Immunocompromised 25: Deaths from Surpassed AIDS In 25, AIDS killed 17,11 Americans CDC reports > 9, get the potentially deadly "superbug" infections annually Recent JAMA surveillance study, only about ¼ of infections involved hospitalized patients More than half were in the health care system People who had recently had surgery or were on kidney dialysis Open wounds and exposure to medical equipment are major ways the bug spreads. 4 th Gen FQ Resistant Bacterial Keratitis after Refractive Surgery Ocular Involvement of Moshirfar M, J Cataract Refract Surg 26; 32: Cases of Bacterial Keratitis resistant to 4 th Gen FQ 1 st pt Pseudomonas following PRK -> had been treated with Vigamox 2 nd pt following LASIK treated with Zymar and Vigamox Culture susceptibilities resistance to both 4 th Gen FQ 4

5 13 Cases of Following Refractive Surgery Multicenter, retrospective chart review of 13 cases of keratitis following refractive surgery 9 were either healthcare workers or exposed to a hospital surgical setting 7 pts were prescribed 3 rd generation FQ, 1 pt prescribed tobramycin, 1 pt was prescribed erythromycin and 3 were prescribed a 4 th generation FQ Solomon. Am J Ophthalmol. 27. Methicillin-Resistant Staphylococcus aureus Infectious Keratitis Following Refractive Surgery A retrospective chart review of cases occurring between May 22 and February 25 in 1 referral cornea and refractive disease practices Prophylactic Antibiotics Tobramycin 1/13 patients Erythromycin 1/13 patients Fourth-generation Gatifloxacin or moxifloxacin 3/13 patients 7.7% Unknown, 1 (bilateral)/13 l)/13 patients t 7.7% 7.7% 23.1% 53.4% Third-generation Ciprofloxacin or ofloxacin 7/13 patients Solomon. Am J Ophthalmol. 27. BPEI Ocular Trends-2-25 Trends in Ocular Isolates- All Sources, (N=2723) % % (N=127) 21 (N=142) 22 (N=143) 23 (N=161) 24 (N=139) 25 (N=93) (N=435) (N=652) (N=722) 2-25 (N=914) N= Total number of S. aureus isolates Ocular S. aureus Isolates by Source (2-25) % conjunctiva (N=375) MSSA (N=66) (N=293) lids (N=97) cornea (N=212) orbit (N=12) Total (N=899) In vitro Susceptibility for Select/Common Ocular Drugs. Antibiotic MSSA (%S) N=19 (%S) N=84 Cefazolin 1 Erythromycin Gentamicin 1 85 Gatifloxacin Moxifloxacin Trimethoprim -sulfa

6 Infectious Keratitis in Refractive Eye Care Clinicians must be alert to the postop patient with signs and symptoms of 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 Healthcare Workers Patients exposed to healthcare facilities who are at higher risk of infection from nosocomial, prophylactically treat blepharitis with lid hygiene and hot compresses preoperatively Consider a nasal swab for carriage Consider bacitracin or a fourth-generation fluoroquinolone or bacitracin for preoperative prophylaxis Treatment of s/p LASIK Irrigating under the flap with fortified vancomycin (5 mg/ml) Antibiotics to include better coverage for -fortified vancomycin every 3 minutes, alternating with topical 4 th Gen q 3 min Bacitracin ointment or Neosporin ointment to the eyelids qid Tracking Resistance TRUST Tracking Resistance in U.S. Today (TRUST) 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 TRUST In vitro susceptibility testing is performed by an independent central laboratory on isolates submitted annually by 2 or more clinical laboratories across all 5 states 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 6

7 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 Ocular TRUST Annually evaluates in vitro antimicrobial susceptibility of Staphylococcus aureus Streptococcus pneumoniae Haemophilus influenzae To ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, penicillin, azithromycin, tobramycin, trimethoprim, and polymyxin B in national samples of ocular isolates Ocular TRUST Tracking Resistance in the United States Today Ocular TRUST is the only nationwide surveillance program to monitor antimicrobial susceptibility in prospectively collected ocular isolates 151 S. aureus isolates Ocular TRUST 51 S. epidermidis isolates 188 S. pneumoniae isolates Asbell PA et al. Ocular TRUST AJO March 28 Asbell PA et al. Ocular TRUST AJO March 28 Ocular TRUST Staphylococci susceptibilities to levofloxacin, gatifloxacin and moxifloxacin were identical, regardless of species or methicillin status Saureushad S. a 52% susceptibility rate had an 18% susceptibility rate Methicillin-sensitive S. aureus (MSSA) had a 93% rate S. epidermidis had a 55% rate MRSE = 32% susceptibility rate MSSE = 9% susceptibility rate Ocular TRUST Macrolides (Azithromycin) had an 8% susceptibility rate, MSSA had a 62% rate MRSE had a 13% rate and MSSE had 4% rate 7

8 Ocular TRUST All S. pneumoniae isolates were susceptible to levofloxacin, gatifloxacin and moxifloxacin 69% were susceptible to treatment with azithromycin. Our Arsenal of Antimicrobial Therapy Ciprofloxacin Levofloxacin Gatifloxacin Moxifloxacin Aminoglycosides Tobramycin Gentamycin The Arsenal Macrolides Erythromycin Bacitracin Azithromycin Dihydrofolate reductase inhibitors Trimethoprim Polypeptides Polymixin B Ophthalmic Antibiotics: The first safe broad-spectrum ophthalmic agents Revolutionized treatment of severe corneal infections Very low sensitization rate Excellent safety profile Comfortable No reports of systemic effects 1 st released for ophthalmic use in early 199 s Represented an important breakthrough for clinicians For the 1 st time strong commercially available antibiotics available to treat bacterial conjunctivitis and ulcerative keratitis Broad spectrum including pseudomonas Ophthalmology July 1999; 16 (7): The BIG problem with the fluoroquinolones has been bacterial resistance! % resistance 2 yrs after release of fluoroquinolones % bacterial resistance 21 1% resistance to staph aureus isolates cultured in endophthalmitis Resistance to cipro, oflox, levoflox 8

9 Resistance to FQ s Alexandrakis et al, Ophthalmology August 2; 17: yr period: 292 cultures; 1468 (5%) recovered Bact Keratitis Resistance to Staph Aures Resistance to Pseudomonas Staph aures Pseudomonas 11% Cipro and Oflox 28 % Cipro and Oflox % % (27) 29% (51) 54% (32) 48% (32) 46% Resistance to FQ s Goldstein et al. Ophthalmology July 1999; 16 (7): Isolates from 825 Cases 1993 to Bact Keratitis Resistance to Staph Aures Resistance to Strep Gram + Gram - 5.8% Cipro 4.7% Oflox 35% Cipro 35% Oflox 51% 5% 81.8% 18.2% 51.4% 48.6% Widespread Decline in Susceptibility to 3rd-Generation In Vitro Susceptibility of Staphylococcus aureus to 3rd-Generation : Campbell Laboratory Survey Keratitis 2 Endophthalmitis 1 Conjunctivitis/Blepharitis Year Kowalski et al. Ophthal Clinics of N. America. 23. ptible Percentage Suscep : Resistance In vitro tests that compare moxifloxacin with other fluoroquinolones suggest that moxifloxacin i is less likely to Be affected by genetic mutations 1,2 Select for resistance 2,3 1. Tankovic J, et al. J Antimicrob Chemother. 1999;43(suppl B): Schedletzky H, et al. J Antimicrob Chemother. 1999;43(suppl B): Balfour JAB, Lamb HM. Drugs. 2;59: Distribution of Bacteria Isolated From Endophthalmitis Coagulase-negative Staphylococcus - 53% ( ) (N = 294) Streptococcus Species - 19% Gramnegatives - 6% Other Grampositives - 1% Staphylococcus aureus - 12% Charles T. Campbell Eye Microbiology Lab. Unpublished Data th Generation Developed to address the issues of resistance Developed to allow for broader coverage for both gram (+) and gram (-) organisms Better gram (+) coverage is needed as the growing trend towards more gram (+) infections 9

10 Macrolides Penicillins 4 th -generation S. pneumoniae H. influenzae M. catarrhalis Have Broader Coverage Atypicals ERSP (erythromycinresistant S.Pneumoniae) PRSP Gram-negative coverage Fluoroquinolone Structure Improved in vitro activity of 4th-generation fluoroquinolones against Gram- positives is due to the 8-methoxy group OCH 3 not present in the 3rd-generation Note: Levofloxacin and Ofloxacin have the same 3 rd - generation structure 4th-Generation: Gatifloxacin 3rd-Generation: Ciprofloxacin Levofloxacin Ofloxacin Fukuda H, et al. Antimicrob Agents Chemother. 21; Ince D, Hooper DC. Antimicrob Agents Chemother. 21. Mechanism of Action: Cause lethal breaks in the bacterial chromosome at their target site Targets of 3rd-generation FQs DNA gyrase in Gram-negatives Topo IV in Gram-positives Targets of 4th-generation FQs are dual binding DNA gyrase AND topo IV in both Gram-positives and Gram-negatives Gatifloxacin and Moxifloxacin Comparison of In Vitro Efficacy Fourth-Generation Far More Effective Than Third-Generation Isolates From Bacterial Endophthalmitis Resistant to Ciprofloxacin, Ofloxacin, and Levofloxacin Fourth-Generation More Effective Than Older-Generation Staphylococcal Endophthalmitis Isolates More Susceptible to Fourth Generation than to Older Moxi Gati Levo Oflox Cipro CoagNeg Staphylococcus (n = 1) Saureus(n = 8) Median MIC (μg/ml) *CoagNeg = Coagulation Negative; Moxi = moxifloxacin; Gati = gatifloxacin; Levo = levofloxacin; Oflox = ofloxacin; Cipro = ciprofloxacin Mather et al. Am J Ophthalmol. 22. Gatifloxacin (n = 33) Moxifloxacin Ciprofloxacin Levofloxacin Ofloxacin (n = 33) (n = 33) (n = 23) (n = 18) In Vitro Susceptibility (Percentage Sensitive) Miller et al. Arch Ophthalmology

11 Gatifloxacin vs Moxifloxacin, MIC 9 for Gram-positive Isolates Gatifloxacin and Moxifloxacin Comparison of In Vitro Efficacy MIC 9 (μg/ml L), SEM Gatifloxacin Moxifloxacin P = Bacillus cereus Staphylococcus aureus Staphylococcus epidermidis Streptococcus pneumoniae Streptococcus pyogenes Streptococcus viridans (n = 5) Enterococcus faecalis Callegan MC and Jensen H. Adv Ther. 24. Gatifloxacin vs Moxifloxacin, MIC 9 for Gram-negative Isolates Comparing Molecules: Gatifloxacin vs Moxifloxacin In Vitro Comparing Commercial Formulations: ZYMAR vs Vigamox In Vitro L), SEM MIC 9 (μg/m Pseudomonas aeruginosa Serratia marcescens Klebsiella pneumoniae (n = 4) Gatifloxacin Moxifloxacin P =.23 Enterobacter aerogenes (n = 4) Callegan MC and Jensen H. Adv Ther. 24. Mean MIC (μg/m L) ZYMAR Gatifloxacin (gatifloxacin ophthalmic solution).3% Moxifloxacin Vigamox n = 6 n = 6 n = 6 <.35 <.3 <.35 Staphylococcus aureus Streptococcus pneumoniae Mean MICs for the Mean active MICs ingredients for the commercial in the fourth-generation formulations using fluoroquinolone clinical isolates using (N clinical = 34) isolates (N = 34) Callegan and Novosad. ARVO. 26; In vitro data. Clinical significance not known. Snyder. ASCRS. 27 n = 6 n = 6 Staphylococcus epidermidis Gram-positive Pathogen <.35 n = 6 Methicillin-resistant S aureus Resistant Pathogens 1.6 n = 1 n = 1 Methicillin-resistant S epidermidis New Dimensions in MIC Testing Conclusions MICs of gatifloxacin in the presence of BAK in the concentrations found in Zymar (5 ppm) were substantially lower than MICs for gatifloxacin alone Comparisons of MICs for antibiotics alone can be misleading and may not represent the marketed formulation s ability to inhibit growth in the clinical setting Blondeau et al. ARVO. 25. The Newest Antibiotic AzaSite (Inspire) Topical Azithromycin 11

12 1% topical azithromycin Macrolide AzaSite Broad spectrum of action particularly against gram-positive organisms It works by inhibiting protein synthesis It is bacteriostatic and not bacteriacidal Bacteriostatic antibiotics inhibit growth and reproduction of bacteria without killing them; killing is done by bactericidal AzaSite Popular among general physicians due to its ease of use It is most often prescribed in the form of a Z-Pac, needing only to be used for two or three days OD/MD s us it for the treatment of Chlamydial conjunctivitis AzaSite: Dosage One drop bid X 2 days, followed by 1 qd for 5 days A French study by Cochereau et al 471 children and adults w/ culture (+) bacterial conjunctivitis Compared a 3 day 1.5% topical azithromycin with tobramycin 3% X 7 days Cure rate was 87.8% for azithromycin and 89.4% for tobramycin. Br. J. Ophthalmol., Apr 27; 91: AzaSite (azithromycin ophthalmic solution) 1% AzaSite is indicated for the treatment of bacterial conjunctivitis caused by susceptible isolates of the following microorganisms: CDC coryneform group G*, Haemophilus influenzae, Staphylococcus aureus, Streptococcus mitis group, and Streptococcus pneumoniae. *Efficacy for this organism was studied in fewer than 1 infections 1. AzaSite [package insert] Durham, NC: Inspire Pharmaceuticals Inc; 27 DuraSite : The AzaSite Vehicle DuraSite contains Polycarbophil USP Sodium chloride, edetate disodium (EDTA), benzalkonium chloride (BAK.3%), purified water and sodium hydroxide to adjust ph 1 DuraSite is an advanced synthetic polymeric mucoadhesive matrix that stabilizes small molecules like azithromycin DuraSite allows for a stable formulation of azithromycin 1 and increase the bioavalability of azithromycin in tissue 2 1. Data on file. Inspire Pharmaceuticals Inc., NDA Quality Summary 2. Data on file. Inspire Pharmaceuticals Inc., NDA Study Report 17U11 Superior Bulbar Conjunctiva 18-fold difference 3 minutes post dose 144 hours post dose 12.8-fold difference 12

13 AzaSite Eradicates Most Common Bacterial Conjunctivitis Pathogens Bacterial Eradication in Pivotal Studies and Pharmacokinetic Study % Eradicated (Isolates Eradicated / Isolates Observed) Strain AzaSite 92.7% (89/96) 9.2% (83/92) 82.5% (33/4) Combined pivotal trials Haemophilus influenzae Streptococcus pneumoniae Staphylococcus aureus 1. Data on file. Inspire Pharmaceuticals Inc., NDA Clinical Summary % Eradicated (Isolates Eradicated / Isolates Observed) Strain AzaSite 1% Moraxella catarrhalis (5/5) Combined pivotal trials AzaSite Effectively Eradicates other Pathogens Streptococcus mitis group Staphylococcus epidermidis 1% (1/1) 88.9% (8/9) AzaSite Eradicated Azithromycin-Resistant Organisms (C AzaSite vs. Vehicle) Strain Azithromycin Staphylococcus aureus 62.5% (5/8) Staphylococcus epidermidis 1% (2/2) Streptococcus mitis group 1% (3/3) Streptococcus oralis 1% (1/1) Streptococcus pneumoniae 91.7% (11/12) Streptococcus viridans 1% (1/1) AzaSite effectively eradicated 85% (23/27) of azithromycinresistant pathogens Resistance determined by NCCLS standards. Potential Limitations of MIC data MIC standards based upon systemic breakpoints Azithromycin likely acts differently on the ocular surface than in broth culture media (i.e. maintains high tissue concentrations at the site of infection over time) Comparing MICs across classes of drugs is not scientifically appropriate (macrolide vs. quinolone) Different chemical structures Different tissue penetration Different susceptibility standards Small infiltrate: < 1-2 mm diameter Located superficial stroma Contain white blood cells Infectious vs inflammatory? CL Infiltrates 13

14 CL Infiltrates Status of epithelium Intact: more likely sterile epithelial defect: infection more likely -> ulcer Ulcer should have excavation of the cornea Infectious infiltrate can occur with intact epi How do you decide?? Infectious vs Sterile Corneal Infiltrates in CL s Stein MD, AJO: June patients Culture negative Minimal pain Minimal to absent AC reaction No discharge No epithelial defect Minimal corneal edema Infectious vs Sterile Corneal Infiltrates in CL s Stein MD, AJO: June patients Culture positive Moderate pain AC reaction Discharge Epithelial defect Corneal edema Predicting Visual Loss after Healing of Bacterial Corneal Infection Rule 1. Cells > 1+ in the anterior chamber (1 cells or greater in 1-mm beam) 2. Dense infiltrate > 2 mm in size in greatest linear dimension 3. Edge of infiltrate < 3 mm from the center of cornea Vital, MC, Belloso M, Prager TC et al. Cornea. 26(1):16-2, January 27. Infectious/Sterile Infiltrates Treatment D/C lens wear Never, Never patch If defect looks infectious 4 th Gen FQ -?q 15 min X 3 hrs, then q 3 min until 12 am, q 1hr after 12 am Cycloplegia for pain If defect looks non-infectious/sterile: 4 th Gen FQ q 4-5 X/day - see 1-2 days Corticosteroids after 48 hrs if inflammation Cohen EJ, Arch of Ophthal Feb 2 Vol 118 Clear margins Clear edges Infiltrate Discharge AC cell or flare CL Related Epithelial Defects 14

15 Infectious vs. NonInfectious Corneal Lesions Choice of antibiotics 4 th Generation FQ Zymar vs. Vigamox Topical Azithromycin Azasite Comparison of Gatifloxacin.3% and Ciprofloxacin.3% for the Treatment of Bacterial Keratitis Parmar P, Salman A, Kalavathy CM et al. AJO 26; 141: Eyes of 14 patients presenting with bacterial keratitis randomized 5 Gatifloxacin vs. 54 Ciprofloxacin Outcome: Healing of the corneal ulcer Significant more of Gatifloxacin exhibited complete healing Gatifloxacin had a significantly better action against Gm (+) cocci 15