Management Of Antibiotic Resistant Pathogens
Management of AntibioticResistant PathogensJonathan J. Juliano, MD, MSPHAssistant ProfessorUNC School of MedicineDirector of Antibiotic StewardshipUNC Hospitals, Chapel HillSPICE ConferenceFriday CenterOctober 17, 2016Conflicts of Interest None10/27/20162
Goals of Lecture Current anti-infectives» Antibiotic development Antimicrobial Resistance» Factors impacting development and spread ofresistance» Mechanisms of Action» Mechanisms of Resistance» Methods for Testing ResistancePractical classification of microbes for choosing anantibiotic » Diagnosis» Choosing an appropriate antibiotic therapy Methods for Testing ResistanceSummary of Dealing with Resistant PathogensTRENDS INANTIMICROBIAL DEVELOPMENT Fewer companies producing antibiotics and fewantibiotics introduced
TRENDS INANTIMICROBIAL DEVELOPMENT Broader spectrum Reduced dosing frequency Novel mechanisms of action and coverage Modifications based on understanding structurefunction relation Newly introduced agents focused on coverageof resistant S. aureus and Enterococcus, HIV,and fungi (especially uncommon Candida spp.and zygomycetes)Antibiotics Approved obactamCeftazidime/Avibactam
American Academy of PediatricsAmerican Gastroenterology AssociationTrust for America’s HealthSociety for Healthcare Epidemiology of AmericaPediatric Infectious Disease SocietyMichigan Antibiotic Resistance Reduction CoalitionNational Foundation for Infectious DiseasesEuropean Society of Clinical Microbiology and Infectious DiseasesSupport the development of 10 new systemic antibacterialdrugs through the discovery of new drug classes as well asexploring possible new drugs from existing classes ofantibiotics.Support the concurrent advancement of improved diagnostictests specific to multidrug-resistant infectionsCID (2010) 50: 8, pp 1081-1083.GoalsGoal 1: Slow the Development of ResistantBacteria and Prevent the Spread ofResistant InfectionsGoal 2: Strengthen National One-HealthSurveillance Efforts to Combat ResistanceGoal 3: Advance Development and Use ofRapid and Innovative Diagnostic Tests forIdentification and Characterization ofResistant BacteriaGoal 4: Accelerate Basic and AppliedResearch and Development for NewAntibiotics, Other Therapeutics andVaccinesGoal 5: Improve International Collaborationand Capacities for Antibiotic ResistancePrevention, Surveillance, Control andAntibiotic Research and Development
Key Terms Antibiotic A drug that kills or inhibits thegrowth of microorganisms Resistant Somewhat arbitrary designationthat implies that an antimicrobial will not inhibitbacterial growth at clinically achievableconcentrations Susceptible Somewhat arbitrary designationthat implies that an antimicrobial will inhibitbacterial growth at clinically achievableconcentrationsKey Terms MIC Minimal inhibitory concentration. Lowestconcentration of antimicrobial that inhibitsgrowth of bacteria. Commonly used in clinicallab MBC Minimal bactericidal concentration.Concentration of an antimicrobial that killsbacteria. Used clinically only in specialcircumstances Breakpoint The MIC that is used todesignate between susceptible and resistant.Arbitrarily set by a committee
PRINCIPLES OF ANTIBIOTICRESISTANCE(Levy SB. NEJM, 1998)1.2.3.4.5.Given sufficient time and drug use, antibioticresistance will emergeResistance is progressive, evolving from low levelsthrough intermediate to high levelsOrganisms resistant to one antibiotic are likely tobecome resistant to other antibioticsOnce resistance appears, it is likely to declineslowly, if at allThe use of antibiotics by any one person affectsothers in the extended as well as the immediateenvironmentSelective Pressures:Antimicrobial Use and ResistanceThe figure summarizes the current goals (purple boxes) in trying to minimize the emergence and spreadof antibiotic resistance genes (ARGs) and antibiotic resistant bacteria (ARB) in the environment and theirtransmission into the clinic. The current needs and limitations that must be resolved to achieve thesegoals are also shown (yellow boxes).Berendonk (2015) Nature Micro.
10/27/2016Antibiotic Use Leads toAntibiotic Resistance Resistant bacteria or theirgenetic determinates areselected when colonizing orinfecting bacteria are exposedto antibioticsResistant bacteria can then betransmitted between patientsHighest risk patients:» Immunocompromised» Hospitalized» Invasive devices(central venous catheters)13
IDSA. Bad Bugs No Drugs. 2004
MDRO Organisms Are a GrowingThreatEMERGING RESISTANT PATHOGENS:COMMUNITY HIV:» Multiple antivirals Pneumococcus:» Multiple drugs (including penicillins/cephalosporins,macrolides) Staphyloccus aureus:» Multiple drugs (including oxacillin) Gram negative enterics:» Cephalosporins, carbapenems Group A streptococcus:» Macolides, tetracyclines Neisseria gonorrhoeae:» Penicillin, tetracycline, quinolones Salmonella typhimurium:» Multidrug (amp-, TMP-SMX, /-quinolones) Mycobacterium tuberculosis:» MDR (INH, rifampin), XDR (INH, rifampin, others)
ANTIBIOTIC RESISTANCE:FACTORS CONTRIBUTING TO SPREAD INCOMMUNITIES Increase in “high-risk” (immunodeficient) populationProlonged survival of persons with chronic diseasesCongregate facilities (e.g., jails, day care centers)Lack of rapid, accurate diagnostic tests to distinguishbetween viral and bacterial infectionsIncreased use of antibiotics in animals & agricultureSource: Segal-Maurer S. ID Clin NA 1996;10:939-957.ANTIBIOTIC RESISTANCE:FACTORS CONTRIBUTING TO SPREAD INCOMMUNITIESReasons for Antibiotic Overuse :Conclusions from 8 Focus GroupsPatient Concerns Want clear explanation Green nasal discharge Need to return to workPhysician Concerns Patient expects antibiotic Diagnostic uncertainty Time pressureAntibiotic PrescriptionBarden L.S. Clin Pediatr 1998;37:665
EMERGING RESISTANTPATHOGENS:HEALTH CARE FACILITIES Staphylococcus aureus:» Oxacillin, vancomycin, linezolid Enterococcus:» Penicillin, aminoglycosides, vancomycin, linezolid,dalfopristin-quinupristin Enterobacteriaceae:» ESBL producers, carbapenems P. aeruginosa, Acinetobacter spp:» β-lactams including carbapenems Candida spp.:» Fluconazole Mycobacterium tuberculosis:» MDR (INH, rifampin); XDR (multiple)ANTIBIOTIC RESISTANCE IN HOSPITALS:FACTORS CONTRIBUTING TO SPREAD INHOSPITALS Greater severity of illness of hospitalized patientsMore severely immunocompromised patientsNewer devices and procedures in useIncreased introduction of resistant organisms from thecommunityIneffective infection control & isolation practices (esp.compliance)Increased use of antimicrobial prophylaxisIncreased use of polymicrobial antimicrobial therapyHigh antimicrobial use in intensive care unitsSource: Shlaes D, et al. Clin Infect Dis 1997;25:684-99.
ESKAPE PathogensEnterococcus faecium (VRE)Staphylococcus aureus (MRSA)Klebsiella and Escherichia coli producing ESBLAcinetobacter baumanniiPseudomonas aeruginosaEnterobacteriaceace
Mechanisms of Action of midesTMP-SMX–Cell A rityGlycylcyclinesGlycylcyclinesRifampinTMP-SMX trimethoprim-sulfamethoxazole.Adapted from: Chopra I. Curr Opin Pharmacol. ACTERIALS:MECHANISMS Interference with cell wall synthesis (bactericidal)» Penicillins: Oxacillin, ampicillin, piperacillin» Cephalosporins: 1o, 2o, 3o, 4o, 5o cephalosporins» Carbapenems: Imipenem, meropenem,ertapenem, doripenem» Monobactams: Aztreonam» Glycopeptides: Vancomycin, Dalbavancin,Oritavancin, Telavancin
ANTIBACTERIALS:MECHANISMS Inhibition of DNA gyrase (bactericidal)» Quinolones: Ciprofloxacin, levofloxacin,moxifloxacinANTIBACTERIALS:MECHANISMS Interference with ribosomal function» Aminoglycosides (bactericidal): Gentamicin,tobramycin, amikacin» Tetracyclines: Tetracycline, minocycline,doxycycline» Glycylcyclines: Tigecycline» Macrolides: Erythromycin, azithromycin,clarithromycin» Chloramphenicol» Lincosamines: Clindamycin» Oxzalidinone: Linezolid» Streptogramin: Dalfopristin-quinupristin
ANTIBACTERIALS:MECHANISMS Antimetabolites» Sulfonamides» Trimethoprim-sulfamethoxazole Inhibition of DNA-directed RNA polymerase» Rifampin, rifapentine, rifabuten Degradation of DNA» Metronidazole Cyclic lipopeptide (effects calcium transport)» DaptomycinMechanisms of ResistanceAntibiotic Degrading Enzymes Sulfonation, phosphorylation, or esterifictation» Especially a problem for aminoglycosides β-lactamases» Simple, extended spectrum β-lactamases (ESBL),cephalosporinases, carbapenemases» Confer resistance to some, many, or all beta-lactamantibiotics» May be encoded on chromosome or plasmid» More potent in gram-negative bacteria
Mechanisms of ResistanceAntibiotic Degrading Enzymes Extended spectrum β-lactamases» Can hydrolyse extended spectrum cephalosporins, penicillins, andaztreonam» Most often associated with E. coli and Klebsiella pneumoniae butspreading to other bacteria» Usually plasmid mediated» Multiple resistance genes (often Aminoglycoside, ciprofloxacin andtrimethoprim-sulfamethoxazole) encoded on same plasmid Class A Carbapenemase» Most common in Klebsiella pneumoniae (KPC)» Also seen in E. coli, Enterobacter, Citrobacter, Salmonella, Serratia,Pseudomonas and Proteus spp.» Very often with multiple other drug resistance mechanisms,resistance profile similar to ESBL but also carbapenem resistant» Spreading across species to other gram-negatives andenterobacteriaceaeMechanisms of ResistanceDecreased Permeability Affects many antibiotics includingcarbapenemsEfflux Pumps Tetracyclines Macrolides
Mechanisms of ResistanceTarget Alteration DNA gyrase Fluoroquinolones Penicillin-binding protein Methacillin/penicillin Gram positive cell wall Vancomycin Ribosome Tetracyclines MacrolidesPrinciples of AntibioticTherapyEmpiric Therapy (85%) Infection not well defined(“best guess”) Broad spectrum Multiple drugs Evidence usually only 2randomized controlledtrials More adverse reactions More expensiveDirected Therapy (15%) Infection well defined Narrow spectrum One, seldom two drugs Evidence usuallystronger Less adverse reactions Less expensive
IMPACT OF ANTIMICROBIALSHospital Mortality %6050403020100All CauseInfection-relatedInadequate Therapy n 169Adequate Therapy n 486Kollef Chest 115:462, 1999DIAGNOSIS Gram stain» Often provide clues to etiology (mayallow presumptive diagnosis in somecases) Gram Stain» Gram Positive» Gram Negative» Non-staining Shape» Cocci» Rods
GRAM POSITIVE ORGANISMS Gram positive cocci» Staphylococcus aureus» Coagulase negativestaphylococcus» Pneumococcus sp.» Streptococcus sp.» Enterococcus sp. Gram positive rods» Bacillus sp. (aerobes)» Clostridial sp.(anaerobes)GRAM NEGATIVE ORGANISMS Gram negative cocci» Neisseria meningitidis» Neisseria gonorrhoeae Gram negative rods (non-enteric)» Pseudomonas aeruginosa» Stenotrophomonas maltophilia» Acinetobacter sp.» E. coli» Klebsiella sp.» Enterobacter sp.» Proteus sp.» Serratia sp.
NON-STAINING PATHOGENS Not stained by Gram’smethod» Legionella sp.» Chlamydia» Rickettsia» Mycobacteria M. tuberculosis Non-tuberculousmycobacteriaZiehl-Neelsen Stain of TBDIAGNOSIS Culture» “Gold standard”» Requires sampling of site of infectionprior to therapy» Allows determination of antimicrobialsusceptibility
Evidence for Efficacy In vitro activity (discussed later)Clinical trials» Gold standard randomized clinical trial» Should be comparative (best available alternative)» Should use appropriate population» Small number precludes discovery of rare adversereactionsPatient Safety Drug interactionsAgePregnancy, breast feedingToxicity (idiosyncratic reactions)Dose adjustment for renal dysfunctionDose adjustment for hepatic dysfunctionAbility to absorb an oral antibiotic
Adherence/compliance Frequency of administrationDuration of therapyMultiple drug therapyAdverse effectsReduction of symptomsTasteCostCOMPLIANCE RELATED TODOSINGCompliance (%)1008060402001x/d2x/d3x/d4x/dDosing ScheduleCockburn J BMJ 1987
Antibiotics with Gram ( ) ActivityS. aureusMRSANafcillin/OxacacillinAmp/Sulb, lavancinTMP-SMXVREE. y)VancomycinClindamycin cinAntibiotics with Gram (-) ActivityE. coliK. pneumoniaeEnterobacterP. Pip/TazoPip/TazoCephalosporinsCephalosporins3rd, 4th, 5th msImip, Cipro and LevoTrimeth/SulfTrimeth/SulfTrimeth/Sulf
Antibiotics with Anti-anaerobicActivity ß-lactams» Ampicillin/Sulbactam*, Piperacillin/Tazobactam*» Carbapenems (imipenem, meropenem, doripenem,ertapenem)*» Cefoxitin» Cefotetan e** Highly activeComparison of ncinStreptococcusGrp A,B,C,G Streptococcuspneumoniae 2 Enterococcusfaecalis Enterococcusfaecium - MSSA CoagulasenegativeStaph. VRE- 3 MRSA VISA- - VRSA- -- -MRSA, methicillin-resistant S. aureus; MSSA, methicillin-resistant S. aureus; VRE, vancomycin-resistant Enterococcus; VRSA, vancomycin-resistantS. aureus1: Cefolozane/tazobactam has activity against some Streptococcus species, but not Staphylococcus species and is not included.2: Not appropriate for respiratory tract infections (e.g., pneumonia); 3: Not active against E. faecium
Comparison of actamE.coli H. influenzae -Klebsiella sp. Enterobactersp. Proteusmirabilis Pseudomonasaeruginosa - - Acinetobactersp. - --ESBL-GNR --- CRE------- CRE, carbapenemase resistant Enterobacteriaceae- ESBL, extend β-lactamase producing Gram negative rods (E. coli, Klebsiella spp.,Enterobacter spp.)- GNR, Gram negative rodsMethods for TestingResistance and Efficacy10/27/201652
Methods for Testing Resistance:Minimal Inhibitory ConcentrationLowest concentration of an antimicrobialKnown quantity of bacteria that results in the inhibition of visiblegrowth of a microorganismplaced into each 8.0µg/mL16µg/mLIncreasing antibioticconcentrationSinus and Allergy Health Partnership. Otolaryngol Head Neck Surg. 2000;123(1 Pt 2):S1.Methods for Testing Resistance:Automated Minimal Inhibitory ConcentrationWell Plate for MICTestingMany Labs UseAutomated Testing
MIC90: Lowest ConcentrationThat Inhibits Growth of 90%of Isolates90%252015108%5MIC (µg/mL)1684210.50.250.120.060.030.020.0102%MIC90 4 µg/mLMethods for Testing Resistance:Kirby-Bauer Disc Diffusion TestSusceptible1. Add test bacteria to smallamount of melted agar.2. Pour over surface of nutrientagar plate, let gel.3. Add paper disks with knowndose of antibiotic to surface.4. Incubate: antibiotic will diffuseinto medium as cells grow.5. Examine plate: look for clearzones around disk where growth isinhibited.6. Measure diameter of clearzones.
Methods for TestingResistance:E-test StripE-test EXAMPLE:Susceptibilitytesting for asingle isolate ofPseudomonasaeruginosa-Breakpoint forintermediate resistancefor meropenem is 4 andforpiperacillin/tazobactam(pip/tazo) 32-Pip/tazo is the betterchoice between the two-Ciprofloxacin is a poorchoice even though theMIC is lowest of the threeConcept of Breakpoint toDetermine yAmpicillin 168ResistantGentamicin24SusceptibleCephalothin 16SusceptibleCiprofloxacin22ResistantAmp/Sulbactam 4/128Susceptible
Principles of Antibacterial Therapy:Synergy and Antagonism of AntibioticsPrinciples of Antibacterial Therapy:Bacteriostatic or BactericidalControlBacteriostatic agents which include mostprotein synthesis inhibitors (exceptaminogylcosides), prevent growth butdon’t kill the organismsLog #bacteriaBactericidal agents which include cell wall inhibitors(usually), quinolones, aminogylcosides, anddaptomycinTimeBactericidal agents required for meningitis,endocarditis and infections in neutropenic hosts
DEALING WITH RESISTANTPATHOGENSHospitalCommunity ProviderecommendedvaccinesAvoid unnecessaryantibioticsUse appropriate drugto cover antibioticresistant pathogensProvide appropriatedose and durationUse short coursetherapy if validated Provide recommendedvaccinesAvoid unnecessaryantibioticsPractice appropriateinfection controlAvoid prophylactic therapyunless supported byscientific evidenceUse appropriate drug tocover antibiotic resistantpathogensProvide appropriate doseand durationUse short course therapy ifvalidatedPractice de-escalationUse early IV to PO switchAcknowledgements David Weber (slides) Chris Ohl (slides modeled after his talks)10/27/201662
May 05, 2017 · SPICE Conference Friday Center October 17, 2016 10/27/2016 2 Conflicts of Interest None. Goals of Lecture . 10/27/2016 13 Antibiotic Use Leads to Antibiotic Resistance Resistant bacteria or the
and the Core Elements of Antibiotic Stewardship for Nursing Homes (23). This 2016 report, Core Elements of Outpatient Antibiotic Stewardship, provides guidance for antibiotic stewardship in outpatient settings and is applicable to any entity interested in improving outpatient antibiotic prescribing and use.
R M AB ARP R R M APP B 3 Completeness of antibiotic prescribing documentation. Ongoing audits of antibiotic prescriptions for completeness of documentation, regardless of whether the antibiotic was initiated in the nursing home or at a transferring facility, should verify that the antibiotic prescribing
The National Action Plan for Combating Antibiotic-Resistant Bacteria (CARB), 2020-2025, presents coordinated, strategic actions that the United States Government will take in the next five years to improve the health and wellbeing of all Americans by changing the course of antibiotic resistance.
environment. For example, water and soil. The following are 3 examples of how antibiotic resistance affects humans, animals, and the environment. - People. Some types of antibiotic-resistant germs can spread person to person. "Nightmare bacteria" carbapenem-resistant Enterobacteriaceae (C R E) can also survive and grow in sink drains at
of all known ARGs in the full-microbial pan-genome is defined as the antibiotic resistome (132). What is most important conceptually about the antibiotic resistome is the potential accessibility of individual ARGs to all bacteria. In this review, we focus on our current knowledge of the evolution of antibiotic resistance in plant-pathogenic .
The four core elements of outpatient antibiotic stewardship are commitment, action for policy and practice, tracking and reporting, and education and expertise. Outpatient clinicians and facility leaders can commit to improving antibiotic prescribing and take action by implementing at least one policy or practice aimed at improving antibiotic
antibiotic-resistant bacteria. In the U.S., more than 35,000 peo-ple die annuallyfrom antibiotic-resistant infections, and antibi-otic treatments are ineffective [2, 3]. In Mexico, Lemmen et al. [4] found 54 patients with methicillin-resistant Gram-positive bacteria (Staphylococcus aureus or enterococci) and 136 with
ASME A17.1 / CSA B44 (2013 edition) Safety Code for Elevators and Escalators ASME A18.1 (2011 edition) Safety Standard for Platform Lifts and Stairway Chairlifts . 3 Other codes important to conveyances adopted through state codes or as secondary references include the following: ASME A17.6 (2010 edition) Standard for Elevator Suspension, Compensation and Governor Systems ASME A17.7 / CSA B44 .
