The Increasing Public Health Exigency of Antimicrobial Resistance Alfred DeMaria, Jr., M.D. Massachusetts Department of Public Health

Why is antimicrobial resistance like global climate change?

“… the greatest possibility of evil in self- medication is the use of too small doses so that instead of clearing up infection, the microbes are educated to resist penicillin and a host of penicillin-fast organisms is bred out which can be passed to other individuals and from them to others until they reach someone who gets a septicemia or a pneumonia which penicillin cannot save.” - Sir Alexander Fleming, 1945

Antimicrobials The only medications that affect the patient being treated and other people at present and in the future

1940s – 1980s “Nosocomial” Organisms

Rehabilitation LTCF Assisted Living Home Care Public Health Patient Safety Healthcare-Associated Infections “New” Organisms Shorter LOS Out-Patient Settings Surgicenters, etc. NOW!

What We Know  Increased antibiotic use, increased resistance  Longer treatment, increased colonization  Resistance more prevalent in healthcare facilities than community  Areas of higher antibiotic use have highest resistance  Antibiotic use correlates with infection with resistant strains during outbreaks

Classes of Antibiotic Resistance  Natural - organism is not and never was susceptible to antibiotic  Acquired -organism originally susceptible, but becomes resistant  Relative – gradual increase in resistance, but still susceptible  Intermediate – concentration dependent  High level (absolute) – sudden increase in resistance  Pseudoresistance – resistant in vitro, effective in vivo

Genetic Mechanisms Of Developing Antibiotic Resistance  Random genetic mutation.  Plasmid swapping during conjugation.  Movement of transposons to plasmids or chromosomes.  Transduction by bacteriophages.  Transformation (acquisition of resistant genes from a recently killed cell and incorporation into a chromosome or plasmid).  Binary fission (replication) can share any of the above.

Cellular and Biochemical Mechanisms of Antibiotic Resistance  Antimicrobial does not get to active site  Decreased permeability (β-lactams, quinolones)  Decreased transport (aminoglycosides)  Increased efflux (tetracyclines, quinolones)  Drug inactivation (enzymes)  Β-lactamases, aminoglycoside modifying enzymes  Target modification (gyrase modification)  Bypass of target (vanA, vanB, TMP resistance)

Resistance Occurs Because:  Genetic variation in microorganisms results in some members of the population being less susceptible to agents than others  Presence of the antibiotic selects for resistant organisms already present

Patients Acquire Resistant Organisms:  By selection of resistant organisms through antibiotic exposure  From another colonized or infected individual  From the environment

Numerous Studies Demonstrate Impact of Antibiotic Use on Resistance

Relationship between antimicrobial use and antimicrobial resistance in Europe. Penicillin-resistant Streptococcus pneumoniae versus outpatient sales. Bronzwaer, et al. Emerging Inf. Dis. 2002; 8:

Proportion of Methicillin-Susceptible Staphylococcus aureus in Massachusetts Hospitals (antibiograms)

MRSA Reported in Massachusetts Under Active Surveillance, Characteristics of Age and Gender Mean/Median Age: 2001 = 70.6/ = 62.4/67.5 Male – 54% Female – 46%

Emerging Gram-Negative Multi-Drug Resistant Bacteria  Extended-spectrum beta-lactamase (ESBL, TEM- 1, TEM-2, SHV-1, etc. ) producing organisms  AmpC-type β-lactamase producers  Carbapenemases  SME, KPC enzymes, etc.  Metallo-β-lactamases  IMP  NDM-1  VIM (Verona integron-encoded metallo-β-lactamase)

All Fluoroquinolone-Susceptibility Rates, (E. coli, p<.0001) Year % Susceptible E. coliE. cloacaeK. pneumoniae

FDA-Approved New Antimicrobials (Modified from Boucher, et al 2013; Spellberg 2004)

Considerations in Antibiotic Selection  Susceptibility of infecting organism  Effectiveness of agent for particular infection  Narrow spectrum of activity  Safety  Cost = most effective, safest, cheapest, active agent, with the narrowest spectrum of activity

MDRO Control Measures  Education ***  Emphasis on hand hygiene ***  Antiseptic hand washes *  Contact precautions and/or gloves ***  Private rooms **  Segregation of cases **  Cohorting of patients *  Cohorting of staff *  Change in antimicrobial use **  Surveillance cultures of patients ***  Surveillance cultures of staff  Environmental cultures  Extra cleaning and disinfection  Dedicated equipment *  Decolonization  Ward closure to new patients

Antibiogram example

Staphylococcus aureas Susceptibility to Oxacillin Over Time, Massachusetts Antibiograms Caveat: Hospitals reporting varies somewhat over time

Escherichia coli Susceptibility to Ciprofloxacin and Levofloxacin Over Time