Antibiotic Resistance

Tiebreaker question: Who is Andrew Speaker?

So what's the problem?

"The fact is, we are simply running out of options. We're already seeing infections that fail to respond to the first or even second antibiotic prescribed. If we continue on this course, we're going to find ourselves back in the Dark Ages, when serious infections had no cure." - Martin Blaser, MD, chair of the Dept. of Medicine at New York University School of Medicine

• CDC estimates 2.8 million drug-resistant infections and 35,000 deaths annually in the US (https://www.cdc.gov/drugresistance/national-estimates.html)
• When including C. diff infections, those numbers increase to >3 million and 48,000 deaths
• Read the complete CDC 2019 Antimicrobial resistance threat report

Major resistant threats

1. CRE: Carbapenem-resistant Enterobacteria (up to 50% mortality)
2. Resistant Neisseria gonorrheae
3. MRSA: > 60% of SA isolates
   • HA-MRSA: MDR; enterotoxin G
   • CA-MRSA: PVL toxin, b-lactamase
4. VRE: > 26%
5. MDR-TB & XDR-TB: 440,000 cases/150,000 deaths annually
6. Penicillin/Erythromycin-resistant S. pneumoniae
7. Cephalosporin-resistant E. coli/Klebsiella
8. MDR Pseudomonas & Acinetobacter
9. Ciprofloxacin resistant bacteria
10. Resistance in food-borne bacteria (Salmonella, Shigella)
11. Clostridioides difficile

Resistance vs. susceptibility

• Susceptibility
• Natural resistance
• Acquired resistance

How does antibiotic resistance develop?

1. Mutation
2. Gene transfer
   • Transformation
   • Transduction
   • Conjugation

Mechanisms of resistance

1. Antibiotic degradation
   • Penicillinase (beta-lactamase)
     • Class A: SHV-1, TEM-1 in G- rods; ESBLs on plasmids
     • Class B: Zn-dependent; vs ALL BLs
     • Cephalosporinases
     • Penicillinases (G- rods)
     • Carbapenemase
2. Antibiotic alteration (aminoglycosides)
   • aminoglycoside phosphotransferase
   • acetyltransferase: streptogramin
   • adenyltransferase
3. Antibiotic efflux pump
   • Many antibiotics, esp. tetracycline, chloramphenicol, cipro
   • New antibiotics, too: Linezolid (Gram -)
4. Decreased antibiotic entry
   • porins (omp genes): tetracycline, chlormaphenicol
   • anti-mycobacterials
5. Reduced binding to cell target: mutation / recombination
   • Penicillin binding proteins (PBP)
     • MRSA: new PBP on plasmid
     • Pen resistance in EF, SP
   • D-ala D-ala terminus: VanA, VanB
   • Ribosomal proteins
   • DNA gyrase/toposiomerase: fluoroquinolones
   • RNA polymerase: rifampin
   • rRNA methylation: Erythromycin, Clindamycin
6. Circumventing antibiotic effect
   • acquired folic acid transporter gene (sulfa resistance)
7. Antiviral drugs
8. Antifungal drugs: ergosterol synthesis genes

Approaches to dealing with antibiotic resistance

"It takes about a minute to write a prescription for an antibiotic, but 15 or 20 minutes to explain why an antibiotic won't work for a viral illness" - Neil Fishman, MD, director of the Antimicrobial Management Program at the University of Pennsylvania Medical Center, Philadelphia

1. Prescribe only when needed and effective
   1. Sensitivity testing
   2. Not for viral illnesses
2. Proper usage
   1. Dosage
   2. Time course
   3. No sharing!
3. Multiple drug cocktails
   1. Trimethoprim/Sulfamethoxasole
   2. Mycobacteria: Ethambutol/rifampin/isoniazid
   3. HAART: Reverse transcriptase inhibitors + protease inhibitor
4. Anti-resistance drugs
   1. Clavulanate - penicillinase inhibitor (e.g. given as Augmentin w/ Amoxicillin)
   2. phosphoryltransferase inhibitors
   3. 5¢-MHC - an efflux inhibitor
5. Limit non-medical uses
   1. Agriculture
   2. http://www.agbioforum.org/v3n23/v3n23a13-follet.htm
6. New drug development: review
   1. Moxifloxacin and Gatifloxacin - FDA approved fluoroquinolones
   2. Linezolid (Zyvox) FDA approved in 2000 - protein synthesis inhibitor
   3. quinupristin/dalfopristin (Synercid - FDA approved 1999) - streptogramin (protein synthesis inhibitor)
   4. Daptomycin - lipopeptide - membrane disruptor/depolarizer
   5. Oritavancin (Phase III) - glycopeptide (cell wall inhibitor)
   6. Dalbavancin (Phase II) - glycopeptide (cell wall inhibitor)
   7. Telithromycin - ketolide (protein synthesis inhibitor)
   8. Tigecycline - (Phase III) glycylcycline (protein synthesis inhibitor)
   9. Ramoplanin - macrocyclic cell wall synthesis inhibitor
   10. Anti-PBP-2 cephalosporins (under development)

Reference links

1. http://www.cdc.gov/narms/index.html
2. http://ecdc.europa.eu/en/aboutus/organisation/Director%20Speeches/111117_Marc_Sprenger_EAAD-2011.pdf
3. http://www.bioteach.ubc.ca/Biodiversity/AttackOfTheSuperbugs/
4. http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/97vol23/23s8/images/fig1vree.gif
5. http://www.microbeworld.org/htm/cissues/resist/resist_4.htm
6. http://www.ahi.org/antibioticsDebate/documents/FinalFactsheet-Surveillance1-15.pdf
7. http://www.ama-assn.org/amednews/2003/05/19/hlsc0519.htm0
8. http://64.233.161.104/search?q=cache:WB5MxWtoKfMJ:www.ansorp.org/isaar/2003/scientific_program_pdf/sj_David_Livermore.pdf+Oritavancin+mode+of+action&hl=en
9. http://www.pjonline.com/Editorial/20001104/society/microbiology_symposium_692-694.html
10. http://medicalreporter.health.org/tmr0297/antibiotic0297.html