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What is antibiotic resistance?

• Antibiotic resistance often confused with virulence

• Virulence refers to factors that enable a bacterium to attach to host cells, invade tissue, avoid the immune system, form biofilms and establish an infection

• Antibiotic resistance refers to the ability of a bacterium to grow in the presence of antibiotics

Mechanisms of Antibiotic Resistance

http://www.textbookofbacteriology.net/resantimicrobial_3.html

Mechanisms of Antibiotic Resistance

http://www.textbookofbacteriology.net/resantimicrobial_3.html

Spread of Antibiotic Resistance• Vertical transmission: Genes passed to

cell’s offspring

• Horizontal transmission: Genes passed to other cells of the same or different species• Conjugation – cell to cell contact *• Transformation – naked DNA picked up by cells• Transduction – viruses carry genes to new cells

* Conjugation may be most common method of horizontal transfer

Marian Koshland Science Museum of the National Academy of Science:http://www.koshland-science-museum.org/exhib_infectious/antibiotics_04.jsp

Conjugation

Marian Koshland Science Museum of the National Academy of Science:http://www.koshland-science-museum.org/exhib_infectious/antibiotics_04.jsp

What is the origin of resistance genes?

• In nature antibiotics function at low concentrations in metabolic and regulatory pathways

• Antibiotic resistance genes coevolved with these “antibiotics”

• In nature resistance genes may function in detoxification of metabolic intermediates; inhibition of virulence factors; regulation of signal trafficking

• In clinical settings, the high concentrations of antibiotics apply selective pressure and the most important function of the genes is for resistance to the deadly effects of the antibiotic

Resistance genes evolved in nature

Moved to humans in commensal bacteria

Evolved in pathogenic bacteria

What effect will they have back in nature?

José L. Martínez, et al., Science 321, 365 (2008)

Selection for Antibiotic Resistance Bacteria

Antibiotic use in animals

• Use: growth promoters and for prophylactic treatment

• 70% of the antibiotics and similar drugs used in the US go into animal feeds

• Sensitive bacteria killed over time and resistant ones survive

www.keepantibioticsworking.com/

Selection for Antibiotic Resistance Bacteria

Antibiotic use in humans - concerns• Prescribing bacterial antibiotics for viruses

• Prescribing the wrong drug or not checking susceptibility of organism

• Not completing the whole course of drugs

• Biofilms at infection site protecting bacteria

Over the Counter Antibiotics• Self-prescribing and

taking meds for too few days

• Antibiotics available in many countries

• 6/6/2010

http://antibiotics.withoutaprescription.net/

Selection for Antibiotic Resistance Bacteria In Biofilms

Am. Sci., November-December 2005 Volume 93, Number 6 Page: 508

Selection for Antibiotic Resistance BacteriaDevelopment of Antibiotic Resistance in Biofilms

Biofilms…..are hiding in plain sight.

•Human sites: middle ear, teeth, intestines, infected lungs

•Conjugation and transformation occur in biofilms spread of resistance genes

Selection for Antibiotic Resistance Bacteria

Commensals

• “Core” and transient colonizers are the major source of resistance genes in human flora

• Some commensals become opportunistic pathogens due to selective pressure

Volume 4, Number 5, 2009 / Microbe, p231

Selection for Antibiotic Resistance Bacteria

Commensals• Alliance for the Prudent Use of Antibiotics

has started a project of evaluating and tracking antibiotic resistance genes in nature since data is scattered and incomplete

• Project called ROAR – Reservoirs of Antibiotic Resistance Network• Collect & analyze genetic data (using literature)• Modeling• Encouraging funding and research for this work• ROAR

Selection for Antibiotic Resistance Bacteria

CommensalsHuman Microbiome

Project• Determining whether

individuals share a core human microbiome

• Understanding whether changes in the human microbiome can be correlated with changes in human health

• Developing the new technological and bioinformatic tools needed to support these goals

Looking at data: Gapminder

Looking at data: Worldmapper• www.worldmapper.org• Can download Excel file with data and notes• Can compare with a territory or pop. map

Pneumonia Deaths - 2002Pneumonia caused 6.9% of all deaths worldwide in 2002, an average was 634 deaths per million people per year.

Looking at data: World Bank Visualizer

Looking at data: MDG Gapminder

Sources of dataThese sites provide data sets-

• World Bank• Gapminder data• Worldmapper data• WHO• UN divisions

Collecting and Analyzing Data• ESAC – European Surveillance of Antimicrobial

Consumption - database

• EARSS – European Antimicrobial Resistance Surveillance System - database

• Example: Examine the relationship between antibiotic consumption and resistance• % Streptococcus pneumoniae that are antibiotic

resistant• % Staphylococcus aureus that are MRSA

(methicillin resistant)

Streptococcus pneumoniae• Part of normal flora of

upper respiratory system

• Causes pneumonia, ear infections, sinusitis

• Leading cause of invasive bacterial disease in children and the elderly

Resistance vs. Consumption

• Strong correlation

• Development of drug resistance after antibiotic introduced occurs faster than the decline of drug resistance after use is terminated

EID, Vol. 10, No. 3, March 2004, p. 515

Working with data• Google Docs Motion Gadget

• Create data in Google Docs spreadsheet• Insert Motion Gadget• Choose the range for data

• http://spreadsheets.google.com/ccc?key=0AsQAokb_R_y-dHFMcVFuenpVaUNQSXJGLWZFVUhKVmc&hl=en

• Data set prepared in Google Docs:• Antibiotic consumption• % Staphylococcus aureus that are MRSA• % Streptococcus pneumoniae that are resistant to

penicillin

Things to consider

• What kind of questions can you ask?

• What happens with missing data?

• Does seeing at a correlation demonstrate causality?

THE END

Antibiotic Mode of ActionInhibits cell wall synthesis

Natural Penicillin – penicillin GSemi-synthetic penicillin - ampicillin & amoxicillin Polypeptide antibiotics – vancomycin

Inhibits protein synthesisStreptomycinErythromycinAzithromycin

Inhibits nucleic acid synthesisRifampinQuninolones & fluoroquinolones – ciprofloxicin & gatifloxicin

Competitive inhibitorsSulfonamides

spa typingThe spa-type database of the Public Health ResearchInstitute Tuberculosis Center includes >950 clinical S. aureusisolates; most (~80%) are methicillin resistant. DNAsequence analysis identified 37 unique, 24-bp SSR types; onetype was 1 codon longer. The number and organization of therepeat types define the S. aureus spa type; to date, 186 spatypes have been identified and catalogued in a relationaldatabase.Loci with short sequence repeat (SSR)regions may have suitable variability for discriminatingoutbreaks (16). Two S. aureus genes conserved within thespecies, protein A (spa) and coagulase (coa), have

variableSSR regions constructed from closely related 24- and 81-

bptandem repeat units, respectively.

• We now know more about the mechanism by which bacteria develop antibiotic resistance. Strains of methicillin-resistant S. aureus have developed through acquisition of mobile genetic elements which carry the mecA gene, which encodes a protein (penicillin-binding protein 2a) that penicillin does not bind or attach to. The effectiveness of penicillin antibiotics relies on the ability to bind to the surface of the bacteria. The mecA gene is carried on a mobile genetic element called a cassette (SCCmec cassette). A genetic cassette may carry a number of genetic elements, much like a compact disc holds more than one song – in the case of MRSA, the cassette carries the mecA gene, and depending on the strain of S. aureus may also carry other resistance factors that provide protection against other antibiotics, as well as a variety of virulence factors.

• Currently, there are 4 recognized clones or types of SCCmec - I through IV, with SCCmec IV being the most common. The structure of the mecA genes are similar, but the gene structure is significantly different than the hospital-acquired strains. Because of the differences in mecA gene structure and cassette components, hospital-acquired strains tend to be resistant to multiple antibiotics, and are associated more often with surgical wound infections, urinary tract infections, bloodstream infections, and pneumonia. Community-acquired strains do not share the same antibiotic resistance patterns as the strains circulating in the hospital, and tend to cause infections associated with methicillin susceptible strains of S. aureus in the community – skin infections (pimples, boils, impetigo, infected cuts, etc.), but can also cause more serious infections like pneumonia.

•

Read more at Suite101: Drug Resistant Bacteria: Relationship Between Community and Hospital Acquired Infections http://microbiology.suite101.com/article.cfm/mrsa__camrsa_and_hamrsa#ixzz0qbYDM6rU