Summary:
Antimicrobial resistance is a monumental health problem, affecting everyone from infected patients and physicians to researchers and drug developers. E.g. evolution from S. aureus to MRSA, hospital acquired versus community acquired. Dangers of SCCmec. Many antimicrobials coming out for resistant Gram-positive bacteria like MRSA, but there is nothing for Gram-negative bacteria. Increased research effort toward understanding mechanisms of resistance, as well as identifying new antimicrobial targets, is greatly needed. Large drug companies are well aware of the problem, but have been fighting an uphill battle to develop antibiotics that exist long enough on the market to profit. Smaller drug companies and academic institutions have taken it upon themselves to develop new antimicrobials. These drug developers require large drug companies to put their discoveries on the market. (Published: 01/05/08)
Notes:
- Alexander Fleming: discovery of penicillin
- mold grown on bacterial culture plate
- closer inspection showed that mold has inhibited the growth of bacteria in area around it
- penicillin, produced by Penicillium species of mold
- penicillin was viewed as panacea by microbiologists and clinicians alike
- though no more microbiological research needed to be done
- but: due to its widespread use in WWII, bacteria quickly became resistant to penicillin
- rendered the antibiotic useless
- bacteria were producing enzymes that could destroy the structure of penicillin
- drug developers produced semi-synthetic versions of penicillin in 1960
- bacteria became resistant year later
- Staphylococcus aureus
- became penicillin resistant
- due to beta-lactamase (penicillinase) production
- methicillin (derivative of penicillin) introduced in 1959 to overcome problem
- S. aureus became resistant in 1961
- methicillin-resistant Staphylococcus aureus (MRSA)
- source of resistance: methicillin-resistant gene (mecA)
- carried on a mobile genetic element, staphylococcal cassette chromosome (SCCmec)
- danger of SCCmec
- not only does it carry the methicillin-resistant gene
- also, carries resistance genes for other microbials
- cassette can be transferred to susceptible bacteria found in the same environment as resistant bacteria
- community-acquired MRSA
- Kunyan Zhang (prof., MD, Calgary):
- "It used to be that MRSA was limited only to the hospital and confined to vulnerable hospital patients. But starting early 1990, MRSA started to be found in the community. This newly emerging, community-associated MRSA is now causing serious community-acquired infections/outbreaks in otherwise healthy children, athletes, and other individuals lacking typical risk factors for nosocomial MRSA acquisition."
- community-associated MRSA appears to be more virulent
- has now gone back to the hospital in a multi-drug resistant form
- Bala Bota (prof., MD, Chicago):
- looked at hospital-acquired MRSA
- found that hospital strain was being replaced by a community-acquired strain, called USA300
- has occurred in half of all US hospitals
- another study showed a seven-fold increase in the incidence of community-acquired MRSA over a seven year period
- those who had served jail time or had lived in public housing were the greates sources of community-acquired MRSA
- efforts to reduce the incidence of MRSA are occurring nationwide
- e.g. hospitals in state of Illinois require that, prior to admission, all patients be screened for MRSA colonization
- Hota: "The common site that S. aureus colonizes individuals is in the nose. What hospitals are doing is taking a cotton swab, rubbing it in the nose and then setting that up for culture. That will either show MRSA or not."
- Hota interested in better characterizing community-acquired strains of MRSA
- for all of the clinical isolates, first the strain type is identified using pulsed-field electrophoresis; determine by PCR whether or not the strain contains the SCCmec4; and, determine by PCR whether or not the strain carries specific toxins such as Panton-Valentine leukocidin (PVL), which is associated with boils produced by MRSA
- "We are finding that SCCmec4 and PVL are very strongly associated with community-associated MRSA strains"
- the results of these tests are then compared to strains from national outbreaks
- Hota's strains are identical to those found in the national outbreaks
- issue of antimicrobial resistance has caused a significant decrease in the number of available antibiotics for treatment
- Margaret Hammerschlag (prof., MD, New York):
- "I think, especially in children, we are running out of therapeutic options."
- "There are many antimicrobials coming out for resistant Gram-positive bacteria like MRSA, but there is nothing for Gram-negative bacteria like Klebsiella sp. and Acinetobacter sp."
- facing bugs that are resistant to every antibiotic and for which there is no forseeable antibiotic development
- "We have got a real crisis. We'll be looking down a hole to the pre-antibiotic era and antibiotics might end up as orphan drugs."
- designing novel antimicrobials to combat resistance requires a higher degree of understanding of the biology of superbugs
- Vanessa Sperandio (Texas), Vincent Tam (PharmD): designing antibiotics to combat the resistance problems in Gram-negative bacteria
- Sperandio: studying signalling system between that allows for communication between bacterial cells and between the bacterial cell and the host (human)
- bacteria can sense that it's inside the colon, the right site for infection
- developed a antimicrobial agent that does not inhibit bacterial growth and does not kill the bacteria
- would cause bacteria to release potent toxin that can cause immediate kidney failure, in some cases leading to death
- "The line of thought is that if you're going to try to develop something that is going to prevent pathenogenesis, but is not at the same time going to kill the bacteria, you're engendering less evolutionary pressure for development of resistance."
- "Basically what the inhibitor does is compete with the signals to bind the kinase. So the signal cannot activate in the animal. And if the kinase does not activate, the virulence genes do not activate. And in this way the bacteria just passes through."
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