Antibiotic Cycling A solution to the evolutionary arms

Antibiotic Cycling A solution to the evolutionary arms race? Presented by Alexandra Roland

An “evolutionary arms race” is an evolutionary struggle between competing sets of co-evolving genes that develop adaptations and counteradaptations against each other, resembling an arms race. The term has been used more and more for the battle between bacteria and antibiotics. An example of a co-evolving gene set is a parasite and its host. In recent years, many bacteria and diseases have been evolving faster than humans can create new antibiotics to treat them.

What are antibiotics? • When someone’s immune system can’t fight off a bacterial infection by itself, they may need more aggressive medical treatment • Antibiotics and other antibacterial drugs are the major weapons against diseasecausing bacteria, and they can kill bacteria or suppress their activity in various ways • They can be natural, synthetic, or semisynthetic organic chemical compounds which can kill or stop the growth of infections • Penicillin is the most well-known antibiotic and has been used to fight many infectious diseases, including syphilis, gonorrhea, tetanus, and scarlet fever http: //encarta. msn. com/encyclopedia_761577894/Antibiotics. html

Antimicrobial Resistance History • Louis Pasteur: first observed antibiotic effect in 19 th century, who discovered that certain saprophytic bacteria can kill anthrax bacilli • Paul Ehrlich: developed salvarsan in 1909, a synthetic compound that remained the only effective treatment for syphilis until purification of penicillin in the 1940 s • Sir Alexander Fleming: 1928, accidentally discovered Penicillin • World War II: renewal of research, Sir Howard Florey and Ernst Chain purified enough penicillin to show that it would protect mice from infection

• Soon after antibiotics were introduced into clinical circulation, cases arose where their ability to effectively stop infection was decreased • As the use of antibiotics became more widespread, the prevalence of antibiotic resistant bacteria increased • Different time frames apply to different bacteria because the number of mutations necessary to develop resistance depend on the strain • ex. Staphylococcus aureus took 5 years to become resistant to penicillin, while Streptococcus pneumoniae took over 50 years

Relevant Definitions • Gram-positive vs. gram-negative bacteria: When gram-positive bacteria are stained with a dye, the cell wall holds the dye inside and the bacteria are stained dark purple. Cell walls of gram-negative bacteria are more permeable - they do not retain much of the dye, and so their cell walls do not show much stain • Selective pressure: The influence exerted by some factor (such as an antibiotic) on natural selection to promote one group of organisms over another. In the case of antibiotic resistance, antibiotics cause a selective pressure by killing susceptible bacteria, allowing antibiotic-resistant

Increasing Trend of Penicillin Resistance in US • Source: http: //www. uihealthcare. com/news/currents/vol 5 issue 2/04 antibioticresistencefig 1. html

E. Coli have become increasingly resistant to antibiotic treatment

Diseases connected with antimicrobial resistance • • Tuberculosis Head Lice Malaria Methicillin. Resistant Staphylococcus aureus (MRSA) • Streptococcus pneumoniae • Gonorrhea • Typhoid Fever • Vancomycin/Glycopep tide-Intermediate Staphylococcus aureus (VISA/GISA) • Vancomycin. Resistant Enterococci (VRE)

How bad is it? • Today, as many as 5 to 10 patients are colonized with resistant bacteria for every patient known to be infected • The majority of antimicrobial resistance occurs in intensive care unit (ICU) due to patients who are more susceptible to nosocomial (hospital-obtained) infections because of underlying illnesses, suppressed immune systems and frequent use of invasive devices • Recently in Atlanta, 25% of bacterial pneumonia cases were shown to be resistant to penicillin, while an additional 25% of cases were resistant to more than one

• Perpetual research and development has become necessary to find new antibiotics to maintain a pool of effective drugs • While the development of resistant strains is inevitable, the speed and scale of development has been aggravated by the practices we use to distribute antibiotics • Variations in resistance exist among different countries, due at least in part to individual antimicrobial use

Antibiotic Cycling: Basics • Organisms resistant to antibiotics have genes that are either carried on the bacterial chromosome or on the small circular DNA plasmids, which direct the synthesis of the traits that protect bacteria from antibodies • Certain resistance genes code for enzymes that degrade antibiotics or chemically modify them to the point of inactivation • Other resistance genes may cause bacteria to modify or replace molecules that are normally bound by an antibiotic, removing the drug's target • Others may possess genes that help eliminate entry points to the cell, or that create pumps to move the antibiotic from the cell before it reaches its target http: //www. paratekpharm. com/i_mechanism. html

Evolution of Bacteria • Through mutations, some bacteria will develop genes that help protect them from antibiotic attack mechanisms • A few bacteria will survive with favorable traits and reproduce, increasing the concentration of the resistant trait in the population • The selective advantage conferred by the resistant trait will cause natural selection and eventually the population will be nearly entirely

Mutations are central to the growth of antibiotic resistance http: //www. ideacenter. org/contentmgr/showdetails. php/id/1096

Methods of Antibiotic Resistance a. ) pumping out of antibiotic prior to reaching target b. ) enzymatic degradation of antibiotics c. ) enzymatic alteration of antibiotics http: //www. paratekpharm. com/i_mechanism. html

Methods • Robert G. Masterton looked at 4 papers on antibiotic cycling, but results from many studies are represented in table form • 14 studies compared include: mainly ICU, with two neonatal and one pediatric • Comparison basis: unit cycling was done in, length and number of cycles, change in resistance of certain antibiotics, change in number of resistant bacteria strains • Cycles lasted 1 -26 months, very high variance in cycle period and number of cycles

Results • Most studies found reduced gentamicin resistance and reduced incidence of Grampositive and Gram-negative infections • General trend of success throughout various studies in reducing development of resistant microbes • Masterton found that almost two-thirds of the studies on antibiotic cycling look at the potential it presents, rather than actual results as ot it’s effectiveness • It was found most successful to use cycles that change class of antibiotic, such as from β-lactams to fluoroquinolones or aminoglycosides

Solutions to Over. Prescription • Improved adherence to prescribing protocol • Programs to persuade patients that putting pressure on doctors to prescribe antibiotics inappropriately can have harmful effects • Higher infection-control delivery and better administration of antibiotics • Education efforts to improve prescribing • Restrict antimicrobial availability and the use of antimicrobial request forms and antibiotic cycling

• A study was done in the LDS Hospital in Salt Lake City the first year they used an automated antibiotic consultant, which helps physicians quickly receive culture results, antibiotics patients are currently on, and antibiotics they have been exposed to • Huge improvements were made in limiting over prescription, leading to excessive dosing 87 times, versus 405 times in the previous two years. • Patients received an average of 4. 7 fewer doses and their antibiotic expenses

Other Reasons for Development of Antibiotic Resistance Beyond Over-Prescribing • Poorly cleaned wards: accumulation of dirt can provide environment for resistant bacteria • Loss of survival for organisms in the presence of a new antibiotic pressure • Inducible resistance phenotypes exist, that have protective mechanisms that are only activated when an antibiotic is there to induce it (can survive in both antibiotic and non-antibiotic environments)

Current Studies • As of September 2005, mathematical modeling to measure the effect of antibiotic cycling has brought into question its effectiveness (Gibbs 2005) • Masterton’s study of the overall success and results of various troubles is the most thorough representation of the success thus far with cycling • Studies lack consistency in parameters so it’s hard to make judgments on how effective cycling is because of no basis of comparison • As of 2006, there are relatively few newly published studies but

Future of Antibiotic Cycling • What is the optimal cycle duration? • Is a hospital-wide strategy better or worse than a unit-specific strategy? • When does it become necessary or is it optimal to begin antibiotic cycling? • How can compliance be increased? • How does antibiotic cost change when beginning a cycling program?

References Primary Article: Masterton, Robert G. "Antibiotic cycling: more than it might seem? " Journal of Antimicrobial Chemotherapy 55 (2005): 1 -5. Journal Access Center. 2006. British Society for Antimicrobial Chemotherapy. 6 Dec. 2006 <http: //jac. oxfordjournals. org/cgi/content/full/55/1/1>. Gibbs, Winter J, and Richard H Drew. "More studies need to define potential role of antibiotic cycling. " Infectious Disease News (Sept. 2005). Medical Matrix. 20 Nov. 2006. Infectious Disease News. 6 Dec. 2006 <http: //www. infectiousdiseasenews. com/200509/frameset. asp? article=pharmconsult. asp>. Van Loon, Harald J, et al. "Antibiotic Rotation and Development of Gram-Negative Antibiotic Resistance. " American Journal of Respiratory and Critical Care Medicine 171 (2005): 480 -487. AJRCCM. org. 2006. American Thoracic Society. 6 Dec. 2006 <http: //ajrccm. atsjournals. org/cgi/content/full/171/ 5/480>. "Glossary. " Alliance for the Prudent Use of Antibiotics. 1999. Alliance for the Prudent Use of Antibiotics. 6 Dec. 2006 <http: //www. tufts. edu/med/apua/ Miscellaneous/Glossary. html>. "'Antibiotics. '" Microsoft Encarta Online Encyclopedia. 2006. Microsoft Corporation. 6 Dec. 2006 <http: //encarta. msn. com/ encyclopedia_761577894_4/Antibiotics. html Yim, Grace. "Attack of the Superbugs: Antibiotic Resistance. " Science Creative Quarterly Sept. -Oct. 2006, Issue Two ed. 6 Dec. 2006 <http: //www. scq. ubc. ca/>.