University of Hawai‘i at Hilo · Hawai‘i Community College HOHONU 2013 Vol. 11 Staphylococcus aureus is a unique species of Evolution of Staphylococcus microbe which has lived alongside mankind since before aureus Following the recorded history. In addition to an intimate familiarity with its host's body, this bacteria is capable of rapidly Introduction of Antibiotic evolving to withstand an ever increasing arsenal of Therapy manmade antibiotics. Against this worthy foe mankind James H. Ziegler, IV, [email protected] is engaged in an arms race: modern medicine against BIOL 357, UH Hilo evolution. The recent evolution of S. aureus can be categorized Introduction as the development of a range of antibiotic resistances, from penicillin to methicillin to vancomycin, accentuated "Without innovative public policy and additional by a series of epidemic outbreaks. As multidrug-resistant fnancial support, fewer and fewer antibiotics will S. aureus spreads from hospitals to communities to the be available to treat the increasing number of drug- food chain, researchers struggle to stay ahead of one of resistant and dangerous microbes that threaten our oldest companions. Americans and the global community." – Infectious Diseases Society of America History of Staphylococcus aureus Staphylococcus aureus is a species of bacteria “It knows how to live on inanimate objects, in our which colonizes the human respiratory system and skin in noses, in our skin, in our genitals. It’s virulent, it’s a commensal relationship. Although generally harmless, adaptive, and it is able to circumvent almost S. aureus can be responsible for a variety of diseases everything we throw at it. It is a perfect pathogen.” including food poisoning, necrotizing pneumonia, and – Dr. Robert Daum, M.D. endocarditis[1]. It is among the most common causes of nosocomial infections worldwide, accounting for some Staphylococcus aureus is among mankind’s oldest 500,000 nosocomial infections per year in America evolutionary companions, benignly colonizing human alone. About 20% of the world's population is colonized hosts for hundreds of thousands of years. This commensal with S. aureus long term, with an additional 60% of the relationship is generally harmless to humans, but certain population will host a colony at some point during their conditions can lead to the bacteria attacking its host, life[2]. resulting in a wide range of infections, from pimples and S. aureus infections can usually be treated with rashes to pneumonia, toxic shock, and bone abscesses. antibiotics of the penicillin family, the discovery of These infections are particularly dangerous because of which is accredited to Alexander Fleming in 1928 when S. aureus’ familiarity with the human immune system: a culture of Penicillium rubens was observed excreting a having colonized mankind for so long, S. aureus has substance with antibiotic properties. By 1945, penicillin developed a huge range of virulence factors – over 70 was being mass produced for medical use[3], but within a enzymes and toxins capable of destroying cells, more decade populations of S. aureus were showing increasing than any other species of bacteria[8]. resistance to what had previously been considered a In addition to being extremely virulent, S. aureus miracle drug. In 1952, methicillin (renamed meticillin has proven to be capable of adapting quickly enough to in 2005) was introduced as an alternative antibiotic overcome any new threat. It began developing defenses due to the increasing rate of penicillin resistance in S. against penicillin as soon as initial testing began on the aureus[4], but by 1961 British physicians were reporting drug, forcing the pharmaceutical industry to develop S. aureus isolates which had acquired resistance to a new drug, methicillin, less than a decade after the methicilli[5]. This methicillin-resistant S. aureus (MRSA) introduction of the frst antibiotics to medicine[4]. With now composes as much as 67% of the S. aureus colonies an atomic structure unlike anything occurring in nature, in developed countries such as the U.S. and Great methicillin was expected to effectively combat S. aureus Britain[6]. Furthermore, MRSA has become synonymous for decades, allowing ample time to develop the next with multidrug-resistance due to a tendency for MRSA generation of antibiotics. This miracle drug, developed in isolates to be resistant to the majority of commonly used 1952, became widely used in 1960. By 1961, S. aureus antibiotics[2]. had developed methicillin resistance[4][5][8]. Another antibiotic, vancomycin, was discovered Methicillin resistance in Staphylococcus aureus soon after penicillin, but was rarely used because other was frst documented in Great Britain in 1961, two years antibiotics were considered more effcacious and less after the drug was licensed for use in England. In 1968, toxic until the 1980s when it became the drug of last MRSA strains began to be identifed in the United States resort for treating MRSA[7]. S. aureus proved slow to at the Boston City Hospital in Massachusetts. At this time develop resistance to this antibiotic, allowing it to be MRSA isolates were only identifed as being acquired used safely for nearly 30 years before vancomycin- in clinical environments, due primarily to the limit of resistant S. aureus (VRSA) isolates were identifed. antibacterial use to hospital settings. Over the next 30 45 University of Hawai‘i at Hilo · Hawai‘i Community College HOHONU 2013 Vol. 11 years the percentage of S. aureus infections identifed Community-Associated MRSA (CA-MRSA) started as MRSA increased slowly but steadily, but remained appearing more frequently. By 2005 CA-MRSA was attributed to clinical environments. By 1998 occurrence occurring regularly in groups of individuals sharing rates of Healthcare-Associated MRSA (HA-MRSA) had close quarters: athletes, military units, urban children, stabilized. and prisoners. By 2006, 67% of S. aureus colonies in Although the occurrence rates of HA-MRSA had developed countries displayed resistance to methicillin[6]. stabilized, 1998 also marks the beginning of the “second The medical establishment eventually accepted the fact epidemic”: the development of MRSA infections from that CA-MRSA was a legitimate threat, but while the the community. This Community-Associated MRSA medical community was slow to accept change S. aureus (CA-MRSA) was frst documented in 1996 by Dr. Robert had continued to evolve. Daum of the University of Chicago. Daum had noticed a Patients suffering the most extreme MRSA infections spike in instances of children being admitted to the Wyler were being treated with vancomycin, a glycopeptide Children’s Hospital with MRSA infections, and a survey antibiotic administered intravenously and used only when of the children’s records had uncovered an anomaly: all other treatments had failed. The complex molecular none of the infected children had recent contact with an structure of this antibiotic, combined with sparing use, environment where MRSA infection was expected. The prevented S. aureus from quickly developing resistance, strain the children had acquired was as virulent as the but in 1998 researchers began documenting colonies of S. HA-MRSA the doctors had grown accustomed to, but aureus with varying degrees of vancomycin resistance[10]. resistant to fewer antibiotics, suggesting a more recent This newly discovered Vancomycin-Resistant S. aureus evolutionary development of methicillin resistance[8][9]. (VRSA) was unaffected by all but the newest and most Daum’s team of researchers isolated samples powerful antibiotics, but Vancomycin-Intermediate S. of S. aureus from two of the aureus (VISA) has proven to be even more diffcult to children who had been admitted treat[8]. with MRSA and used pulsed- The danger presented by Vancomycin-Intermediate feld gel electrophoresis (PFGE) S. aureus (VISA) is the insidious nature of its vancomycin to compare them with older resistance. VISA colonies are not strongly resistant to samples of HA-MRSA. The vancomycin. Instead the term is applied to colonies results (fgure, right) showed that which appear to be susceptible to normal doses of the MRSA of the two children vancomycin while hosting smaller colonies with enough (lanes 5 and 6) were genetically resistance to survive treatment. Administration of identical and distinct from any of vancomycin treatment successfully kills the susceptible the samples taken from previous portion of the colony, reducing competition for the more patients, despite the children being admitted 6 months resistant strains[8]. While these more resistant strains may apart, with no contact to each other[9]. Despite this be susceptible to higher doses, the adverse side effects evidence, Daum's fndings were rejected by the medical associated with vancomycin (including kidney damage community. It took two years for the Journal of the and deafness) make such dosage increases dangerous for American Medical Association to publish the fndings, the patient. along with an editorial which suggested that the research With S. aureus developing resistance to was fundamentally fawed and should be disregarded. vancomycin, new, novel antibiotics are being developed The opinion of the JAMA was shared by a majority to treat the most extreme infections. Unfortunately, of the medical community. There had been only one by the time new antibiotics become available to the other well-documented case of a MRSA outbreak in the medical community resistance is already being reported community,