Streptococcus+pneumonie

//("Medicinal chemistry project," )// Since the development and introduction of vaccines and antibiotics into many societies worldwide, the bacteria they intended to harm have embarked on a steady path of transformation. This evolutionary process has been noted especially in relation to //Streptococcus pneumoniae//, one of three primary causative agents of bacterial meningitis. Bacterial meningitis, or the inflammation of the meninges surrounding the brain and spinal cord, is a serious disease that advances quickly into a life-threatening condition if not diagnosed immediately.
 * TITLE:** Bacterial Meningitis: Resistance Profile of //Streptococcus pneumoniae//
 * AUTHOR:** Melissa Casas
 * DATE:** December 7th, 2010
 * ABSTRACT:**

Antimicrobials are highly specific and designed to interact exclusively with a certain bacterial strain on a molecular level. As with //S. pneumoniae//, the transfer of genetic material within and between species is altering the preferred mechanism of action for antimicrobials, eventually causing the bacterium to become resistant. //S. pneumoniae// is becoming especially resistant to two commonly prescribed groups of antibiotics, β-lactams and macrolides. Ultimately, changes in the antibiotic binding proteins, alterations in genes, and the presence of virulence factors are permitting //S. pneumoniae// to survive outside of our control. The overuse or misuse of antibiotics internationally is a potential cause of the mutating bacterial strains. By examining the resistance profile of pathogenic bacteria, such as //S. pneumoniae//, it is possible to begin developing new antimicrobials with different mechanisms of action. Also, with this information it is necessary to educate both the social and scientific spheres of health care on the effects of inappropriate antimicrobial use.

Bacterial meningitis is a pathogenic disease affecting children and adults not only in the United States, but worldwide as well. The potential for this disease to progress to a life-threatening situation if left undetected makes bacterial meningitis a medical emergency to treat. If suspected, bacterial meningitis can be confirmed through careful analysis of the cerebrospinal fluid (CSF) surrounding the brain and spinal cord. The CSF will contain an abnormally high number of white blood cells due to the inflammation of the meninges, or the lining of the brain and spinal chord. After detecting the presence of inflamed meninges it is necessary to verify the exact causative agent by means of a gram stain and a culture of the CSF. Three pathogens//, Haemophilius influenzae, Nesseria meningitides, and Streptococcus pneumoniae//, have been proven to explain over 80% of the reported cases in the U.S from the years of 1978 to 1981 (Nudelman & Tunkel, 2009). (Tortora //et al//., 2010)
 * INTRODUCTION:**

Throughout the past few decades the epidemiology of bacterial meningitis has changed drastically. The introduction of conjugate vaccines to help decrease the prevalence of meningeal pathogens is partly responsible for the evolution of the bacteria causing this disease (Nudelman & Tunkel, 2009). Along with the development of vaccines, the misuse of antibiotics has aided in the selective properties and survival of particular bacteria, especially //S. pneumoniae// (Reinert, 2009). Antimicrobials appear to have a disturbingly short-lived existence before they are no longer effective. Cases of resistant bacterial isolates almost always appear shortly after the distribution of a particular antibiotic (Garcia-Rey //et al.//, 2006). The purpose of this paper is to investigate the resistance profile of //S. pneumoniae//. The importance of understanding the factors contributing to antimicrobial resistance against current medications is invaluable in the search for future, effective treatment options.

Currently, //S. pneumoniae// is the most frequently diagnosed causative agent of bacterial meningitis accounting for about 61% of the cases reported in the United States with a mortality rate of 19% to 26% (Nudelman & Tunkel, 2009). Since the development of conjugate pneumococcal vaccines there has been a remarkable decrease in the number of invasive infections, thus proving to provide an effective defense from diseases such as bacterial meningitis. To illustrate, rates of pneumococcal meningitis have decreased from 0.8 to 0.55 cases per 100 000 population (Nudelman & Tunkel, 2009). In spite of this accomplishment, the number of cases caused by serotypes of pneumococcal meningitis not included in the vaccine has risen. This concern holds true for a variety of pneumococcal strains that are resistant to numerous antimicrobial agents as well.
 * DISCUSSION:**

Molecular factors, including the transformation of genetic material between bacteria, contribute largely to the antibacterial resistance of //S. pneumoniae.// To exemplify this point, the alterations of penicillin-binding proteins (PBPs) have subsequently increased the frequency of //S. pneumoniae// strains that are not susceptible to penicillins. PBPs exist naturally in many bacteria and perform functions inherent to the species. In addition, they serve as binding sites for β-lactam antibiotics. Any shift in the molecular structure of a PBP will inhibit the binding of the specific penicillin product made for that site, as a result the pneumococcal pathogen will no longer be harmed by the antibiotic. In terms of the development of β-lactam resistance, the most influential PBPs found in //S. pneumoniae// include 1a, 2b, and 2x (Zhang //et al//., 2008). As stated by Reinert, “this resistance is thought to be the result of intraspecies and interspecies gene transfer” (Reinert, 2009). The widespread use of β-lactam antibiotics has ultimately favored gene transfer between pathogenic //S. pneumoniae//, enhancing the resistance to their action (Zhang //et al//., 2008). //("Molecular basis of," )// The resistance of //S. pneumoniae// to macrolides, such as erythromycin, is a substantial concern when treating pneumococcal infections. One study, intended to compare antimicrobial activity, reported that 37.2% of //S. pneumoniae// isolates from patients tested positive for erythromycin resistance (Reinert, 2009). Macrolide resistance seems to be as unpredictable as penicillin resistance, with various justified mechanisms of action. For instance, conferred resistance could be due to a mutation in the erm(B) gene, encoding for methylase, or it may be attributed to the mef(A) gene, encoding for an antibiotic efflux pump (Reinert, 2009). Typically, the erm(B) genotype contributes more to macrolide resistance than the mef(A) genotype, but occasionally there a dual genotype can exist. Changes in genotypes are often explained in terms of Darwinian natural selection and fitness, “a genotype with a higher fitness for survival will then be naturally selected by evolution” (Reinert, 2009).

In Spain, an interesting study called The Willow (SAUCE) Project enabled researchers to gather data pertaining to bacterial species, including //S. pneumoniae//, that display critical antimicrobial resistance. As noted by Garcia-Rey //et al.// the project permitted, “[them] to associate total or local resistance prevalence with antibiotic consumption in different ways in order to explore the specific relationship between resistance and drug use” (Garcia-Rey //et al//., 2006). Based on the finding from the Willow (SAUCE) Project, it has been determined that the overuse of particular antibiotics, mainly cephalosporins (class of β-lactam antibiotics) and long half-life macrolides, is a probable explanation for the increasing antimicrobial resistance of //S. pneumoniae//. Furthermore, macrolides emerged as a more important force than β-lactams when examining the local differences in resistance of //S. pneumoniae.// (Garcia-Rey //et al//., 2006)

As discussed previously, shifts in both the erm(B) gene and mef(A) gene have been known to influence the resistance of S. pneumoniae to macrolide antibiotics. A recent study published in the //Indian Journal of Medical Microbiology// discusses the influence of other genes, including pneumolysin and autolysin, among antibiotic resistant //S. pneumoniae// isolates. Polymerase chain reaction (PCR) amplified //S. pneumoniae// DNA, which allowed for the detection of the autolysin (lytA) gene and the pneumolysin (ply) gene. Autolysins are responsible for the lysis, or death, of the cell by degrading the peptidoglycan cell wall. During this process, acids are released causing an inflammatory response in the surrounding host environment, in this case the meninges. The autolysin (lytA) gene was found in 23 out of 24 of the antimicrobial resistant strains of //S. pneumoniae//. Pneumolysin serves as an indicator of the virulence of S. pneumoniae, it is a toxin consisting of 471 amino acids. Out of the 24 //S. pneumoniae// isolates tested, 17 contained the pneumolysin (ply) gene. The presence of these two specific virulence genes not only results in greater tissue damage during a meningeal infection, but also helps confer resistance to antimicrobial agents. (Sourav //et al//., 2010)

Garcia-Rey, C., Martin-Herrero, J.E., & Baquero, F. (2006). Antibiotic consumption and generation of resistance in //Streptococcus pneumoniae//: the paradoxical impact of quinolones in a complex selective landscape. //European Society of Clinical Microbiology and Infectious Diseases//, //15//(3), 55-66.
 * LITERATURE CITED:**

//Medicinal chemistry project//. (n.d.). Retrieved from http://www.sitemaker.umich.edu/mc13/bacterial_meningitis_causative_organism

//Molecular basis of antibiotic translocation//. (n.d.). Retrieved from www.faculty.iu-bremen.de/mwinterhalter/antibiotics/CThe%20Project.html

Nudelman, Y, & Tunkel, A.R. (2009). Bacterial meningitis: epidemiology, pathogenesis, and management update. //Drugs//, //69//(18), 2577-2596.

Reinert, R.R. (2009). The antimicrobial resistance profile of //Streptococcus pneumoniae//. //European Society of Clinical Microbiology and Infectious Diseases//,//15//(3), 7-11

Sourav, S., Patricia, A., Sharma, S., Kanungo, R., & Jayachandran, S. (2010). Detection of pneumolysin and autolysin genes among antibiotic resistant //Streptococcus pneumoniae// in invasive infections. //Indian Journal of Medical Microbiology//, //28//(1), 34-39.

Tortora, G.T., Funke, B.B., & Case, C.L. (2010). //Microbiology: an introduction//. San Francisco, CA: Pearson Education, Inc.

Zhang, T., Zhao, N., Zhang, T., Black, S., & Xu, B. (2008). Meta-analysis of antibiotic susceptibility and the genotype of penicillin-binding proteins in //Streptococcus pneumoniae//. //Scandinavian Journal of Infectious Diseases//, //40//, 797-803.