Leptospirosis+Sp14


 * DISEASE/DRUG OF INTEREST **: Leptospirosis; Penicillin G


 * MOTIVATION AND BACKGROUND **:

Leptospirosis is an emerging zoonosis with a worldwide distribution [1]. The disease arises from contact with //Leptospira interrogans// bacteria, typically found in warmer climates’ freshwater that animal urine has contaminated [2]. The animals with urine with //Leptospira interrogans// include cattle, pigs, horses, dogs, rodents, and other wild animals [3]. The bacteria in the urine can survive in water or soil from weeks to months [3]. //Leptospira interrogans// can enter the body through the mucous membranes of the eyes, nose, and mouth, broken skin, and by drinking contaminated water [3]. It is important to note that leptospirosis cannot spread from person to person [2]. In fact, it is rare for the disease to even be transmitted from mother to her unborn child during pregnancy or from mother to child during breast feeding [2]. Leptospirosis is very susceptible to impoverished populations in developing countries, especially those in the tropical regions that experience frequent flooding [1]. Many of the recent large outbreaks have occurred in Nicaragua, Brazil, India, Southeast Asia, and the United States [4]. The bacterial infection is relatively rare in the continental United States but the state of Hawaii has had the highest number of cases in the country [2]. The attack rates for leptospirosis are as high as 25% to 40% in exposed populations [5]. People at risk for the disease include those subjected to occupational exposure (farmers, ranchers, sewer workers, military personnel), recreational activities (fresh water swimming, kayaking, canoeing), and household exposure (by domesticated livestock, infected rodents, rainwater catchment systems) [2].



The length of time between the exposure to //Leptospira interrogans// bacteria and detected Leptospirosis symptoms ranges from two days to four weeks [3]. There are two phases of the disease effects. The first phase has an average of ten days [2]. T begins with a fever, then may come a combination of chills, headaches, muscle aches, vomiting, and diarrhea [3]. The patient may recover for a short period of time without medication [3]. The patient may enter the second phase with more severe effects: meningitis, jaundice, and/or organ failure, most frequently reported, kidney and liver failure [3]. Leptospirosis has attained a high mortality rate between 5% to 15% [4].
 * TARGET INFORMATION **:

For Leptospirosis treatment, there is currently no abnormal, malfunctioning protein to target. Instead, penicillin targets bacteria themselves, in this case, //Leptospira interrogans//. //Leptospira interrogans// is a gram negative aerobe that is motile and assumes a helical shape [7]. The bacteria can attach to several different host cells and thus attack different organs, surviving notably well in the kidneys (causing kidney infections, and even kidney failures) [8]. Most bacteria like //Leptospira interrogans//, have a cell wall, partly made of peptidoclycan, a macromolecule made of sugars and amino acids [9]. Penicillin prevents the last cross-linking step, also known as the transpeptidation, in the assembly of the peptidoclycan, resulting in a fragile cell wall that bursts. This essentially kills the bacterium and haults further reproduction of it [9].



**DRUG INFORMATION: ** Penicillin was discovered by Alexander Fleming in 1929 [11]. He found that //Penicillium// fungi produced a substance (penicillin) that created a zone of growth inhibition for bacterium [11]. Penicillin lyses the peptidoclycan of the cell walls, making the cell burst, thus killing the bacterium [9]. It was later found that penicillin can treat a wide range of bacterial infections [11]. There are various kinds of penicillin but penicillin G has been typically used to treat leptospirosis. Penicillin G’s chemical formula is C16H18N2O4S with a molecular weight of 334.39012 g/mol and its CAS number as 61-33-6 [12]. Penicillin G comes in a variety of delivery forms: tablets, capsules, syrups, and injections [13]. A brand name for Penicillin G is Pfizerpen, manufactured by the Pfizer Company [14]. Penicillin G is not a patented drug. Side effects for the drug include diarrhea, allergic reactions, dizziness, convulsions, erythema, hepatitis, nephritis, dermatitis, thrush, and blood disorders [15].

Seven clinical trials compared penicillin to no treatment or placebo, along with comparing penicillin to other agents. The results provided “inconclusive” support for or against antibiotic therapy in leptospirosis [16]. In addition, there was no statistically significant difference in the intervention in mortality or fever duration in severe leptospirosis [16] A different clinical trial however stated that even though the general use of antibiotics is uncertain, evidence suggest that penicillin may cause more good than harm seeing that 95% recover from the disease [17]. Alternatives to treating leptospirosis include ampicillin, azinthromycin, ceftriaxone, and doxycycline [2]. A recent clinical trial demonstrated that third-generation cephalosporins like ceftriaxone provide results just as effective as doxycycline and penicillin in treating acute leptospirosis [16]. [1] Picardeau, M.; Bertherat, E.; Jancloes, M.; Skouloudis, A.N.; Durski, K.; Hartskeerl, R.A., Rapid Tests For Diagnosis of Leptospirosis: Current Tools and Emerging Technologies. //Diagnostic Microbiology and Infectious Disease// **2014**, 78, (1), 1-8. [2] Leptospirosis. //Medline Plus// **2012.** <span style="font-family: Cambria,serif; font-size: 11pt;">[3] Leptospirosis. //Centers for Disease Control and Prevention// **2012.** <span style="font-family: Cambria,serif; font-size: 11pt;">[4] Levett, P.N., Leptospirosis. //Clinical Microbiology Reviews// **2001**, 14, (2), 296-326. <span style="font-family: Cambria,serif; font-size: 11pt;">[5] Brett-Major, D.M.; Coldren, R., Antibiotics for Leptospirosis. //Cochrane Database of Systematic Reviews// **2012**, (2). <span style="font-family: Cambria,serif; font-size: 11pt;">[6] Nordqvist, C., What is Leptospirosis? What Causes Leptospirosis? //Medical News Today// **2012.** <span style="font-family: Cambria,serif; font-size: 11pt;">[7] Leptospira Interrogans. //Microbe Wiki// **2011.** <span style="font-family: Cambria,serif; font-size: 11pt;">[8] Johnson, R.C., Leptospira. //Medical Microbiology// **1996**, 4, (35). <span style="font-family: Cambria,serif; font-size: 11pt;">[9] Mobley, H., How Do Antibiotics Kill Bacterial Cells But Not Human Cells? //Scientific American// **2006**. <span style="font-family: Cambria,serif; font-size: 11pt;">[10] Key Protein In Leptospirosis Bacterium Identified. //Science Daily// **<span style="font-family: Cambria,serif; font-size: 11pt;"> 2007. ** <span style="font-family: Cambria,serif; font-size: 11pt;">[11] Deacon, J., Penicillin and Other Antibiotics. //The Microbial World// **<span style="font-family: Cambria,serif; font-size: 11pt;"> 2003. ** <span style="font-family: Cambria,serif; font-size: 11pt;">[12] Penicillin G. //Pubchem// (Accessed Feb 1, 2014) <span style="font-family: Cambria,serif; font-size: 11pt;">[13] Penicillin (Oral Route, Injection Route, Intravenous Route, Intramuscular Route). //Mayo Clinic// **<span style="font-family: Cambria,serif; font-size: 11pt;">2013. ** <span style="font-family: Cambria,serif; font-size: 11pt;">[14] <span style="font-family: Cambria,serif; font-size: 11pt; line-height: 1.5;">Roerig, Pfizerpen(Penicillin G Potassium) Powder, For Solution. //Daily Med// **<span style="font-family: Cambria,serif; font-size: 11pt; line-height: 1.5;">2013. ** <span style="font-family: Cambria,serif; font-size: 11pt;">[15] Paddock, M., What is Penicillin? How Do Penicillins Work? //Medical News Today// **2011.** <span style="font-family: Cambria,serif; font-size: 11pt; line-height: 1.5;">[16] Gompf, S.G.; Velez, A.P.; Diaz, J.D.; Jezior, M.R.; Peterson, C.K.; Morris, J.T., Leptospirosis Treatment and Management. //<span style="font-family: Cambria,serif; font-size: 11pt; line-height: 1.5;">Medscape //**<span style="font-family: Cambria,serif; font-size: 11pt; line-height: 1.5;">2014 **<span style="font-family: Cambria,serif; font-size: 11pt; line-height: 1.5;">. <span style="font-family: Cambria,serif; font-size: 11pt; line-height: 1.5;">[17] Guidugli, F.; Castro, A.A.; Atallah, A.N., Antibiotics For Treating Leptospirosis. //<span style="font-family: Cambria,serif; font-size: 11pt; line-height: 1.5;">Cochrane Database Syst Rev //**<span style="font-family: Cambria,serif; font-size: 11pt; line-height: 1.5;">2010 **<span style="font-family: Cambria,serif; font-size: 11pt; line-height: 1.5;">, (1).
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