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| Streptococcus agalactiae|
Streptococcus Agalactiae, also known as Group B streptococci, are Gram-positive cocci distinguished from other streptococci by the presence of the group B antigen. These bacteria range in size from 0.6 to 1.2 υm and arrange themselves in chains, forming shorter chains in clinical specimen and longer chains in culture specimen. 
S. agalactiae colonize the lower gastrointestinal tract and the genitourinary tract in a commensal relationship that is often asymptomatic, but can cause bacterial sepsis, neonatal sepsis, pneumonia, meningitis, postpartum infection and other infections in infected hosts.  
S. agalactiae inhabit a human host, colonizing the lower gastrointestinal tract and the genitourinary tract. Colonization is frequent in pregnant women, where the bacteria colonize 15% to 45% of women  . In pregnant women, colonization can be transferred in utero to the fetus, or transferred from the birth canal during delivery. 
Cell structure and metabolism
S. agalactiae are facultative anaerobes that are mostly B-hemolytic (1%-2% are non hemolytic)  (hemolysis is the breakdown of red blood cells and is used to identify certain bacterial strains on culture plates). 
Different strains of S. agalactiae have been identified based on serologic markers that have classified different groups based on the presence of either a B antigen or group specific cell wall polysaccharide antigen, a surface (C) protein and a type-specific capsular polysaccharides. The type-specific capsular polysaccharides have been labeled Ia, Ia/c, Ib/c, II, IIc, III, IV, V, VI, VII, VIII and are used as epidemiologic markers. 
The cell structure of S. agalactiae helps to contribute to the organism’s virulence in several different ways. S. agalactiae contains a thick peptidoglycan cell wall layer that prevents desiccation and allows for the organism to live on dry surfaces. The capsular polysaccharides Ia, III and V further contribute to the organism’s virulence by preventing the immune response of complement mediated phagocytosis. In addition, the organism’s virulence is heightened by the presence of hydrolytic enzymes that aide in the spread of bacteria and allow for host tissue destruction.
As there are several isolates of S. agalactiae, the genome sequence of different isolates have been determined and comparatively analyzed with other S. agalactiae strains. One such study, performed by Herve Tettelin, et. al (2002), sequenced the genome of the S. agalactiae type V isolate 2603. In order to understand the S. agalactiae genome, the study compared the sequenced type V isolate 2603 genome to the genomes of other known S. agalactiae serotypes and streptococci strains. 
The study found that the circular S. agalactiae type V genome consists of 2,160,267 base pairs, including a G + C content of 35.7%, 80 tRNAs, 7 rRNAs and 3 sRNAs. The project predicted that the genome encodes for 2,175 proteins, 61% of which (1,333) were identified, while the remaining proteins coded by the genome are “of unknown function.”
In addition, the genome sequencing experiment identified various genes that act as possible virulence factors. Several genes such as Sip (SAG0032), CAMP factor (SAG2043), R5 protein (SAG1331), Streptococcal enolase (SAG0628), hyaluronidase (SAG1197) and hemolysin/cytolysin (cylE, SAG0669), have been identified as coding for surface proteins or secretory proteins that contribute to the organism’s virulence or aide in the organism’s immunity against host defenses.
The genome project highlighted the unique membrane structure of S. agalactiae as it identified the S. agalactiae genomic sequences that code for the B antigen present on the surface of all S. agalactiae strains and the capsular polysaccharide specific to each strain of S. agalactiae. The project also recognized nine differing capsular polysaccharides types, each one containing salic acid structures. These units are part of a repeating structure that prevent the activation of the host’s alternative complement pathway and thereby contribute to the organism’s virulence.
The sequencing project also undertook comparative genomics, comparing the genome of S. agalactiae to that of its common streptococci, S. pneumoniae and S. pyogenes. The analysis discovered 1,060 homologous genes in the three genomes and identified 683 genes specific to S. agalactiae only. These findings are in line with the relationships between the different strains, which must have similar gene factors as they all cause invasive diseases, but cannot have identical genomes as they each colonize and invade different areas and cause different diseases. For example, while S. agalactiae codes for the synthesis of arginine, asparate and citruline, it is missing the genes that S. pneumoniae and S. pyogenes use to synthesize fucose, lactose, mannitol, raffinose, lysine, and threonine. The differing genes are most probably a reflection of the differing organs that play host to each of the bacteria.
While there are various different serotypes of S. agalactiae, the genomic variations between and within serotypes are not well recognized. It has been hypothesized, however, that these variations are mainly unique to S. agalactiae, as while 260 (38%) of S. agalactiae’s unique 683 genes vary amongst different S. agalactiae serotypes, only 47 (4%) of the genes found in all three streptococci strains vary amongst different S. agalactiae serotypes. 
S. agalactiae colonization can result in infection and serious diseases in pregnant women, infants, men and non-pregnant women. S. agalactiae virulence and pathology varies amongst the various serotypes of the bacteria, with types Ia, II, III, and V found to be the most virulent  
The bacteria are well known for the serious infections and complications it causes in pregnant women and neonates. While carriage rates for pregnant women are very high (10%-30%), infection rates are much lower. In fact, the majority of pregnant women colonized with the bacteria are asymptomatic, with only 2%-4% of patients diagnosed with a urinary tract infection, the most common infection associated with pregnant women and the bacteria.  These infections occur during and after pregnancy and generally clear up quite quickly. In very few cases, more serious complications such as endocarditis, meningitis, and osteomyelitis can occur. 
S. agalactiae colonization complicates childbirth, as the rate of passing along colonization to the newborn is extremely high. In fact, over half – approximately 60% - of colonized mothers pass along the bacteria to newborns.  Various risk factors including heavy bacterial colonization, premature delivery, prolonged membrane rupture, and fever during labor (>100.4°F) increase the probability of passing along colonization. Colonization in the baby can occur while the baby is developing in utero, during birth or in the first few months of a baby’s life. In utero colonization can have serious effects on neonates, as fetal aspiration of the bacteria can lead to stillbirth, neonatal pneumonia or neonatal sepsis . Colonization during childbirth can also seriously infect an infant’s health. While a majority of mothers pass along colonization during childbirth, only a very small percentage of colonization results in infection (only 1%-2%) . Early onset disease, which presents within an infants’ first week, is usually caused by in utero or birth colonization. Early onset disease usually presents itself as bactermia, pneumonia or meningitis.  In fact, S. agalactiae is considered the main cause of these diseases in infants . Medical advancements have led to more efficient diagnosis and care of newborns colonized with S. agalactiae and have reduced the mortality rate to less than 5%. However, while the mortality rate is low, many infected newborns do not completely recover from meningitis and develop neurologic sequelae, an immulogical condition that often includes mental retardation, blindness and deafness. S. agalactiae colonization can also occur in older infants, resulting in late-onset diseases that occur from one week after birth to 3 months of age. Such infections usually present as sepsis, pneumonia, meningitis, osteomyelitis or septic arthritis  . While the mortality rate is low for infants with late onset disease, developmental complications from meningitis are common. 
S. agalactiae colonization occurs in individuals throughout the population, including non-pregnant women and in men. In such individuals, colonization in conjunction with compromised immunity can result in diseases such as bacteremia, pneumonia, bone and joint infections, and skin and soft-tissue infections. Mortality is higher for these patients and falls between 15% and 32%. 
In search of a way to prevent the dangerous infections caused by S. agalactiae infection, much research has gone into how to treat S. agalactiae colonization in pregnant patients. The Center for Disease Control and Prevention (CDC) has issued guidelines for detecting and treating S. agalactiae colonization in pregnant patients. These guidelines, last updated in 2002, have been largely responsible for the lowered infant mortality rate. The CDC promotes two methods of detecting colonization. The risk-based method analyzes a particular patient’s risk of colonizing the bacteria by identifying risk factors correlated with S. agalactiae infections. The presence of these factors, which include premature delivery (before 37 weeks), having a temperature during labor and delivery (greater than 100.4 degrees Fahrenheit), or premature rupture of the amniotic fluid, indicate a high probability of S. agalactiae colonization. . The screening-based method cultures swabs taken from pregnant women between 35 and 37 weeks to test for vaginal and rectal S. agalactiae colonization. Both methods indicate that an infected patient should receive antibiotics during labor in order to reduce the risk of passing along colonization to the infant. While penicillin is generally regarded as the first choice for intrapartum antibiotic prophylaxis, ampicillin can be used for patients with penicillin allergies. .
As S. agalactiae can cause many different infections and complications, various different medical treatments are often used to treat patients sickened by the bacterium. Current research is focusing on the development of a vaccine to create immunity against the bacteria and many in the medical community are rallying to work on ways to better diagnose and treat non-pregnant patients with colonization. 
S. agalactiae affects three main groups within the population: pregnant women, infants, and non-pregnant women and men. Following the 2002 release of the CDC’s treatment guidelines, a major epidemiological study (Phares, et. al) was published studying the trends of S. agalactiae disease within the population. The study, conducted from 1999-2005 and studying the population in 10 U.S. states, found that there 14,573 cases of S. agalactiae disease. 1,348, or 9.25% of these cases resulted in death. The incidence of early onset disease (which the study defined as from birth until 6 days old) decreased during the study, as from 1999-2001 the rate was 0.47 per 1000 live births and from 2003-2005 the rate decreased by 0.12 to 0.34 per 1000 live births. .This decrease occurred at the same time of the revised CDC treatment guidelines, indicating that the guidelines were effective in reducing disease. The study also measured the incidence of late onset disease and reported the ratio to be relatively stable throughout the study at 0.34 per 1000 live births. The study reported 409 S. agalactiae invasive infections in pregnant women, a ratio of 0.12 per 1000 live births. Half of these cases (203/409) were urinary, placental or amniotic sac infections that caused fetal death. A large majority of these pregnant patients, 81% (330/409) did not present with previous medical conditions (such as asthma, diabetes, obesity, or alcohol and drug abuse) . While the study only knew the pregnancy outcomes of 368 of the 409 pregnant women, data from the 368 known pregnancies are known. 61% of these pregnancies never came to term and ended in miscarriage or stillbirth, 4% had induced abortions, 5% delivered babies with infections and 30% delivered healthy babies. The study reported an incidence of 233 cases of S. agalactiae infections in children aged 90 days to 14 years, with a ratio of 0.56 per 100,000. This ratio, like the ratio of late-onset neonatal disease, was relatively stable throughout the study. The majority of these cases (61%, 143/233) were found in children younger than a year, while the remaining infections were evenly spaced amongst children older than year. The study reported the incidence of 6087 causes of S. agalactiae infections in adults (age 15 through 64) and 5576 cases in senior citizens (age 65 and older). The 2005 ratio for the first group (aged 15 through 64) was 5.0 per 100,000, a 48% increase from the 1999 ratio of 3.4 per 100,000. A similar increase was seen in the senior citizen group that rose 20% from a 1999 ratio of 21.5 per 100,000 to 26.00 per 100,000.  While this study shows the success of the CDC regulations in decreasing incidence of early-onset disease and maintaining the rate of late onset disease, the increase in adult disease and the continual incidence of pregnancy and neonatal disease (it has not been eliminated) has highlighted the importance of researching a vaccine to help relieve infection. .
A recent study conducted by Drs. Karen M. Puopolo, Lawrence C. Madoff and Eric C. Eichenwald attempted to understand the continual incidence of S. agalactiae infections despite updated CDC regulations and treatment plans to combat and eliminate the infections. The study, conducted over a six year time period from 1997 to 2003, reviewed the all cases of S. agalactiae infections at the Brigham and Women’s Hospital in Boston Massachusetts. By studying these cases of early onset S. agalactiae infections, the researchers hoped to determine if clinical, procedural or microbiological factors were responsible for the continual occurrence of infections, despite updated regulations and treatment protocol. 
Though the study coincided with the release of the CDC’s updated protocol in 2002, Brigham and Women’s Hospital requires pregnant women to be tested for S. agalactiae colonization by rectovaginal swabs, a protocol that follows the CDC’s 2002 guidelines. Thus, this study was examining the effectiveness of the screening based method. .
During the study, 67,260 babies were born in the hospital, of which 25 were infected with S. agalactiae colonization. 17 of these babies were term infants and 8 were preterm. As some mothers were preterm, only 21 of the 25 mothers had been screened for colonization, and 16 (64%) were found negative. Of the 17 term babies, 12 were asymptomatic or mildly ill, while 5 had more invasive infections, and one of these 5 died. The 8 preterm babies were all more critically ill, and 3 died. . The study observed that while 19 (76%) of the mothers presented with identifiable risk factors of S. agalactiae colonization (including positive signs of S. agalactiae colonization, delivering earlier than 37 weeks, intrapartum fever greater than 100.4°C, or clinical chorioamnionitis) only 4 received intrapartum antibiotic prophylaxis. . In fact, two term mothers who tested for colonization did not receive antibiotics. While one of these cases were the result of hospital error (and the other was due to a quick and unexpected delivery) the study concluded that hospital error was not responsible for most of the infection cases, as only 3 cases in total were caused by such errors. Additionally, the study observed that antibiotic resistance was not responsible for infection, as this only occurred in 1 of the 25 cases. Rather, the study references the high incidence of S. agalactiae infections in patients with negative cultures and suggests that in the presence of a negative culture, many other risk factors are ignored. This results in “a false sense of reassurance”  which prevents these factors from being recognized, the proper steps being taken and increases the infection rate. The study identified a 4% "false-negative" colonization rate, a percentage that can have serious implications when this is the only screening method used and other risk factors are ignored. This study therefore highlights the need for a risk based method to accompany the screening method in order to help decrease S. agalactiae infections. .
While CDC regulations have helped to decrease the amount of S. agalactiae invasive diseases in mothers and neonates, the continual incidence of disease, as well as the increase in adult infections, have led to increased research concerning an S. agalactiae vaccine. A recent (2006) study, conducted by Scilla Buccato, et al, researched such a vaccine that would provide patient immunity to S. agalactiae infections. The study focused on the bacterial pili that extend outside of the S. agalactiae cell, acting as adhesive factors that help with host colonization and virulence. Research has shown that there are 3 types of pili present in S. agalactiae, and genome sequencing of 8 S. agalactiae serotypes have shown that at least 1 pili is present in each strain of the bacteria.  These pili are coded by genomic islands, a once mobile part of the genome that can be removed and transferred to a new genome.  As a pathogenic factor found in all strains of S. agalactiae, the pili present as a possible vaccine component. A vaccine was made when a S. agalactiae pilus 1 operon was inserted into the Lactociccus lactis species. In order to test the vaccine’s ability to provide immunity and pass along antibodies to neonates, mice were immunized with the recombinant microorganism (the vaccine) and their offspring were later exposed to S. agalactiae. The vaccine proved to pass along immunity to the offspring, as after parental immunization with 107 cfu of the recombinant bacteria, more than 70% of the offspring survived exposure to S. agalactiae that was meant to kill 90% off the offspring. Mucosal immunization was also tested, as the vaccine was also given intranasaly. The intranasal mucosal immunization, like the subcutaneous injected vaccine, was found to successfully pass along immunity to the offspring, as a “statistically significant protection” with P>.0002 was found. While the experiment successfully immunized mice against S. agalactiae infection, the mice were not totally immune to all infections, as different serotypes of S. agalactiae have different pili. The researchers attempted to make a hybrid vaccine, made up of genes for two or more of the bacterial pili. Such a sequence, made up of genes that encode for pili on island 1 and island 2, was made and inserted into L. lactis. This vaccine was tested in a similar way as the pili 1 vaccine and the offspring of immunized mice were found to be immune to infections from each of the individual pili that the hybrid vaccine was made of. Thus, the L. lactis pili vaccine was found to not only confer immunity upon mice and their offspring, but also serves as a way to recombine different pili in order to provide protection against infection. By creating such a hybrid, the experiment exposed groundbreaking research on the path to making a vaccine to combat "S. agalactiae" infections. .
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 [ Murray R., Rosenthal S. and A. Pfaller. “Streptococcus.” Medical Microbiology, Fifth Edition, Elsevier Mosby: United States, 2005. 247-250]
- ↑ 2.0 2.1 2.2 2.3 [Tettelin, H., Masignani, V., Cieslewicz, M., Eisen, J.,Peterson, S., Wessels, M., et. al. (2002) Complete genome sequence and comparative genomic analysis of an emerging human pathogen, serotype V Streptococcus agalactiae. PNAS 99.19, 12391-12396.]
- ↑ 3.0 3.1 3.2 3.3 3.4 3.5 [Woods, Christian J. and Charles S. Levy, “"Streptococcus" Group B Infections.” Emedicine March 2009. 22 April 2009. <http://emedicine.medscape.com/article/229091-overview>]
- ↑ [Medline Plus. 20 April 2002 <http://www.nlm.nih.gov/medlineplus/ency/article/002372.htm >]
- ↑ 5.0 5.1 [Glaser, P., Rusniok, C., Buchrieser, C., Chevalier, F., Frangeul, L., Msadek, T., et al, (2002) Genome sequence of Streptococcus agalactiae, a pathogen causing invasive neonatal disease. Molecular Microbiology 45(6), 1499-1513 ]
- ↑ 6.0 6.1 6.2 6.3 6.4 [Schrag, S., Gorwitz, R., Fultz-Butts, K., and Anne Schuchat (2002) Prevention of Perinatal Group B Streptococcal Disease, Revised Guidelines from CDC. Center for Disease Control and prevention, Division of Bacterial and Mycotic Diseases, National Center for Infectious Diseases]
- ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 [Phares, C.R., Lynfield R., Farley, M., et al. (2008) Epidemiology of Invasive Group B Streptococcal Disease in the United States, 1999-2005. JAMA. 2008; 299(17):2056-2065]
- ↑ 8.0 8.1 8.2 8.3 8.4 8.5 8.6 [Puopolo, K., Madoff, L., and Eric C. Eichenwald. (2005) Early-Onset Group B Streptococcal Disease in the Era of Maternal Screening. PEDIATRICS 115.5:1240-1246 ]
- ↑ 9.0 9.1 [Buccato, S., Maione, D., Rinaudo, C., Volpini, G., Taddei, A., Rosini, R. (2006) Use of Lactococcus lactis Expressing Pili from Group B Streptococcus as a Broad-Coverage Vaccine against Streptococcal Disease. The Journal of Infectious Diseases 194: 331-340]
- ↑ Definition of Genomic Island. Everything Bio. 25 April 2009 <http://www.everythingbio.com/glos/definition.php?word=genomic+island>