Antibiotic Resistance Genes Database (ARDB)

Antimicrobial Drugs in general

Due to the fact that bacteria differ with eukaryotics with respect to morphology ,  and metabolism, many antibacterial drugs have been found which can inhibit processes in bacteria without disrupting them in the host. Such drugs are typically antibiotics which target bacterial enzymes that are distinct from their eukaryotic counterparts or which are involved in pathways like cell wall biosynthesis that is absent in eukaryotic cells.

Inhibitors of Peptidoglycan Synthesis:

Beta-Lactams: Inhibitors of peptidoglycan synthesis include the beta-lactams. Beta-lactams include the following:

1) penicillins: Penicillin was discovered by Alexander Fleming in 1928 and in 1940, several years before the introduction of penicillin as a therapeutic, a bacterial penicillinase was identifed by two members of the penicillin discvoery team. Maybe the most famous fungi species that produces penicillin is Penicillium chrysogenum.

Once the antibotic was used widely, resistant strains capable of inactivating the drug became prevalent, and synthetic studies were undertaken to modify peniccilin chemically to prevent cleavage by penicillinase (Beta-lactamases). Interestingly, the identification of a bacterail penicillinase before the use of the antibotic can now be appreicated in the light of recent findings that a large number of antibiotic r genes were componetns of natural microbial populations. This raises the question as to which came first, the antibiotic or resistance? (Davies, “origins and Evolution of Antibiotic Resistance” Microbiology and Molecualr Biology Reviews, 2010, p. 417-433)

–Ampillin:

2) cephalosporins.

Bacteria have evolved a host of strategies to resist beta-lactams such as beta-lactamases which hydrolyze beta-lactams. For example, CDC recommends a single dose of 500 mg of intramuscular ceftriaxone. Ceftriaxone belongs to the class of medicines cephalosporin antibiotics. Alternative regimens are available when ceftriaxone cannot be used to treat urogenital or rectal gonorrhea. See CDC

Inhibitors ofolic acid Synthesis :

Sulfanilamides inhibit steps of folic acid biosynthesis in bacteria. Examples include sulfamethoxazole

Inhibitors of replication and transcription:

Quinolones which act on  (enzymes involved in super coiling). Examples include ciprofloxacin

Inhibitors of RNA polymerase:

Rifamycins: such as Rifampin.

Inhibitors of  protein synthesis:

Inhibitors of protein synthesis include 4 classes of drugs:

A) tetracyclines prevents binding of f-met (which is the 1st residue in almost all polypeptide chains of bacteria)  tRNA to the 30S subunit (bacteria have 30S and 50S subunits)

B) aminoglycosides which inhibit peptide elongation,

C) chloramphenicol which binds to the 50S subunit and also blocks peptide extension and

4) macrolides which also binds the 50S subnunit of the ribosome and prevents peptide bond formation.

–Azithromycin is a broad-spectrum macrolide antimicrobial among the most prescribed antimicrobial drugs in the United States. It is a erythromycin derivative with greatly enhanced activity against gram-negative bacteria (including Enterobacteriaceae) and provides coverage of many gram-positive organisms. Like other macrolide antimicrobials, azithromycin binds to the 23S portion of the 50S bacterial ribosomal subunit. It inhibits bacterial protein synthesis by preventing the transit of aminoacyl-tRNA and the growing protein through the ribosome. Azithromycin is less prone to disassociation from the gram-negative ribosome than erythromycin, conferring its greater efficacy against gram-negative pathogens. Pharmacokinetically, azithromycin rapidly moves from the bloodstream into tissues and, once there, readily crosses cellular membranes, allowing efficacy against intracellular pathogens. The usual dose is 250 mg or 500 mg, given once daily for 3 to 5 days, and in severe infections, a higher dose is used. A single dose is occasionally used at 30 mg/kg for otitis media and at 1 g for adults with Chlamydia. See Sandman, Azithroycin

Antibiotics (See Outline)

Biomarkers for determining Treatment:

Procalcitonin (PCT): is a blood marker for bacterial infections and has emerged as a promising tool to improve decisions about antibiotic therapy. Several randomised trails ahve demonstrated the feasibility of using procalcitonin for starting and stopping antiboiotics. Procalcitonin increases in bacterial infections and deccreased when pateints recover from the infection. Procolcitonin can be measured in the bood of patients by different commercially available assays with a turnaround time of about 1-2 hours and support clinical decision making about initiation and discontinuation of antibiotic therapy. (Shuetz, “Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections” University o fGroningen (2017?

Administration of Antibodies as a Potential Treatment Strategy

Recent development in a number of areas are converging to make the medium-term future permissive for antibacterial mAb development. The majority of problematic infections with respect to failing antibiotic treatment is caused by ESCAPE pathogens (Enteroccocus faecium, S. arueeus, Clostridium difficile, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacteriaceae including E coli and Kelbsiella pneumoniae. The widespead antibiotic resistance of these pathogens is most alarming in the hospital setting (noscoomial infections). For ccertain bacterial infections, soluble toxins are major contributors to pathogenesis. Oleksiewicz, Archives of Biochemistry and Biophysics, 526: 124-131 (2012).

IgA: Traditionally, immunoglobulin preparation for the prophylaxis and treatment of infection were largely compirsed of IgG. However, the successful use of breast milk for the prophylaxis and treatment of infant diarrhaea highlighted the potential benefits of plasma (monomeric) and mucosal (secretory) IgA for immunotherapeutic use. A clinical trial conducted by Eibl indciates that oral feeding with a plasma derived IgA rich immunoglobulin preparation may present the development of necrotizing enterocolitis. Oral feeding with IgAbulin also displays a therapeutic effect in immunodeficinet patients suffering from Clostridium difficile or Campylobacter jejuni induced diarrhaea. Hemmingsson and Hammarstrom (1993) also prophylactically adminsitered IgA rich immunoglobulin preparation in a nasal spray and reducts the incidence of respiratory tract infections in elite skiers and elite rowers.  (WO00/41721).

SIgA (secretory IgA): is one of the immune components of colostrum and plays a role in protecting against infection. An immunogloublin preparation dervied form bovine colostrum reacts against toxins associated with E. coli and Shigella infections in cell cultures in vitor. S-IgA from human colostrum also inhibits adherence of Vibrio cholera to intestinal tissue in vitro. Results form three separate bovine colostrum are anti-diarrheal in adult AIDS?HIV patients suffering from infection by C. parvum. (US 2002/0119928).

Simon (US 8,021,645) discloses a composition that incldues dimeric secretory IgA and pentameric IgM for treatment of C. difficile. The IgA or IgM therapeutic is optionally enterically coated or microencapsulated to withstand gastrointestinal exposure associated with oral delivery.

Administration of Antimicrobial Peptides

Antimicrobial peptides are produced by higher organisms as part of their immune defenses. They disrupt cell membranes and once inside bacterial can disrupt DNA, RNA and various proteins. Scientisits are developing peptides as alternative to antibiotics. Antimicrobial peptides have a positively charged region that pokes through the bacterial cell membranes and a hydrophobic stretch that enables interaction with and translocation accross these membranes. Another advantage of antimicrobial peptides is that as they recruit immune cells to combat infection, they also suppress overactice inflammatory responses which can cause sepsis.

Clavanin-A: is a naturally occurring antimicrobial peptide, originally isolated from the tunicate, a marine animal. The original form of the peptide kills many types of acteria but has been engineered to improve its effectiveness. The resulting molecules, called clavanin-MO is very potetent against a number of bacterail strains such as E coli and S. aureus that are resistant to most antibiotics.

Bacterialphages to treat Drug Resistant Bacteria

Bacterial infections that can’t be treated successfully with known antibiotics are a serious threat to health. Researchers have been searching for new ways to kill these resistant bacteria. Viruses called bacteriophages, or phages, are one method under study. Phages prey on bacteria. They infect certain bacteria, replicate inside them, and burst out, killing the bacteria. Dr. Graham F. Hatfull’s research laboratory at the University of Pittsburgh for example has been building a collection of phages. Over many years, college students in a global science program have isolated more than 10,000 phages from nature and has shown page treatment success against the Mycobacterium abscessus isolated from the patient’s infection, dubbed GD01, which was resistant to all nine antibiotics tested. See NIH

In a new study, MIT biological engineers showed that they could rapidly program bacteriophages to kill different strains of E. coli by making mutations in a viral protein that binds to host cells. These engineered bacteriophages are also less likely to provoke resistance in bacteria, the researchers found. See Science Daily

Bacteriophages (phages) have demonstrated inhibitory effects against ciprofloxacin-resistance bacteria. (Chegini, “Bacteriophages: The promising therapeutic approach for enhancing ciprofloxacin efficacy against bacterial infection” J Clin Lab Anal, 2023).

Small Molecule Inhibition of virulence gene expression

Increasing antibiotic resistance requires the development of new approaches to combating infection. Virulence gene expression in vivo represents a target for antibiotic discovery that has not yet been explored. A high-throughput, phenotypic screen has been used for example to identify a small molecule 4-[N-(1,8-naphthalimide)]-n-butyric acid, virstatin, that inhibits virulence regulation in Vibrio cholerae. By inhibiting the transcriptional regulator ToxT, virstatin prevents expression of two critical V. cholerae virulence factors, cholera toxin and the toxin coregulated pilus. See Hung

Targetting Biofilm Formation 

Degrading enzymes: The biofilm extracellular matrix serves as a protective physical barrier that shelters the resident bacteria against antibiotics and host immune defenses. Therefore, approaches to disrupt the matrix by enzymatically degrading the chemical components have been investigated. DNase I-mediated degradation of extracellular DNA appears to be effective in disrupting early S. aureus biofilms and treatment with trypsin or proteinase K disrupts the protein components of the biofilm matrix.  Likewise, dispersin B, a glycoside hydrolase produced by the periodontal pathogen Actinobacillus actinomycetemcomitans, is able to breakdown the polysaccharide components of staphylococcal biofilms and can promote antibiotic penetration, resulting in synergistic killing when combined with the antibiotics cefamandole nafate or triclosan. Additional glycoside hydrolases, α-amylase and cellulase, and lysostaphin, a glycine endopeptidase produced by Staphylococcus simulans that cleaves the pentaglycine bridge in the staphylococcal cell wall, have also been shown to significantly reduce matrix biomass of S. aureus biofilms in vitro. Although these in vitro results are promising, the application of exoenzymes as therapeutic drugs may be limited due to the possibility of protein-induced inflammatory responses in the host, toxicity, or immunity. Alternatively, these enzymes could be employed in an approach similar to an “antibiotic lock” where a high concentration is applied to catheter lumens to prevent catheter-associated S. aureus infections.  See Skaar

Targeting bacterial iron metabolism through the use of chelators and gallium-based therapeutics has been demonstrated to effectively disrupt staphylococcal biofilms.

Inhibiting quorum sensing: Virulence factor production in S. aureus is regulated by quorum sensing (QS), a cell to-cell communication mechanism bacteria use to regulate gene expression in response to cellular density. The S. aureus QS system is under the control of the accessory gene regulator (agr) system and activation of the agr system by an accumulation of auto-inducing peptide (AIP) leads to activation of the agr regulatory network that controls expression of virulence factors by RNAIII, the major effector for downstream virulence expression and biofilm dispersal. Inhibiting QS would prevent the production of QS-regulated toxins such as delta-toxin, staphylococcal enterotoxin C, and Panton-Valentine leukocidin, thus restricting S. aureus’ ability to evade the host immune system, kill host cells, and disseminate.  See Skaar

Adaptive antibiotic resistance of P. aeruginosa is a recently characterized mechanism, which includes biofilm-mediated resistance and formation of multidrug-tolerant persister cells, and is responsible for recalcitrance and relapse of infections. The discovery and development of alternative therapeutic strategies that present novel avenues against P. aeruginosa infections are increasingly demanded and gaining more and more attention. Although mostly at the preclinical stages, many recent studies have reported several innovative therapeutic technologies that have demonstrated pronounced effectiveness in fighting against drug-resistant P. aeruginosa strains.  See Cheng

–Use of Essential Oils: The biofilm formation of pathogenic bacteria is considered a big challenge for the food industry and human/animal health. The QS mechanism regulates the bacterial biofilm formation; thus, destroying and/or disrupting this mechanism can help to prevent biofilm formation and then solve many health problems. EOs are composed mainly from two groups of single substances, terpenoids (monoterpene, sesquiterpene and di-terpene) and phenylpropanoids. Many plant EOs display promising anti-QS properties by preventing biofilm formation, which could be very important in reducing the virulence and pathogenicity of drug-resistant bacteria, especially for those that are food pathogenic. In fact, the use of plant EOs in food industry do not change the organoleptic properties of foods, and their use could thus be a promising natural alternative for several synthetic food preservatives. Finally, many plant EOs can represent a possible substitute for many traditional antimicrobial drugs, which have a significant negative impact on the environment and human/animal health. See Feo

WHO list of bacteria for which antibiotics are urgently needed     NYC Public Health testing laboratory manual (good resource for types of viral and bacterial diseases and tests used to identify them)

Vaccine Adverse Even Reporting System

Companies: Entasis Therapeutics

Bacteria are a significant cause of disease. Most critical are the multidrug resistant bacteria which cause problems in hospitals, nursing homes and among patietns using devices such as ventilators and blood catheters. Such drug resistant bacterial include acientobacter, Pseudomonas, and various enterobacteriaceae (including Klebsiella, Escherichia coli, Serratia and Proteus). They can cause severe and often deadly lung and bloostream infections.  Other increasingly drug resistant bacteria that cause more common disease such as gonorrhoea and food poisoning.

One estimate puts some 13.7 million infection related deaths in 2019 of which 7.7 million deaths were assocaited with 33 bacterial pathogens. Five leading pathogens -Staphyloccous aureus, Escherichia coli, Streptococcus pneumoniae, Klebsiella pneumoniae and Pseudomonas aeruginosa were responsible for 54.9% of deaths among the investigated bacterial The age-standardised motality rate assocaited with these bacterial pthogens was highest in the sub-Saharan Afica super-region with 230 deaths per 100k population and lowest in the high incoe super-region with 52.5 deaths per 100k population. S. aureus was the leading bacterial cause of death in 135 countires and was also associated with the most deaths in individuals older than 15, globally. (“Global mortality associated with 33 bacterail pathogens in 2019: a systematic analysis for the Global Burden of Disease Study 2019, GBD, 2013)

Affecting the Cardiovascular and Lymphatic System

Anaplasmosis: Anaplasma is a small inracellular bacterium that shares lifestyle characteristics with Ehrichia (below) and casues nearly identical clinical manifestations. But the two bacteria differ in geographic distributions and are carried by two different species of ticks. Treatmnet of anaplasmosis is by doxycycline.

Bruceliosis: is a bacterial genus that contains tiny, aerobic, gram-negative coccobacilli. Several species can cause the disease in humans: B. melitensis, B. abortus and B. suis. Brucellosis often casues severe outbreaks of placental infection in levestock, which results in devasting economic impacts. The potential economic impact is one reason the CDC lists it as a possible bioterrorism agent.

Cat-Scratch disease: is one of a group of diseases caused by different species of the small gram-negative rod Bartonella. Bartonella species are considered to be emrging pathogens. They are fastidious but not obligate intracellular parasites, so they will grwo on blood agar. B. henseelae is the agent of cat scratch disease, an infection connected with being clawed or bitten by a cat. It is transmitted among cats by fleas. The pathogen is present in over 40% of cats, especially kittens. Tehre are aobut 25,000 cases per year in the U.S., 80% of them in children of 2-14. The symptoms start after 1-2 weeks, with a cluster of small papules at the site of inoculation. Mmost infections remain localized and resolve in a few weeks, but drugs such as azithromycin, erythromycin and rifampin can be effective therapies. The disease can be prevented by flea control and by through antiseptic cleansing of a cat bite or scratch.

Endocarditis: 

Endocarditis is an inflammation of the endocardium, or inner lining of the heart. Endocarditis is divided into “acute” and “subacute”.

—signs and symptoms: are similar for both acute and subacute endocarditis except that in the subactue condition they develop more slowly.  Symptoms include fever, fatigue, joint pain, endema (swelling of feet, legs and abdomen), weakness, anemia, abormal hearthbeat and soemtimes symptoms similar to myocardial infarction.

–causes:  The acute form of endocarditis is most often casued by Staphyloccoccus aureus. Other agents includes Sreptococcus pyogenes, Sreptococcus pneumononiae and Neisseria gonorrheoeae, as well as a host of ther bacterial.  Most commonly, subactue endocarditis is caused by bacterial of low pathogenicity often originating int he oral cavity. Alpha-hemolytic streptococci, such as Streptococcus sanguis, S. oralis and S. mutans are most often responsible, although normal biota form the skin and other bacteria can also colonize abnormal valvues and lead to this condition.

–Transmission: Minor disruptions in the skin or mucous membranes, such as those induced by overly vigorous toothbrushing, dental procedures, or relatively minor cuts and lacerations can introduce bacteria into the blood stream and lead to valve colonization.

–Prevention: the practice of prophylactic antbiotic therapy in advance of surgical and dental procedures on patients with underlying valve irregularities has decreased the inidicne of this infection.

Ehrichiosis: Ehrlichia is a small intracellular bacterium with a strict aprasitic existence and associated with ticks (Ixodes species). The species of tick varies with the geographic location. The signs and symptoms include an acute febril state resulting in headache, muscle pain, and rigors. Most patients recover rapidly with no lasting effects, but about 5% of older, chronically ill patients can die. Rapid diagnosis is done through PCR tests and indirect fluorescent antibody tests. It cn be critical to differentiae coinfection with Lyme disease Borrelia, which is carried by the same tick. Doxyclycline will clear up most infections within 7-10 days.

Septicemia (Sepsis):

Septicemia occurs when organisms are actively multiplyng in the blood.

–signs and symptoms: include fever, altered mental state, shakin, chills and gastrointestinal symptoms. Often an increased breathing rate is exhibited, accompanied by respitratory alkalosis (increased tissue pH due to breathing disorder). Low blood pressure is a hallmark of this condition and is caseud by the inflammatory response to infectious agents in the blood, which leads to a loss of fluid from the vasculature.

–causes: in the vast majority of cases are by bacteria. MRSA is a very common cause. About 10% of cases are caused by fungal infections. Polymicrobial bloodstream infections increasinly are being identified in which more than one microorganisms is causing the infection.

–pathogenesis and virulence factos: Gram-negative bacteria multipolying in the blood release large amounts of endotoxin sitmulating a massive immune response mediated by a host of cytokines. This response invariabley leads to a drastic drop in blood pressure, a condition called “endotoxic shock”. Gram-postive bacteria can instigate a similar cascade of events when fragments of their cell walls are released into the blood.

–Transmission: in many cases is due to parenteral introduction of the microorganisms via intravenous lines or surgical procedures. Other infetions may arise from serious urinary tract infections or from renal, prostatic, pancreatic, or gallbladder abscesses. Patietns with underlying spleen malfunction may be predisposed to multiplication of microbes in the blood stream. Meningitis, osteomyelitis (bione infections) and pneumonia can all lead to spesis. At least 200,000 cases occur in year in the U.S. resulting in more than 100,000 deaths.

–Diagnosis: is by a blood culture.

–prevention and treatment: empiric therapy, which is begun immediately after blood cultures are taken, often begins with a broad spectrum antibiotic. Once the organisms is identified, and its antbitoic susceptibility is known, treatment can be adjusted. In spesis, the capillaries become leaky, cuasing fluid volume to leave the blood vessels and move to the interstitial space. With depleted plasma volume, the pateint experiences low blood pressure. The rapid adminsitration of intravenous fluid volume is often necessary to resuscitate a patient with sepsis. Medications may also be started to help support the patient’s blood pressue.

Lyme Disease: 

–cause: Borrelia burgdorferi is considered the casue of Lyme disease. They are unusual spirochetes.

–pathogenesis and virulence factors: The bacterium is a master of immune evasion. It changes its surface antigens while it is int he tick and again after it has been transmitted to a mammalian host. It provokes a strong humoral and cellular immune response, but this repsonse is mainly ineffective, perhaps becasue of the bacterium’s abiliyt to switch its antigens.

–transmission and epidemiology: B. burgdorferi is transmitted priarmily by hard ticks of the genus Ixodes, in the northern part of the U.S. Ixodes scapularis (the black legged deer tick) passes through a complex 2 year cycle that involves two principal hosts. In California, the transmission cycle involves Ixodes pacificus, another black legged tick, and the dusky fotted woodrat as reservoir. The greatest concentrations of Lyme disease are found in areas having large populations of obth the intermediate and efinitive hosts.

–diagnosis: culture is not useful. Diagnosis inthe early stages if the rash is present, is usually accomplished based on symptoms and history of possible exposureto ticks. In alte stages, ELISA and/or Wetern blots can be used to detect antiboides in the blood. It is important to consider coinfection with Anaplasma or Babesia since these organisms are transmitted by the same kind of ticks.

–prevention and treatment. Anyone invovled in otudoor activites whould wear protective clothing, boots, leggins and insect repellent containing DEET. One should also inspect their bodies for ticks and remove ticks gently wihtout crusing, preferably with forcepts or fingers protected with gloves, becasue it is possible to become infected by tick feces or boidy fluids. Early, prolonged (2 weeks) treatment with doxycyline or amoxicillin is effective and other antbiotics such as centriaxone and penicillin are used in late Lyme disease therapy.

Plague:

Pneumonic plague is a resptirotry disease. However, bubonic plague enteres the lmph nodes and is filtered by a local lymph node.

–cause: The cause of bubonic plague is a tiny gram-ngeative rod, Yersinia pestis, a member of the family Enterobacteriaceae. Y. pestis displays unusual bipolar staining that makes it look like a safety pin.

–Pathogenesis and virulence factors: the number of bacteria required to initiate a plague infection is small, perhaps only 3-50 cells.

–Transmission and epidemiology: The plague bacterium residues in over 200 species of mammalian hosts. Some of these, such as mice and voles, serve as long term endemic reservoirs, which are not affected by the disease. Other psecies, including rats and rabbits, are amplifying reservoirs, which get sick and tend to be closely connected to outbreaks of plague in humans. The principal agents in the transmission of the plague bacterium are fleas.  After a flea ingests a blood meal from an infected animal, the bacteria multiply in its gut. The bacterium promotes its spread by causing coagulation and blockage of the flea’sesophagus. Being unable to feed properly, the ravenous flea jumps from animal to animal in a futile attempt to get nourishment. Regurgitated infectious material then is inoculated into the bite wound. The distribution of plague is extensive. Although the diase has been reduced in the devleoped world., it has been increasing in Afical and other parts of the world. In the US sporadic cases (usually 1020 per year0 occur as a result of contact with wild and domestic animals. It is considered endemic in US western and southwestern states. Persons most ar risk are veterinatrians and people living and working near woodlands and forests. Dogs and cats can be infected with the plague, often from contact with infected wild aimals such as prairie dogs.

-signs and symptoms: infection: infection causes inflammation and necrosis of the node, resulting in a swollen lesion called a bubo, usually in the groin or axilla. The incubation period lasts 2-8 days, ending abruptly with the onset of fever, chills, headache, nausea, weakness and tenderness of the bubo. Mortaility rates, even with treatment, can reach up to 15%.

Treatment: is streptomycin or gentamicin.

Rocky Mountain Spotted Fever: is casued by a bacterium called Rickettsia rickettsii that is transmitted by hard ticks such as the wood tick, the American dog tick and the Lone Star tick. After 2-4 days of incubation, the first symptoms are sustained fever, chills, headache and muscular pain. A distinctive spotted rash usually comes on within 2-4 days after the prodome which usually appers first on the wrists, forearms and ankles before spreading. Early lesions are slightly mottled like measles, but later ones can change shape to look like other types of rashes. In the most severe untreated cases, the enlarged lesions merge and can become necrotic, predisposing to gangrene of the toes or fingertips. The most serious manifestations are cardiovascular disruption, including hypotension, thrombosis and hemorrhage. Conditions of restlessness, delirium, convulsions, tremor and coma can occur in about 20% of untreated cases and 5-10% of treated cases.

Tularemia (rabit fever): 

–cause: is a facultative intracellular gram-negative bacterium called Francisella tularensis: It is a zoonotic disease of assorted mammals endemic to the Northern Hemisphere. Becasue it has been associated with outbreaks in wild rabits, it is sometimes celld rabbit fever. It is on a Category A bioterrorism list.

–signs and symptoms: after an incubation from a few days to 3 weeks, acute symptoms of headache, backache, fever, chills, coughing and weakness appear.

–Epidemiology:

During 2011–2022, a total of 47 states reported 2,462 tularemia cases, but four central states (Arkansas, Kansas, Missouri, and Oklahoma) accounted for 50% of all reported cases. Incidence was highest among children aged 5–9 years (0.083 per 100,000 population) and adult males aged 65–84 years (range = 0.133–0.161). Incidence among American Indian or Alaska Native persons (0.260) was approximately five times that among White persons (0.057). See CDC

–transmission and epidemiology:

Although rabbits and rodents (muskrats and ground squirrels) are the chief reservoirs, other wild animals (skunks, beavers, foxes, opossum) and some domestic animals are implicated as well. The main route of transmission has been through the activity of skinning rabbits, but now transmission via tick bites is more common. Mites and mosquitos cna also transmit it. With an estimated infective dose of 10-50 organisms, F. tularensis is often considered one of the most infectious of all bacteria. Cases have appeared in people who have accidnetally run over rabbits while lawn mowing, presumably form inhaling aerosolized bacteria. There are several hundred cases in the U.S. per year and itnernationally 500,000 cases.

–prevention and treatment: antimicrobial therapy must not be discontinued prematurely becasue F. tularensis can lead to relpases. Posexposure proplylaxis with doxycycline or ciprofloxacin can prevent the disease in lab workers or thers who may have been exposed. Laboratroy workers must wear gloves, masks and eyewear.  The eath rate in the most serious forms of disease is 30%, but proper treatment with gentamicin or streptomycin reduce mortality to almost zero.

Q Fever:

The name of this diease arose from not being able to identify its cause; Q standing for “query”. Its cause however is the bacterium Coxiella burnetti. Clinical manifestations of acute Q fever are abrupt onselt of fever, chills, head and muscle ache, and, occasionally, a rash. These disease is soemtimes compolicated by pneumonitis (30% of cases), hepatits, and endocarditis. C. burnetii is a very small pleomorphic (variously shaped) gram-negative bacterium. It is apparently harbored by a wide assortment of vertebrates and athropods, specially ticks. However, ticks do not directly transmit the disease to humans. Humans aquire infection largely by means of environmental contaimination and airbone spread. Soruces of infection include urine, feces, milk and airbone particles form infected aiamsls. The primary protals of entry are the lungs, skin conjunctiva and gastroinestinal tract. People at highest risk are farm workers, meat cutters, veterinarians, laboratory technicians and consumers of raw milk products.

Affect the skin (Also see Bacteria)

Cellulitis: is a condition caused by a fast spreading infection in the dermis and in the subcutaneous tissue below it. It causes pain, tenderness, swelling and warmth. Fever and swelling of the lymph nodes draining the area may also occur. Fequently, red lines leading away from the area are visicle. Most common causes of the condition in healthy people are Staphylococcus aureus and Streptococcus pyogenes, although almost any bacterium and some fungi can cause the condition in an immuncompromised patients. In infants, group B streptococci are a frequent cause. The mild cellulitis responds well to oral antibiotics chosen to be be effective against S. aureus and S. pyogenes. Keep in mind that if it is caused by S. aureus, it usually of the methicillin resistant variety (MRSA). More involved infections in immunocompomised people require intravenous antibiotics.  If there is extensive areas of tissue damage, surgical debridement is warranted.

Conjunctivities: is relatively common. It can be caused by specific microorganisms that have a prediliection for eye tissues, by contaminants that proliferate due to the presence of a contact lens or an eye injury, or by accidental inoculation of the eye by a traumatic event. Cases of neonatal eye infection with Neiseeeria gonorrhaeae or Chlamydia trachomatis are usually transmitted vertically from a genital tract infection in the mother. Bacterial conjunctivities in other age groups is monst commonly casued by Stpahylococcus epidermidis, Streptococcus pyogenes or Streptococcus pneumoniae, although Haemophilus influenzae and Moraxella species are also frequent causes. No. gonorrhaeae and C. trachomatis can also cause conjunctivitis in adults. These infections may result from autoinoculation from a genital infection or from sexual activity, although No.gonorrhaeae can be part of the normal biota in the respiratory tract. A wide variety of bacteria, fungi and protozoa can contaminate contact lenses and lens cases and then be transferred to the eye, resulting in diasease that may be very serious. Newborn children in the U.S. are administered antimicrobials in their eyes after delivery to prevent neonatal conjunctivitis from either N. gonorrhaeae or C. trachomatis.

Cutaneous Anthrax: This form of antrax is the most common and least dangerous version of infection with Bacillus anthracis. It is caused by endospores entering the skin through small cuts or abrasions. Germination and growth of the pathogen in the skin are marked by the production of a papule that becomes increasingly necrotic and later ruptures to form a painless balck eschar. In the fall of 2001, 11 caes of cutaneous anthrax occured in the U.S. as a result of bioterrorism. Mail workers and others contracted the infection when endospores were sent rhough the mail. Left untreated, even the cutaneous form of antrax is fatal about 20% of the time. A vaccine exists but is recommended only for high risk persons and the military.

Impetigo: is a superficial bacterial infection that causes the skin to flake or peal off. It is not a serious disease but it is highly contagious and children are the primary victims. It can be casued by either S. aureus of S. pyogenes and some cases are probably casued by a mixture of the two. Impetigo is highly contageious and transmitted through direct contact but also via fomites and mechanical vector transmission. The peak incidence is in the summer and fall. The only current rpeention is good hygiene. The lesion of impetigo looks variously like peeling skin, crusty and flaky sabs or honey colored crusts. Lisions are most often found around the mouth, face and extremities, although they can occur anywhere on the skin. It is very superficial and it itches.

Keratitis: is a serious eye condition that can lead to complete corneal destruction. Any microrganism can cause this condition, especially after trauma to the eye, but miscellaneous bacteria cause 80% of the infectious keratitis cases.

Staphylococcus aureus, often referred to as “staph”, is a common type of bacteria that is found in about 25 to 30 percent of healthy people, primarily on the skin or in the nose. Most of these individuals are colonized by the staph bacteria, meaning that the bacteria are present but are not causing disease. Some people become infected with staph bacteria indicating that the bacteria are present and cause disease. Although staph bacteria do not usually cause infection, they can bring about disease if they penetrate through a break in the skin or through mucous membranes. Staph bacteria are one of the most common causes of skin infections and sometimes produce relatively minor skin infections such as pimples and boils. However, they can cause more serious illnesses such as surgical wound infections, bloodstream infections, bone infections, and pneumonia. In the past few decades, a more dangerous form of staph has emerged. This form is known as methicillin-resistant Staphylococcus aureus and is usually referred to by the acronym MRSA.

–MRSA infections: of the skin tend to be raised, red tender, localized lsions often featuring pus and feeling hot to touch. They occur easily in breaks in the skin casued by injury, hsaving or even just abrasion. They may localize around a hair follicle. Fever is a common feature. MRSA is a common containinant of all kinds of surfaces you touch, especially those not sanitized. Gym equipment, airplane tray tables, electronic devices, razors are all sources.

MRSA is categorized by the setting in which it is acquired. The first type, healthcare-acquired MRSA (HA-MRSA), has been recognized since the 1960s. Strains of staph were identified in patients in hospital and healthcare facilities that were resistant to methicillin (resistance to penicillin had occurred even earlier). The incidence of this infection has been increasing over time, with patients who have had surgery, medical devices implanted, or weakened immune systems being particularly at risk. Of greater concern is a second type of MRSA which appeared in the 1990s and is known as community-acquired MRSA (CA-MRSA). CA-MRSA occurs outside of hospital settings and usually manifests itself as a skin infection in an otherwise healthy individual. CA-MRSA can develop into a more serious, life-threatening illness. CA-MRSA tends to occur under conditions where people are in prolonged physical proximity, such as in childcare and long-term care facilities, and in soldiers, prisoners, athletes involved in skin-to-skin contact sports such as wrestling, and in individuals sharing personal items such as towels. Unlike HA-MRSA, the source of infection for CA-MRSA is often difficult to identify.  See Baylor College of Medecine

CA-MRSA usually enters the body though a cut or scrape. The first sign of infection is commonly described as resembling a spider bite – a spot on the skin that is red, swollen, and painful. The site may produce pus. Infrequently, CA-MRSA infection can progress to a more serious disease, such as bloodstream infection or pneumonia. CA-MRSA can, in rare cases, lead to death. Highly publicized accounts of the deaths of at least three students from CA-MRSA in late 2007 prompted concern among students, parents, and school officials. The best defense against MRSA is to maintain good hygiene, including frequent and thorough hand washing, and to avoid the sharing of personal care items.

Scientists are working to understand the genetic changes in MRSA that allow the bacterium to cause serious illness in otherwise healthy individuals. To begin to answer this question, MVM scientists and others at Baylor College of Medicine initiated a project to obtain the DNA sequence of a strain of CA-MRSA called USA300. They chose the USA300 strain, one of two strains that cause the majority of CA-MRSA cases, because it has emerged as the predominant strain causing skin infections, as well as more serious infections, in both pediatric and adult patients in many states. Before 2000 this strain was rarely found in the community; today it accounts for 70 percent of CA-MRSA patients at Texas Children’s Hospital. Another reason for the interest in the USA300 strain is that it appears to be more virulent than other strains. The scientists concluded that the USA300 strain that they sequenced was very similar to other staph strains. This suggests that the increased virulence of the USA300 strain is due to subtle genetic changes within its genome. One intriguing finding of their study is that the bacterium has picked up a plasmid that contains a gene that confers resistance to bacitracin, an antibiotic commonly found in over-the-counter skin ointments. See Baylor College of Medecine

All pathogenic S. aureus strains typically produce coagulase, an enzyme that coagulates plassma. Because 97% of all human isolates of S. aureus produce this enzyme, its presence is consdiered a diagnostic characteristic. PCR is routinely used to diagnose MRSA. Alternatively, cultivation on blood agar is useful.

Treatment often starts with incision of the lesion and drainage of the pus. Antimicrobial treatment should include more than one antibiotic. Current recommendations in the U.S. are for teh use of vancomycin. Manuka honey is currently used as a wound treatment and suggested to be effective in Methicilin-resistant Staphylococcus aureus (MRSA) elimination. Manuka honey comes from New Zealand and Australia. It is harvested by European honeybees (Apis mellifera) that have pollinated and collected nectar primarily fomr the Manuka tree. (Frydman “Manuka honey microneedles for enhanced wound healing and the prevention and/or treatment of Methicilin-resistant Staphylococcus aureus (MRSA) surgical stie infection” Scientific Reports, 10, 2020).

Mycobacterium abscessus (also called M. abscessus): is a bacterium distantly related to the ones that cause tuberculosis.  It is part of a group of environmental mycobacteria and is found in water, soil, and dust. It has been known to contaminate medications and products, including medical devices. M. abscessus can cause a variety of infections. Healthcare-associated infections due to this bacterium are usually of the skin and the soft tissues under the skin. It is also a cause of serious lung infections in persons with various chronic lung diseases, such as cystic fibrosis. People with open wounds or who receive injections without appropriate skin disinfection may be at risk for infection by M. abscessus.  Rarely, individuals with underlying respiratory conditions or impaired immune systems are at risk of lung infection. See CDC

Afficting the Urinary Tract (UTIs)

Generally:

The urinary tract is responsible for removing substances form the blood, regulating certain body processes and forming urine and transporting it out of the body. The urinary tract includes the kidneys, ureters, bladder and the urethra. Urine in addition to being acidic, aso contains the antibacterial proteins, lysozyme and lactoferrin. Lactoferrin is an iron binding protein that inhibits bacterail growth. Lysozyme is an enzyme that breaks down peptidoglycan. The urine also contains secretory IgA.

–Transmission:

UTIs acquired in health care facilities are almost always a result of catheterization. Community acquired UTIs are nearly always transmitted not from one person to another but from one organ system to anotehr, namely from the GI tract to the urinary system. In 95% of UTIs, the cause is bacteria that are normal biota in the gastrointestinal tract with E coli being the most common. They are more common in women than in men because of the nearness of the female urethral opening to the anus.

–Symptoms: Common symptoms of UTIs include burning sensations during urination, feverish conditions, constant, strong urge to urinate, pain the the rectal region for mails and pain in the pelvis in females, intense passing out of small amounts of urine, urine with appearance of blood and/or foul odor and pain around the hips, abdomen, or lower back region.

–Treatment: Sulfa drugs such as trimethoprim-sulfamethoxzole are most often used for UTIs of various etiologies. Often another nonantibiotic drug called phenazopyridine (Pyridium) is adminsitered simultaneously. This drug relieves the uncomfortable symptoms of burning and urgency. A large percentage of E coli strains are resistant to penicillin derivatives, so these should be avoided.

Clostridium perfringes: is a Gram-positive, rod-shapped, anaerobic, spore-forming pathogenic bacterium of the genus Clostridium. C. perfringes is ever-present in nature and can be found as a normal component of decaying vegentation, marine sediment, the intestinal tract of humans and other vertebrates, insects, and soil. Its densopores are able to survive long periods of exposure to air and other adverse environmental conditions. It is wone of the most common causes of food borne illnesses.

E. coli: Urinary tract infections (UTIs) are very common infections in humans, and Escherichia coli (E. coli) is the main cause of UTIs. Escherichia coli and urinary tract infections are often discussed together as E. coli (uropathogenic E. coli, UPEC) and is often indicated as the major cause of UTIs.

E. coli as a Gram-negative bacillus belongs to the Enterobacteriaceae family. Treating infections caused by E. coli is challenging due to antibiotic resistant strains. The generation of extended spectrum
beta-lactamas (ESBL) in E. coli causes its resistance against several antibiotics. Beta lactamases can be
generated by Gram-negative bacteria and are present in the Enterobacteriaceae family. ESBL-producing bacteria are resistant to cephalosporins, penicillin, tazobactam/piperacillin and other antibiotics such as co-trimoxazole, fluoroquinolones, and tetracycline. Also, the ESBL-coding plasmid easy transfer is an important threat to hospitalized patients. See Farzinpoor

Leptospirosis: 

Leptospirosis is a zoonotic bacterial disease spread through the urine of infected animals; the typical incubation period is 5–14 days. In approximately 90% of human cases, illness is asymptomatic or mild, characterized by fever, chills, myalgia, nausea, vomiting, diarrhea, headache, calf pain, and conjunctival suffusion, but severe illness can progress to multiorgan dysfunction and death. See CDC

–signs and symptoms: during the early phase, the pathogen appears in the blood and crebrospinal fluid. Symptoms include sudden high fever, chills, head-ache, muslce aches, conjunctivitis and vomiting. During the second phase, the blood infection is cleared and symptoms include milder fever, headache due to leptospiral meningitis and in rare cases, Weil’s syndome, a cluster of syptoms characterized by kidney invasion, hepatic disease, jaundice, anemia and nuerological distrubances. Long term disability and even death can result from damage to the kidneys and liver, but they occur primarily with the most virulent strains in the elderly persons.

-causative agent: Leptospires are typical spirochete bacterai marked by tight, regular, individual coils with a bend or hook at one or both ends.

–Transmission: infection occurs almost entirely through contact of skin abrasions or mucous membranes with animal urine or some environmental source containing urine. In 1998, dozens of ahtletes competing in the swimming phase of a triathlon in Illinois contactred leptospirosis form water. It is a common pathogen in areas of Latin America and Asia.

–Treatment: early treatment with doxycycline, peniccilin G, or ceftriazone rapidly reduces symptoms and shortens the course of disease, but delayed therapy is less effective.

Affecting the Genitourinary System

The genital system has reproduciton as its major function. The male reproductive system produces, maintains and transports sperm cells and is the source of male sex homrones. It consists of the testes, which produces sperm cells and hormones and the epididymides, which are coild tubes leading out of the testes. Each epididymis terminates in a vas deferns, which combines with the seminal vesicle and terminates in the ejaculatory duct. The contents of the ejaculatory duct empty into the urethra during ejaculation. The prostate gland is a walnut shapped structure at the base of the urethra. It also contribues to the released semen.

The female reproductive system consists of the uretru, the fallopian tubes and vagina. It also includes the cervix, which is at the lower one third of the uterus and the part that connects to the vagina.

Chancroid:

–Cause: Chancroid is caused by a pleomorphic gram-negative rod called Haemophilus ducreyi.

–Symptoms: this ulcerative disease usually beings as a soft apule, or bump, at the point of contact and develops into a “soft chancre” (in contrast to the hard symphilis chancre), which is very painful in men but may be unnoticed in women. Inguinal lymph nodes can become very swollen and tender.

–Epidemiology: Chancroid is very common in the tropics and subtropics and is becoming more common in the U.S.

–Transmission: Chancroid is transmitted exclusively through direct contact, especially sexually. The disease is associated with sex workers and poor hygiene. Uncircumcised men seem to be more commonly infected than those who have been circumcised. People may carry this bacgerium asymptomatically.

Chlamydai: is the most common reportable infectious diasese in the U.S. Annually, more than 1 million cases are reported, but the actual infection rate may be 5-7 times more. Chlamydia trachomatis affects mostly young women, but it can occur in both men and women and in all age groups. It’s not difficult to treat, but if left untreated it can lead to more-serious health problems.  See Mayo Clinic

The sequences of bothChlamydia trachomatisandChlamydiapneumoniaehave been determined with the hope that a comparison between the two genomes will significantly enhance the understanding of both pathogens. 

–signs and symptoms:

Chlamydia doesn’t usually cause any symptoms. So you may not realize that you have it. People with chlamydia who have no symptoms can still pass the disease to others. If you do have symptoms, they may not appear until several weeks after you have sex with an infected partner. See MedlinePlus

In males, the bacterium can cuase an inflmmation of the urethra. The symptoms mimic gonorrhea; discharge and painful urination. Females who experince symptoms have cervicitis, a discharge, and often sapingitis.

Certain strains of C. trachatis can invade the lymphatic tissues, resulting in alymphogramuloma venereum. The condition is accompannied by headache, fever, and muscle aches. The lymph nodes near the lesion begin to fill with granuloma cells and become enlarged and tender. These “nodes” can cause long term lymphatic obstruction that leads to chronic, deforming edema of the genitalia or anus. The disease is endemic to South America, Afica and Asia, but occasionally occurs in other parts of the wrold.

Babis born to mothers with chlamydia can develop eye infections and also pneumonia if they become infected.

–causative agent: C. trachamatis is a very small gram negative bacterium. It lives inside host cells as an ogligate intracellular parasite.

–transmission: The microbe shows an astoundingly borad distribution within the population and incidence is rising. Adolescent women are more likely than older women to harbor the bacterium because it prefers to infect cells that are prevalent on the adoslescent cervix. It is transmitted sexually.

–Immune Response: The first and most important immune response to Chlamydia infection is a local one, whereby immune cells such as leukocytes are recruited to the site of infections, and subsequently secrete pro-inflammatory cytokines and chemokines such as interferon gamma. Immune cells also work to initiate and potentiate chronic inflammation through the production of reactive oxygen species (ROS), and the release of molecules with degradative properties including defensins, elastase, collagenase, cathespins, and lysozyme. This long-term inflammation can lead to cell proliferation (a possible precursor to cancer), tissue remodeling, and scarring, as well as being linked to the onset of autoimmune responses in genetically disposed individuals. See RedGrove

–Detection: is with PCR or ELISA.

–Prevention: avoiding contact with infected tissues and secretions or barrier protection is the only means of prevention.

–Treatment: Chlamydia is treated with antibiotics. The recommended antibiotic treatment is doxycycline taken twice a day for seven days or azrithromycin taken in one single dose. Other alternative medications may be used but are not as effective as azrithromycin and doxycycline. Persons being treated for chlamydia should not have sexual intercourse for seven days after single dose therapy (azrithromycin) or until completion of all seven days of antibiotics (doxycycline). Patients can be re-infected if their sex partners are not treated. See NY State Dept Health

Gonorrhea: has been known as an STD since ancient times.

–signs and symptoms: In the male, infection of the urethra elicity urethritis, painful urination, and a yellowish discharge, although a relatively large number of ases are symptomatic. In ost cases, infection is limited to the distal uronetical tract, but it can occasionally spread from teh urethra to the prostate gland and epididymis.  See WebMD.

In the female, it is likely that both the urinary and genital tracts will be infected during sexual intercourse. A mucopurlent (containing mucos and pus) or bloody vaginal discharge occurs in a minortiy of the cases, along with painful urination if the urethra is affected.

–Causative agent: N. gonorrhaeae is a pyogenic (pus forming) gram-negative diplococcus. It apepars as paris of kidney bean shaped bacterial, with their flat sides touching.

Transmission: gonorrhea is a strictly human infection that ranks among the most common STDs.

–Diagnosis: Specific microbiologic diagnosis of N. gonorrhoeae infection should be performed for all persons at risk for or suspected of having gonorrhea; a specific diagnosis can potentially reduce complications, reinfections, and transmission. Culture, NAAT, and POC NAAT, such as GeneXpert (Cepheid), are available for detecting genitourinary infection with N. gonorrhoeae; culture requires endocervical (women) or urethral (men) swab specimens. Culture is also available for detecting rectal, oropharyngeal, and conjunctival gonococcal infection. NAATs and POC NAATs allow for the widest variety of FDA-cleared specimen types, including endocervical and vaginal swabs and urine for women, urethral swabs and urine for men, and rectal swabs and pharyngeal swabs for men and women. See CDC

–Prevention/screening: no vaccine is available. Using condoms is an effective way to avoid transmission.

Annual screening for N. gonorrhoeae infection is recommended for all sexually active women aged <25 years and for older women at increased risk for infection (e.g., those aged ≥25 years who have a new sex partner, more than one sex partner, a sex partner with concurrent partners, or a sex partner who has an STI) (149). Additional risk factors for gonorrhea include inconsistent condom use among persons who are not in mutually monogamous relationships, previous or coexisting STIs, and exchanging sex for money or drugs. Clinicians should consider the communities they serve and consult local public health authorities for guidance regarding identifying groups at increased risk. Gonococcal infection, in particular, is concentrated in specific geographic locations and communities. MSM at high risk for gonococcal infection (e.g., those with multiple anonymous partners or substance abuse) or those at risk for HIV acquisition should be screened at all anatomic sites of exposure every 3–6 months (see Men Who Have Sex with Men). At least annual screening is recommended for all MSM. Screening for gonorrhea among heterosexual men and women aged >25 years who are at low risk for infection is not recommended (149). A recent travel history with sexual contacts outside the United States should be part of any gonorrhea evaluation. See CDC

—-NGoXIM is a prophylactic vaccine against gonorrhea which has gained funding from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH). NGoXIM candidates uses Intravacc’s outer-membrane vesicle (OMV) platform technology and Therapyx GneX12 sustained-release microspheres to deliver recombinant human IL-12 intranassaly. OMVs are speherical buddings that are rleased spontaneously on the oter membrane of many Gram-negative bacteria during growth. Such vesicles present surface antigens in a native conformation and have natural properites such as immunogenicity, self-adjuvation and uptake by immune cells. Those features make OMVs a good basis for vaccines against pathoglenic bacteria. The OMVs for the gonorrhea vaccine are dervied form genetically modified Neisseria gonorrhaeae. An intranasal vaccine also causes an immune response in other mucosal tissues such as the genital tract, thus hleping to endure induction of an immune resonse at the site of potential infection as with gonorrhea.

–Symptoms: Urethral infections caused by N. gonorrhoeae can produce symptoms among men that cause them to seek curative treatment soon enough to prevent sequelae, but often not soon enough to prevent transmission to others. Among women, gonococcal infections are commonly asymptomatic or might not produce recognizable symptoms until complications (e.g., PID) have occurred. PID can result in tubal scarring that can lead to infertility or ectopic pregnancy. See CDC

–Treatment: treatemnt includes treating chlamydia also since N. gonorrhaeae is freqeuntly coinfected with Chlamydia. CDC recommends a single dose of 500 mg of intramuscular ceftriaxone. Alternative regimens are available when ceftriaxone cannot be used to treat urogenital or rectal gonorrhea. Although medication will stop the infection, it will not repair any permanent damage done by the disease. The CDC has this bacterium in its Urgent Trheat category for antibiotic resistance.  See CDC

Syphilis: 

–cause: Treonema pallidum which is a spirochete, regularly coiled cell with a gram-negative cell wall. See CDC

–Symptoms: Untreated symphilis is marked by distinct clinical stages designated as primary, secondary and tertiary symphilis. The disease also has latent periods of varying duration during which it is quiescent. The primary stage is marked by the appearance of a hard chancre at the site of entry of the pathogen. Because these culcers tend to be pianless, they may escape notice, especially when they are on internal surfaces. The chancre heals spontaneously without scarring in 3-6 weeks. About 3-6 weeks after the chancre heals, the secondary stage appears. By then, many systems of the body ahve been invaded and simptoms include fever, ehadache and sore throat, followed by lymphadenopathy and peculiar red or brown rash that breaks out on all skin surfaces including the palms of the hands and soles of the feet. A person’s hair often falls out. Like the chancre, the lesions contain viable spirochetes and disappear spontaneously in a few weeks. The major complications at this stage occur in the bones, hair follicles, joints, liver, yes and brain.  See Web MD

–Transmission: Human appear to be the sole natural hosts and source of T. pallidum. The bacterium is extremely fastidious and sensitive and cannot survive for long oustide the host, being rapidly destroyed by heat, drying, disinfectants, soap, hogh oxygen tension and pH changes. It survives a few minutes to hours when protected by body secretions and about 36 hours in sotred blood. The risk of infection from an infected sexual partner is 12-20% per encounter.

–Prevention: People identified as being at risk fo syphilis are given immediate prophylactive penicilline in a single long acting dose. The barrier effect of a condom provides excellent proteciton during the primary phase. Protective immunity apparently does arise in humans, allowing the prospect of an effective immunization program in the future, although no vaccine exists currently.

–Treatment: Syphillis can have very serious consequences if left untreated. Current recommendations are for ciprofloxacin or levofloxacin. See Mayo Clinic.   See Drugs.com.  History of treatment

–Diagnosis: There is a rapid plasmin reagin (RPR) test which is coupled with an immunoassay specific for treponemal antigens.

Vaginosis: also known as BV or bacterial vaginosis

–cause: Bacteria Vaginosis (BV) is an infection that is associated with a group of pathogenic anaerobic microorganisms rather than a specific pathogen. It is a very common manifestation among the women population. Although the exact causative pathogen has not been figured out, it has been observed that there is a corresponding decrease in the population of the lactobacilli species. This results in the increase in the pH of the vaginal lumen due to the reduction in the lactic acid production. Apart from the lactic acid, the production of lactocin and H2O2 also receives a setback. In general, the lactobacilli is replaced with the increased population of pathogenic gram-negative anaerobic bacteria such as E. coli, Gardnerella vaginalis, Mycoplasma hominis, and Mycoplasma curtisii.bacterium Garderella. Vaginosis is most likely a result of a shift from a predominance of good bacteria (lactobacilli) to the vagina to a predominance of bad bacteria such as Gardnerrela vaginalis. The genus of bacteria is a facultative anaerobe and gram-positive, although in a Gram stain it usually appears gram-negative. Some texts refer to it as gram-variable fo this reason. Probably a mixed infections leads to the condition. See Kumar

–symptoms, pathogenesis: vaginal discharge which often ahs a fishy order. Itching is also common. Many women have no noticeable symptoms. Vaginosis can lead to complications such as pelvic inflmmatory disease, infertility and more rarely ectopic pregnancies.

–transmission and epidemiology: 30% of women between 15-44 in the US are estimated to have bacterial vaginosis. Rates are greater in non-whte women.

–Treatment: A lot of antimicrobial agents (e.g., ampicillin, penicillin, and metronidazole) have been used in the treatment of bacterial vaginitis. Metronidazole have evolved as a drug of choice for the treatment of BV and is the widely prescribed drug. It is a nitroimidazole derivative having activity against anaerobic microbes and protozoans. It has been administered either orally or locally. Tablets of metronidazole are easily available for oral administration. Formulations for the local administration of the drug include gels and suppositories. See Kumar

Affecting the Gastrointestinal Tract

Acute Diarrhea: In the U.S., up to a third of all acute diarrhea is transmitted by contaminated food. The most common agents are Salmonella, norovirus, Campylobacter, E. coli STEC strains and Clostridium perfingens. The bacterial agents are described here. Although most diarrhea epidoses are self-limited, other such as E. coli 0157:H7 can have serious effects. In most diarrheal illneses, antimicrobial treatment is contraindicted but some such as Dhigellosis call for quick treatment with antibiotics. Thus it is important to know which agents are causing diarrhea.

–E coli: is a Gram-negative, rod-shaped bacterium that is commonly found in the lower intestine. Most E. oli strains are harmless, but some serotpyes can casue serious food poisoning in humans. The harmless strains are part of the normal floa of the gut, and can benefit their hosts by producing vitamin K2, and by preventing the establishment of pathogenic bacteria within the intestine. Certain strains such as O157:H7 produce potentially lethal toxins. Food poisoning casued by e. coli can result from eating unwashed vegetables or undercooked meat.

In sub-Saharan Africa, with deteriorating environments attributed to high levels of open defecation, drinking water sources remain vulnerable to faecal contamination. See Gwimbi

–Norovirus:

Norovirus is the leading cause of acute gastroenteritis in the United States. In 2012, CDC established the Norovirus Sentinel Testing and Tracking Network (NoroSTAT) to improve timeliness and completeness of surveillance for norovirus outbreaks that occur in the United States. NoroSTAT is a collaboration between CDC and 12 state health departments. See CDC

Noroviruses are divided into 10 genogroups; viruses in genogroups GI, GII, GIV, GVIII, and GIX cause illness in humans. Norovirus GIX was first identified in fecal samples collected in 1990 from US troops deployed to Saudi Arabia. On March 31, 2021, the Utah County Health Department and Utah Department of Health were notified of an outbreak of gastrointestinal illness at LTCF A. The outbreak was believed to have originated from 2 residents on March 28 and 29. One resident vomited in a well-trafficked, carpeted hallway, which likely contaminated the environment. By mid-April, 4 other LTCFs (B–E) within 20 miles of facility A reported similar outbreaks. Nucleic acids were extracted from fecal specimens using the NucliSENS easyMAG instrument (bioMérieux), and genotyped norovirus-positive samples by using conventional reverse transcription PCR. Purified PCR products were submitted to Sequetech for Sanger sequencing and genotyped by using the human calicivirus typing tool. Norovirus-positive samples were analyzed by performing next-generation sequencing (NGS) of complete genomes using the Illumina MiSeq platform and a GIX-specific forward oligonucleotide primer (5′-ATGGCGTCGARTGACGTCGYTACTGCCYTTGGC-3′). Sequences were analyzed by using the Viral NGS Analysis Pipeline and Data Management tool. norovirus phylogenetic trees for complete RNA-dependent RNA polymerase (RdRp) (1,430 nt) and major capsid (1,668 nt) genes by using MEGA11 software. See Osborn, CDC

–Salmonella: The genus Slmonella causes a variety of illnesses in the GI tract CDC estimates that Salmonella casues about 1.4 million infections a year in the U.S. It has a high infectious dose meaning a lot of organisms ahve to be ingested in order for disease to result. Animal products such as meat and milk can be readily contaminted with Salmonella during slaughter, collection and processing. Salmonella bacteria are normal intestinal biota in cattle, pultry, rodents and reptiles nad each has been a documented source of infeciton and disease in humans. The only prevention for salmonellosis is avoding contact wiht the bacterium. Uncomplicated cases of Salmonellosis are treated with fluid and electrolyte replacment. If a patient is immunocompromised or the disease is severe, trimethoprim-sulfamethoxazole is recommneded.

–Shigella: Shigella bacteria are gram-negative rods, nonmotile and non-endospore-forming. They do not product urease or hydrogen sulfide, which aids in their identification. The symptoms of shigellosis include frequent, watery stools, fever and often intense abdominal pain. Nausea and vomiting are common. Stools often contain blood (diarrhea containing blood is also called dysentery). Transmission can be by direct person to person contact because only a small ID is required, in addition to the usual oral route. Prevention as with most diarrheal diseases is good hygiene. Unlike toher acute diarrhea, all cases of shigellosis should be treated with antibiotics: trimethoprim/sulfamethoxazole if it is sensitive to it, and ciprofloxacin in resistant cases of shigellosis.

–Shiga-Toxin-Producing E. coli (STEC): Dozens of different strains of E. coli exist, most of which cause no disease at all. A handful cause various degrees of intestinal symptoms. Some also cause urinary tract infections. E. coli 0157:H7 caused an outbreak originating in a chain of Jack-in-the-Box restaurants in the Pacific Northwest. Shiga toxin producing E. coli is the agent of a spectrum of conditions, ranging form mild gastroenteritis with fever to blood diarrhea. A minority of patients will develop hemolytic uremic symdrom (HUS) which is a several hemolytic anemai that can cause kidney damage and failure. Neurological symptoms such as blindness, seizure, and strok are also possible. Siga toxin interrups protein synthesis in its target cells and appears responsbile for the systemic effects of this infection. The most common mode of transmission is the ingestion of contaminated and undercooked beef, alhtough other foods and beverages can be contaminated. In 2015, the Chipotle chain of restaurants was the source of two distinct E. coli O26 outbreaks in the u.S. In 2016, there was a multistate outbreak of two STEC strains, E. coli O12 and E. coli 026, which were traced to flour manufactured by General Mills. The CDC reminds consumers not to consume raw dough or even to taste batters before they are cooked. The best prevention is good food hygiene. Antiotics may be contraindicated as they may incdrease the pathology by releasing more toxin, leading to HUS. Supportive therapy, including plasma transfusion to dilute toxin in the bood is a good option.

–Campylobacter: is one of the most common bacterial causes of diarrhea in the U.S. The symptoms of campylobacteriosis are frequent watery stools, fever, vomiting, headaches and abdnominal pain. The symptoms may last longer than most acute diarrheal episodes, sometimes extending beyond 2 weeks. They may subside and then recure over a period of weeks. Campylobacter jeuni is the most common cause alhtough there are other pathogenic Campylobacter species. Campylobacters are slender, curved, or spiral gram-ngeative bacteria propelled by polar flagella at one or both pools, often appearing in S-shaped or gull-winged pairs. These bacterai tend to be microaerophilic inhabitants of the intestinal tract, genitourinary tract and oral caivity of humans and animals. Transmission is via the ingestion of contaminated beverages and food, expecially water, milk, meat and chicken. Once ingested, C. jejuni cells reach the mucosa at the last segment of the small intestine (ileum) near its junciton with the colon. They adhere, burrow through the mucus and multiply. Symptoms commence after an incubation period of 1-7 days. The mechansism of patholoy appears to involve a heat labil enterotoxin that stimulates a secretory diarrhea like that of cholera. In a small number of cases, infection can sead to Guillain Barre syndrome, a serious neuromuscular paralysis. GBS is the leading cause of acute paralysis in the U.S. since the eradication of polio. However, many patients recover completely form the paralysis. The disease appears to be an autoimmune reaciton that can be brought on by infection with viruses and bacteria and by vaccination in rare cases and even by surgery. The single most common precipitating event for the onset of GBS is Capylobacter infection.

–Clostridioides difficile: is formerly known as Clostridium difficile and often called C. difficile or C. diff. C. diff is a germ (bacterium) that causes severe diarrhea and colitis (an inflammation of the colon). Most cases of C. diff infection occur while you’re taking antibiotics or not long after you’ve finished taking antibiotics.C. diff can be life-threatening. See CDC

Rebyota is a rectally delivered product developed by Ferring Pharmaceuticals that secured FDA approval in 2022 for treating C. difficile. Another poduct Vowst is an orally devliered product devloped by Seres Therapeutics that securted FDA approval in 2023. Both products are derived form donor supplied materials. Whereas Rebyota is a fecal microbiota suspendsion, Vowst contains purified bacterial spores.

—-Etiology/Transmission/Prevention:

Clostridium difficile is a gram positive endospore forming rod found as noraml biota in the intestine. In most cases, the infeciton seems to be precipitated by therapy with broad spectrum antibiotics such as ampicillin, clindamycin or cephalosporins. although, C. difficile is relatively noninvasive, it is able to superinfect the large intestine when drugs have disrupted the normal biota. It produced two enterotoxins, toxins A nad B, that casue areas of necrosis in the wall of the intestine. More severe cases exhibit abdominal cramps, fever and leukocytosis. The colon is inflammed and gradually soughs off loose, membrane like patches. If the condition is not stopped performation of the cecum and death can result. C. diff releases endospores whcih contaminate the environment. Hospitalized patients must be put in isolation and constant attention to disinfection is required. If a patient is receiving clindamycin, ceftriaxone, or a fluoroquinolone for a different infection and displays C. diff symptoms, the frist step is to withdraw the offending antibiotic. In mild C. Diff infections, metronidazole should be administered. In severe cases, vancomycine is the drug of choice.

High rates of metronidazole resistance have been observed for C. difficile isolates carrying the 7-kb plasmid pCD-METRO, in particular for isolates belonging to PCR ribotype (RT) 010 and RT020 (clade 1) and the epidemic strain RT027 (clade 2). This plasmid has been reported in C. difficile isolates from countries in Europe. Since the discovery of pCD-METRO, we have implemented PCR that uses primers oBH-1 (5′-CCTCGTAGAATCCGGTGCAA-3′) and oBH-2 (5′-TATTTCCTTGCCGCTGAGGT-3′) for national sentinel surveillance and diagnostics of C. difficile infections in the Netherlands. The primers are specific for open reading frame (ORF) 6 of pCD-METRO. In conclusion, the plasmid pCD-METRO confers metronidazole resistance in Clostridioides difficile. We showed high sequence similarity among pCD-METRO plasmids from different isolates and identified pCD-METRO and associated metronidazole-resistant isolates in clinical and veterinary reservoirs in the Americas. We recommend using PCR or genomic assays to detect pCD-METRO in metronidazole-resistant C. difficile. See Kuijiper CDC

The incidences of C. difficile infection (CDI) in developed countries have become increasingly high which may be attributed to the emergence of newer epidemic strains, extensive use of antibiotics, and limited alternative therapies.  The uses of antibiotics usually modify the intestinal microbiome and permit propagation of C. difficile. It has been noticed that hospitalized patients are the prime target of CDI, although C. difficile also present as a colonizer in 2-3% of healthy individuals and 70% in healthy children. C. difficile produces heat-resistant spores that can persist in the environment for several months, thus providing the basis for nosocomial outbreaks even after extensive cleaning measures. The diagnosis of C. difficile colitis should be suspected in any patient with diarrhea, who has been under antibiotics treatment over the previous 3 months or has been recently hospitalized. Having a confirmed CDI, it is crucial that proper infection control measures are in place to avoid further spread of the infection within the same ward or hospital. To avoid spreading of Clostridium spores, hands need to be washed, patients should kept in isolation, and importantly, gloves and protective clothing must be worn by all staff along with continuous hand hygiene after each patient contact. See Arijallila

—–Diagnosis:

Example: Sequence librarires for C. difficile were generated using Twist Library Preparation EF 2.0 kit and Twist UDI Primer (Twist Bioscience). Geneomic DNA was extracted by using the chemagic 360 extraction instrument and chemagic DNA Tissue Kit (boht PerkinElmer). Quantity of DNA in the libraries was assessed using Qubit 3.0 and Qubit dsDNA HS Assay kit (ThermoFisher Scientific) and assesed quality by using the 4200 TapeStation and DNA1000ScrenTap (Agilent). The quantified final library products were quantified for cluster eneration and performed next generation sequencing on an Illumina NovaSeq 6000 sequencer system (Illumina) in 300 bp paired end format according to the Illumina paired-end sequencing protocol. De novo assembly of sequences was performed by using Unicycler version 0.48 and analyzed core genomic multilocus sequence typing using EnteroBase. Statitistical analysis was performed and graphs created by suing both SPSS Statistics 26.0 (IBM Corp) and R verion 4.2.2 (the R Project for Statistical Computting) with a significance level set at 0.05. (Kim, “Identifying contact time required for secondary transmission of Clostridioides difficile Infections by using real-time locating system” Emerging Infectious Diseases, 30(5), 2024).

—-Treatment:

A procedure some might consider unconventional has proven to be an effective treatment for a serious and chronic type of bowel disorder. Fecal Microbiotal Transplantation, or FMT, calls for the transplantation of healthy fecal material into the colon of a person infected with Clostridium difficile, also called C. difficile or CDI. The procedure restores compromised stool and stops the recurrence of CDI. See Michigan medecine

–Vibriosis: The genus Vibrio consists of 103 species. Of these, only ten species have been implicated to cause gastrointestinal and extra-intestinal diseases in human beings. Vibrio species are generally inhabited in marine niches. In humans, Vibrio species has been isolated from stool, vomitus, blood, or wound infections and also from environmental niches such as seawater, sediments, plankton, shellfish (oysters, clams and crabs). Vibrio species which have great medical implications include: V. alginolyticus, V. carchariae, V. cholerae, V. cincinnatiensis, V. fluvialis, V. furnissii, V. metschnikovii, V. mimicus, V. parahaemolyticus, and V. vulnificus.

Vibriosis causes an estimated 80,000 illnesses and 100 deaths in the United States every year. People with vibriosis become infected by consuming raw or undercooked seafood or exposing a wound to seawater. Most infections occur from May through October when water temperatures are warmer.  See CDC

—-Vibrio cholerae: has been a devasting disease for centuries. These bacteria are rods with a single polar flagellum. They belong to the family Vibrionaceae. There are many serogroups of V. cholerae, but only two – O1 and O139 – cause outbreaks. V. cholerae O1 has caused all recent outbreaks. V. cholerae O139 – first identified in Bangladesh in 1992 – caused outbreaks in the past, but recently has only been identified in sporadic cases. It has never been identified outside Asia. There is no difference in the illness caused by the two serogroups. SEE WHO

After an inucubation period of a few hours to a few days, symptoms begin abruptly with vomiting, followed by copious watery feces. If cholera is left untreated death can occur in less than 48 hours and the mortality rate is between 55-70%. V. cholerae has a relatively high infections dose (106 cells). The bacteria survive in water sources for long peridos of time. Prevention is contingent on proper sewage treatment and water purificaiton. Vaccines are available for traverls and people living in endemic regions. For adults traveling from the United States to areas affected by cholera, a vaccine called Vaxchora is available in the United States. It is a liquid dose taken by mouth at least 10 days before travel. See Mayo Clinic

The key to treatment is prompt replacement of water and electrolytes. Oral rehydration therapy is very simply and astonishingly effective. This simple treatment consists of a mixture of the electroytes sodium chloride, sodium bicarbonate, potassium chloride and glucose or sucrose dissolved in water. When admisntiered early in amounts ranging from 100-400 milliliters per hour, the solution can restore patients in 4 hours.

—-Vibrio mimicus: named because of its close metabolic and genetic similarity to V. cholerae, is recognized globally as a cause of foodborne and waterborne diarrheal disease. In June 2019, the Florida Department of Health in Alachua County (DOH-Alachua; Gainesville, FL, USA) received reports of multiple cases of diarrheal illnesses associated with eating at a local seafood restaurant. Six case-patients were subsequently identified who met the case definition of having eaten seafood at the implicated restaurant within a 2-day time window and who experienced acute onset of diarrhea within 96 hours of the reported meal or had a clinical diagnosis of vibriosis. DOH-Alachua determined that the foods most commonly consumed by case-patients were steamed blue crab (5 case-patients), steamed snow crab (5 case-patients), and steamed shrimp (4 case-patients). Only 1 case-patient reported eating oysters. A joint environmental health assessment by DOH-Alachua, the Florida DOH regional environmental epidemiologist, and the Florida Department of Business and Professional Regulation documented multiple food safety violations (i.e., substantive overall sanitation issues, thawing frozen shrimp overnight at room temperature, returning cooked crabs to crates that previously held live crabs), and a lack of required state-approved employee education. Fecal samples from the patients hospitalized at UFHealth were initially screened by using a culture-independent diagnostic PCR technique (BioFire FilmArray GI Panel; BioFire Diagnostics. See CDC

Food Poisoning; should be expected if a patient presents with severe nausea and fequent vomiting accompanied by diarrhea and reprots that companions with whom she shared a recent meal (within the last 1-6 hours) are suffering the same fate. Food poisoning refers to symptoms in the gut that are caused by a preformed toxin of some sort. In many cases, the toxin comes from Staphylococcus aureus. In others, the source of the toxin is Bacillus cereus or Clostridium perfringens.

Chronic Diarrhea: is definted as lasting longer than 14 days. It can have infectious causes or can reflect noninfectious conditions. A person’s HIV status should be considered if she presetns with chronic diarrhea. One type of E. coli, enteroaggregative E. coli is particularly assocaited with chronic disease, especially in children.

Tooth Decay: Dental caries involve the dissolution of solid tooth surface due to the metabolic action of acteria. In the presence of sucrose and to a lesser extent, other carbohydrates, S. mutans and other streptococci produce sticky polymers of glucose called fructans and glucans. These adhesives help bind them to the smooth enamel surfaces and contribute to teh sticky bulk of the plaque biofilm. If mature plaque is not removed form sites that readily trap food, it can result in a carious lesion. This is due to the action of the streptococci and other bacteria that produce acid as they ferment the carbohydrates. If the acid is immediately flushed form the plaque and diluted in the mouth, it has little effect. however, if the denser regions of plaque, the acid can accumulate in direct contact with the enamel surface and low the pH to blow 5, which is acidic enough to begin to dissolve the calcium phosphate of the enamel in the spot. This intial lesion can remain localized in the enamel and can be repaired with various inert materials (fillings). Once the deterioration has reached the level of the dentin, tooth dstruction speeds up and the tooth can be rapdily destroyed. The best way to prevent dental caries is thorugh dietary restriction of sucrose and other refined carbohydrates. Regular brushing and flossing to remove plaque are also important. Most municpal communities in the U.S. add trace amounts of fluoride to drinking water because fluoride when incorporated into the tooth structure, can increase tooth hardness. The CDC estimates that the rate of tooth decay is decdreased by 25% by the addition of fluoride to drinking water.

Periodontal diseases: is so common that 97-100% of the population ahs some manifestation by age 45. Most kinds are due to bacterial colonization and varying degress of inflammation that occur in response to gingival damage. The initial stage of periodontal disease is gingivitis, the signs of which are swelling, loss of normal contour, patches of redness and increased bleeding of the gums (gingiva). Spaces or pockets of varying depth also devlop between the tooth and the gingiva. If this condition persists, a more serious diasese called periodontitis results. The deeper invovlement increases the size of the pockets and can cause bone resorption severe enough to loosen the tooth in its socket. Data fromt eh Human Microbiome Proejct revel that the composition of the microbial community, rather than single organisms is the casue of dental caries or periodontitis. Most periodontal disease is treated by removal of calculus and plaque and maintenance of good oral hygine. Often, surgery to reduce the depth of periodontal pickets is required. Antibiotic therpay, either systemic or applied in periodontal packings, may also be utilized.

Gastritis and Gastric Ulcers: Gastritis is experience as sharp or buring pain emanating from the abdomen. Gastric or peptic ulcers are actual lesions in the mucosa of the stomach (gastric ulcers) or in the uppermost porition of the small intestine (duodenal ulcers). Severe ulcers can be accompanied by bloody stools, vomoting or both. The symptoms are often worse at night, after eating, or under conditions of psychological stress. The curved cells of Helicobacter were first detected by J. Robin Warren in 1979 in stomach biopsies from ulcer palteints. The fifth most common cancer in the world is stomach cancer and ample evidence suggest that long term infection with Helicobacter pylori is a major contributing factor. Helicobacter pylori is a curved fram-ngegative rode. H. pylori si probably transmitted form person to person by the oral-oral or fecal-oral rotue. It seems to be acquired ealry in life and carried asymptomatically unless its activities because to damage the digestive mucosa. This bacterium has also been found in water sources suggesting that perhpas proper sanitation may reduce transmission. The best treatment is a course of antibiotic augmented by acid suppressors. The antibiotics most prescirbed are clarithromycin or metronidazole.

Affecting the Nervous System

Botulism: is casued by clostridium botulinum, which like Clostridium tetani below, is an endospore-forming anaerobe that does its damage through the relaese of an exotoxin. C. botulinum commonly inhabits soil and water and occasionally the intestinal tract of animals. It is distributed world wide, most often in the Northern Hemisphere. The CDC maintains a supply of antitoxin, which, when adminsitered soon after diagnosis, can preent the worst outcomes of the disease.

Foodborne botulism outbreaks occur in home processed foods, including anned vegetables, msoked meats adn cheese spreads. Endospores can be present on teh vegetables or meat at the time of gathering and are difficult to remove completely. When contaminated food is put in jars an steamed in a pressure cooker that does not reach reliable pressure and temperature, some endospores survive.

Botulinum neurotoxins, causative agents of botulism in humans, are produced by Clostridium botulinum, an anaerobic spore-former Gram-positive bacillus. Botulinum neurotoxin poses a major bioweapon threat because of its extreme potency and lethality; its ease of production, transport, and misuse; and the need for prolonged intensive care among affected persons. See Dutta

Meningitis: is an inflammation of the meninges. Many different microorganisms can casue an infection of the meninges, adn they produce a similar set of symptoms. The more serious forms of acute meningitis are casued by bacteria, but it is thought that their entrance to the CNS is often facilitated by coinfection or previous infection with respiratory viruses. Whenever meningitis is uspected lumba puncture (spinal tap) is perforemd to botain CSF, which is then examined by Gram stain and/or culture. Most physicians will begin treatment with a broad-spectrum antibiotic immediately and shift treatment if necessary after a diagnosis has been confirmed.

–Meningococcal disease is caused by bacteria called Neisseria meningitidis. People with meningococcal disease spread the bacteria to others through close personal contact such as living together or kissing. A person with meningococcal disease needs immediate medical attention. Neisseria meningitidis appears as gram-negative diplococci (round cells occurring in joined pairs) and is commonly known as the meningococcus. This organisms causes the most serious form of acute meningitis and accounts for 15-20% of all meningitis cases. Most cases occur in young children because vaccination of otherwise healthy children against the disease is not recommended until age 11. Although 12 different strains with different capsular antigens exist, serotypes B, C and Y are responsible for most cases in the U.S. In Afica other serotypes are prominent. The bacteria enters the body via the upper respiratory trace, moves into the blood, rapidly penetrates the menignes and produces symptoms of meningitis. The disease has a sudden onset, marked by fever higher than 40C or 104F, sore throat, chills, delirium, severe widespread areas of bleeding under the skin, shock and coma. Because meningococci do not survive long in the environment, these bacteria are usually aquired through close contact (e.g., living in close quarters such as college dormitories and military barracks) with secretions or droplets. Meningococcal meningitis has a sporadic or epidemic incidence in the late winter or early spring. The continuing reservoir of infection is humans who harbor the pathogen in the nasopharynx.

The highest risk groups are young children (6-36 months old) and older children and young adults (10-20 years old). Cases peak in January and Febraury in the U.S. Suspicion of bacterial meningitis constitutes a medical emergency and differential diagnosis must be done with great haste and accuracy. It is improtant to confirm (or rule out) meningococcal meningitis becasue it can be rapidly fatal. Treatment is usually started until it can be ruled out. Crerebrospinal fluid, blood or nasopharyngeal samples are stained and observed directly for the typical gram-negative diplococci. Cultivation is the preferred method of diagnosis because it also enable a quick assessment of antimicrobial resistance. Specimens are streaked on modified thayer-martin medium (MTM) or chocolate agar and incubated in a high CO2 atmosphere. Presumptive identification of the genus is obtaind by Gram stain and oxidase testing on isoalted colonies. Specific rapid tests are also avaialble for detecting the capsular polysaccharide or the cells directly from specimens without culturing. When family members, medical personnel or children in day care or school have come in close contact with infected people, they should recive a vaccination. Preventive therapy with rifampin or tetracyline may also be warranted.

In the US immunization begins at the age of 11, followed by a booster dose. Vaccines are also available for younger children and for adults over the age of 55 who are high risk for infection. Routine immunizaiton is with one of two meningococcal vaccines that protect against serotypes A, C, W and Y. At about the time a booster is need (16 years) the CDC recommends additionally the first dose of the new vaccine effective against seroptye B.  See CDC. Two meningococcal serogroup B vaccines are icensed for use in the US. MenB-4C (Bexsero GSK), one of two licensed meningococcal serogroup B vaccines, protects agasint serogroup B N. meningitidis and is licensed for persons aged 10-25 years. On October 24, 2024, the Advisory Committee on Immunization Practices (ACIP) voted to update its recommendations for teh MenB-4C dosing interval and schedule ot align with the new FDA label. ACIP recommends extending the itnerval for the 2 dose series of MenB-4C from 0 up to 1 month to 1 and 6 months for healthy adolescents and young adults aged 16-23 years based on shared clinical decision making and has added a recommendation for a 3 dose series with doeses administered at 1, 1-2 and 6 months for person age 10 or more at increased risk. Two manufactuers provide three MenB vaccine products that are licensed and available for use in the US. MenB vaccines from different manufctuers are not interchangeable; all doses in a series, as well as booster doses, should be form the same manufacturer.

–Steptococcus pneumoniae (pneumococcus): causes the majority of bacterial pneumonias. However, meningitis is also casued by this bacterium. It is the most frequent cause of community acquired menidngitis and is also very severe. It does not cause the petechiae (pinpoint round spots that appear on the skin due to bleeding) as with meningococcal meningitis and that difference is sueful diagnostically. As many as 25% of pneumococcal meningitis patients will also have pneumococcal pneumonia. Pneumococcal meningitis is most likley to occur in patients with underlying susceptibility, such as alcoholic patients and patients with sick-cell disease or those with defective spleen function. This bacterium is also a respiratory disease (see below). The bacterium is a small gram-positive flattened cocus that appears in end-to-end pairs. It has a distinctive appearance in a Gram stain of cerebrospinal fluid. Stianing or culturing the nasopharynx is not useful becasue it is often normal biota there. Many strains are resitant to the first line antibiotic, penicillin. In pneumococcal meningitis initial treatment with vancomycin and ceftriazone is recommended. If the isolate comes back as penicillin sensitive (the crebrospinal fluid must be cultured before beginning antibotic treamtent), then treatment can be switched.

Two vaccine are available for S. pneumoniae: a thirteen-valent conjugated vaccine (Prevnar) which is recommended as part of the hcildhoold immunizaiton schedule, and a 23-valent polysaccharide vaccine (Pneumovax 23), which is available for adults. Current recommendations fo runvaccinated adults call for initial vaccination with Prevnar, follwed by Pneumovax 6-12 months latter.

–Haemophilus influenzae: the meningitis casued by this bacterium is severe. Before the vaccine was introduced in 1988, it was a very common casue of severe meningitis and death. In the course of the alst 13 years, meningitis casued by this bacterium is much less common in the U.S., a situation that can always change if a lower percentage of people get the vaccine and herd immunity is compromised. Cases that occur in the U.S. are now mostly casued by nosertopye B strains. Globally, it is still common, and is an improtant casue of the disease in children under the age of 5.

–Listeria monocytogenes: is a gram positive bacterium that ranges in morphology from coccobacilli to long filaments in palisades formation. Listeria is not fasitdious and is resistant to cold, heat, salt, pH extremes and bile. It grows inside host cells and can move directly from an infected host cell to an adjacent healthy cell. Listeriosis in healthy adults is often a mild or subclinical infection with nonspecific symptoms of feverl, diarrhea, and sore throat. However, in elderly or immuncomplromised patients, fetuses adn neonates, it usually affects the brain and menignes and results in speticemia. Some strains target the heart. The deat rate is about 20%. The primary reservoir is apaprently soil and water and animals, plants and food are secondary sources of infection. Most cases of listeriosis are associated with ingesting contaminated dairy products, pultry, and meat. The pathogen ahs been isoalted in 10-15 of ground beef and in 25-30% of chicken and turkey carcasesses and is also present in 5-10% of luncheon meats, hot dogs and cheeses.

–Tetanus: is a nueromuscular disease whose alternate name, lockjaw, refers to an early effect of the disease on the jaw muslce. C. tetani releases a pwoerful exotoxin that is a nuerotoxin, tetanospasmin, that binds to target sites on periopheral motor nuerons, spinal cord and brain, and in the sympathetic nervous system. The toxin acts by blocking the inhibition of muscle contraction. Without inhibition of contraction, the muscles contract uncontrollably, resulting in spastic paralysis. The first symtpoms are clenching of the jaw, followed in succession by extreme arching of the back, flexion of the arms, and extension of the legs. A pateint with a clinical appearance suggestive of tetanus should immediately receive antitoxin therapy with human tetanus immune gloublin (TIG) adn Pnicillin G.

The etiologic agent, Clostridium tetrani, is a gram-positve, spore-forming rod.

The recommended vaccination series for 1-3 month old babies conssits of three injections of DTap (diphtheria, tetanus, and acellular pertussin) given 2 months apart, followed by booster doses aobut 1-4 years later. Alternativley, they may be vaccinated with a vaccine called “DT” which protects only agaisnt diptheria and tetanus. Chidlren thus immunized probably have protection for 10 eyrs. At that point and every 10 years thereafter, they should recive a dose of TD, tetanus-diptheria vaccine.

Affecting the Respiratory System

Acinetobacter: is a group of bacteria (germs) commonly found in the environment, like in soil and water. While there are many types, the most common cause of infections is Acinetobacter baumannii, which accounts for most Acinetobacter infections in humans. Acinetobacter infections typically occur in people in healthcare settings.Acinetobacter can live for long periods of time on environmental surfaces and shared equipment if they are not properly cleaned. The germs can spread from one person to another through contact with these contaminated surfaces or equipment or though person to person spread, often via contaminated hands. Acinetobacter infections are generally treated with antibiotics. To identify the best antibiotic to treat a specific infection, healthcare providers will send a specimen (often called a culture) to the laboratory and test any bacteria that grow against a set of antibiotics to determine which are active against the germ. The provider will then select an antibiotic based on the activity of the antibiotic and other factors, like potential side effects or interactions with other drugs. See CDC

–Acinetobacter baumannii can cause infections in the blood, urinary tract, and lungs (pneumonia), or in wounds in other parts of the body. It can also “colonize” or live in a patient without causing infections or symptoms, especially in respiratory secretions (sputum) or open wounds.  Acinetobacter baumannii is a bacterium that can cause a range of diseases. It typically infects people inside a healthcare facility — doctors refer to these as “nosocomial” infections. There are many different species of Acinetobacter that can cause disease, but A. baumannii accounts for about 80 percent of reported Acinetobacter infections in the United States, according to the Centers for Disease Control and Prevention (CDC).

Symptoms of A. baumannii infections are often clinically indistinguishable from those of infections caused by other opportunistic bacteria, such as Klebsiella pneumoniae and Streptococcus pneumoniae. Bloodstream infections often initially cause symptoms like fever and chills, rash, and confusion or other altered mental states, and are often associated with an elevated lactic acid level that’s found with severe sepsis. UTIs typically cause various urinary symptoms, including pain or burning sensations while urinating, foul smelling urine that may be cloudy or bloody, and a strong urge to urinate frequently. Meningitis may cause a number of flu-like symptoms ncluding fever, headache, confusion, sensitivity to bright light, and nausea (with or without vomiting). The CDC considers Acinetobacter, including A. baumannii, a serious public health threat because it’s often resistant to multiple antibiotics. 63 percent of Acinetobacter strains are multi-drug resistant, the CDC notes. Before the 1970s, A. baumannii infections could be treated with a range of different antibiotics, such as aminoglycosides, β-lactams, and tetracyclines, according to a report in the journal Clinical Microbiology Reviews. Today, however, some strains of A. baumannii are resistant to most antibiotics, including first-line antibiotics and carbapenems, which are often used only as a last resort. Treating an A. baumannii infection generally requires drug susceptibility tests, which check for antibiotics that are still effective against the particular strain of bacteria. In some cases, sulbactam and polymyxin antimicrobial drugs still work against A. baumannii when other antibiotics fail. See Everyday Health

AB is remarkable in that it is ubiquitous, exists in diverse habitats (e.g., human skin), can survive for long periods of time on dry inanimate surfaces (e.g., hospital bed rails) and as already mentioned can acquire antimicrobial resistance extremely rapidly. These factors combined, especially the latter two, greatly facilitate MDR-AB outbreaks in the ICU, in physical therapy wound clinics and even multi-facility outbreaks. See Buckle

Bordetella pertussis causes whooping cough (pertussis), an acute respiratory infection marked by severe, spasmodic coughing episodes during the paroxysmal phase. Leukocytosis with lymphocytosis is also common during this phase of the illness. Dangerous complications are bronchopneumonia and acute encephalopathy. Bordetella parapertussis can cause a milder form of pertussis. The bordetellae are small, Gram-negative, aerobic coccobacilli. Bordetella pertussis produces a number of virulence factors, including pertussis toxin, adenylate cyclase toxin, filamentous hemagglutinin, and hemolysin. Agglutinogens and other outer membrane proteins are important antigens. The genus Bordetella contains the species B pertussis and B parapertussis, which cause pertussis in humans. Other members of the genus are B bronchiseptica, causing respiratory disease in various animals and occasionally in humans, and B avium as well as B hinzii, which cause respiratory disease in poultry and are very rarely found in humans. See Medical Microbiology

Pertussis, a respiratory illness commonly known as whooping cough, is a very contagious disease caused by a type of bacteria called Bordetella pertussis. These bacteria attach to the cilia (tiny, hair-like extensions) that line part of the upper respiratory system. The bacteria release toxins (poisons), which damage the cilia and cause airways to swell. See CDC

Diphtheria is a highly contagious bacterial infection of the nose and throat. Thanks to routine immunization, diphtheria is a disease of the past in most parts of the world. There have only been five cases of the bacterial infection in the United States in the last 10 years. Diphtheria can infect the respiratory tract (parts of the body involved in breathing) and skin. In the respiratory tract, it causes a thick, gray coating to build up in the throat or nose. This coating can make it hard to breathe and swallow. Diphtheria skin infections can cause open sores or shallow ulcers. See CDC

Sinusitis: is one of the most common health complaints leading to a physician visit in the United States, as well as one of the leading causes of antibiotic prescriptions. In 1 year, there were up to 73 million restricted activity days in patients with sinusitis and total direct medical costs of almost $2.4 billion (not including surgery or radiographic imaging). In addition, up to 14.7% of people in one National Health Interview Survey had sinusitis the preceding year. Causes are a combination of environmental and host factors. Acute sinusitis is most commonly due to viruses and is usually self-limiting. Approximately 90% of patients with colds have an element of viral sinusitis. Those with atopy commonly get sinusitis. It can be caused by allergens, irritants, viruses, fungi, and bacteria. Popular irritants are animal dander, polluted air, smoke, and dust. No laboratory tests are indicated in the emergency department for acute uncomplicated sinusitis because the diagnosis is usually clinical. Humidification, nasal wash, decongestants (topical or systemic) such as pseudoephedrine. Remember that oxymetazoline cannot be used for more than 3 days due to rebound congestion and that oral decongestants should be used with caution in hypertensive patients.  Antihistamines have not been shown to be useful and can lead to impaired drainage. They are only of benefit in early allergic sinusitis.  Topical steroids are used to diminish nasal mucosal edema but are more efficacious in chronic and allergic sinusitis. Only start antibiotics if you strongly suspect bacterial disease. See Battistti

Stenotrophomonas maltophiliais an environmental global emerging Gram-negative MDRO that is most commonly associated with respiratory infections in humans. S. maltophiliais not a highly virulent pathogen, but it has emerged as an important nosocomial pathogen associated with crude mortality rates ranging from 14 to 69% in patients with bacteremia. see Brooke

Pneumonia (Pneumococcal disease): Pneumonia is a common infection of the lungs affecting millions of people worldwide. There are over 30 micro-organisms that cause pneumonia, including several types of bacteria, viruses, and fungi. Pneumonia is most often caused by the bacteria Streptococcus pneumonia, but infection can also be due to a number of viruses, fungi, and mycoplasmas. Pneumonia infection is classified based on how it is acquired and can be categorized into community-acquired, hospital-acquired, healthcare acquired, or aspiration pneumonia. Hospital-acquired pneumonia is a lung infection obtained during a hospital stay. This form of pneumonia can be serious because often times the patient, by nature of being in the hospital in the first place, is in an immune-weakened state due to illness or traumatic injury and thus is more susceptible to infection. The bacteria responsible for this type of pneumonia are often resistant to first-line antibiotics, further complicating treatment regimens. Ventilator tubes or other tubes that open a patient’s throat provide a direct point of access for airborne bacteria and viruses to enter the lungs.

“Pneumococcal disease” is a name for any infection caused by bacteria called Streptococcus pneumoniae or pneumococcus. Bacteria called Streptococcus pneumoniae, or pneumococcus, can cause many types of infections. Some of these infections like pneumonia below can be life threatening. See outline under “streptococcus pneumonaie”.

Community-acquired pneumonia (CAP) is the seventh leading cause of death in the United States, and the cost of these hospitalizations is estimated to cost up to $9 billion in the United States (US) dollars each year. Thirty-day hospital mortality associated with CAP has been estimated to be as high as 22% and is the leading cause of death amongst all infectious diseases.

–Streptococcus pneumoniae is the bacterium that has historically been the most common pathogen to cause CAP worldwide. In the era before antibiotics, S. pneumoniae was estimated to be the cause of 95% of all cases of pneumonia. Currently, however, S. pneumoniae accounts for up to 15% of pneumonia cases in the United States and 27% of cases worldwide today. Blood cultures are positive in only 20% to 25% of all pneumonia cases that are caused by S. pneumonia making it a challenging diagnosis for the clinician. See Dion

Although most commonly a commensal of the human respiratory tract, Streptococcus pneumoniae (the pneumococcus) remains a cause of infectious diseases, including otitis media, community-acquired pneumonia, sepsis, and meningitis. The organism’s thick layer of capsular polysaccharide (CPS) enhances its ability to colonize its host and is required for invasive infection. See Weiser

Tuberculosis (TB) is an infectious disease that usually attacks the lungs but can affect almost any part of the body. Though tuberculosis is spread from person to person through the air, it is not easy to become infected. TB can be fatal if it’s not treated, but taking medicine as directed can almost always cure TB. TB is caused by the bacterium M. tuberculosis. It spreads person to person when an infected individual coughs or sneezes out the bacteria, spreading it through the air to be breathed in by others. It takes prolonged exposure to become infected with TB, so you would typically get sick from a close family member or co-worker, not a casual acquaintance. Once you have inhaled the bacterium, the bacterium lodges in the lung tissue. Healthy individuals may contract latent TB, but the disease may not become active until months or years later, at a time when the immune system becomes weak for some reason. However, people with weakened immune systems are at a greater risk for developing active TB right away. When they breathe in the bacterium, it settles in their lungs and starts growing because their immune systems cannot fight the infection. In these instances, TB disease may develop within days or weeks after the infection. Your doctor will start by collecting a patient history to determine if you may have been exposed. During a physical exam, they will use a stethoscope to listen to your lungs and check the lymph nodes in your neck for swelling. If you have become infected with TB, but do not have the active TB disease you should get preventive therapy. This treatment kills germs that could cause problems if the disease becomes active. The most common preventive therapy is a daily dose of the antibiotic isoniazid (INH) taken as a single daily pill for six to nine months. You are not contagious if you have latent TB. If you have an active TB disease you will probably be treated with a combination of antibacterial medications for a period of six to 12 months. The most common treatment for active TB is isoniazid INH in combination with three other drugs—rifampin, pyrazinamide and ethambutol. You may begin to feel better only a few weeks after starting to take the drugs but treating TB takes much longer than other bacterial infections. You must continue taking your medication as prescribed for the entire time your doctor indicates or you could get sick again, have a harder time fighting the disease in the future and spread the disease to others. Not completing your entire course of medication could also contribute to drug-resistant TB. See American Lung Association. See CDC

CDC Travellers Reccomendations by Country:  Mexico

Smart Traveller (diseases you can get overseas)

Infectious Diseases Generally: (see also bacterial, viral and parasitic diseases)

Prions: prions are proteinaceous infectious particles containing, apparently, no genetic material. They are known to cause diseases called transmissible spongiform encephalopathies (TSEs) neurodengerative diseases with long incubation period but rapid progressions once they start. The human TSEs are Creutzfeldt-Jakob isease (CJD). Symptoms of CJD include altered behaviro, demential, memory loss, impaired senses, delirium and prmature senility. The transmissible agent in CJD is a prion. In the late 1990s, it became apparent that humans were contracting a variant form of CJD after ingesting meat form cattle that had been afflicted by bovine sponiform encephalopathy.

Infectious diseases are diseases caused by organisms such as bacteria, viruses, fungi, protozoa or helminths.

Diagnostics/Testing for Infectious Disease:

Biomerieux (has panel testing for infectious disease)

WasteWater Monitoring:

Companies: WasteWater Scan

Wastewater surveillance is used to monitor human shedding of pathogens, including SARS-CoV-2, at a community level and is independent of symptoms, testing access, and care-seeking behavior.See MMWR

During May 12–July 13, 2024, high influenza A virus levels were detected in wastewater in four states, including three states with seasonal human influenza virus activity noted during this time. The H5 subtype was detected in wastewater in nine states; follow-up investigations in many of these states revealed likely animal-related sources, including those related to milk processingWastewater samples collected from approximately 750 sites in 48 states and the District of Columbia during May 12–July 13, 2024, were tested for influenza A virus by state and local health departments, a CDC contractor, or an academic partner program (WastewaterSCAN)

Water Safety with respect to Pathogens

Usafe water is responsible for 1.2 million deather per year world-wide. See Our World in Date 1 in 9 people lack access to safe drinking water. See Water Org. Globally, 946 million people still open defecate (9 out of 10 live in rural areas), 2.4 billion people lack access to basic sanitation (7 out of 10 in rural areas), 663 million lack access to basic water sources, and diarrhea is the second leading cause of death in children under five much of which is preventable by clean water and sanitation. See GWPP

The greatest microbial risks are associated with ingestion of water that is contaminated with human or animal feces. Wastewater discharges in fresh waters and costal seawaters are the major source of fecal microorganisms, including pathogens. Microbial waterborne diseases even affect developed countries. In the USA, it has been estimated that each year 560,000 people suffer from severe waterborne diseases, and 7.1 million suffer from a mild to moderate infections, resulting in estimated 12,000 deaths a year. 

Before widespread application of drinking water disinfection treatments, cholera and typhoid were major causes of death in the U.S. 43 million US residents are served by private wells or domestic water systems that are not regulated by the EPA safe drinking water Act, leaving homeowners responsible for maintaining and monitoring water quality in their wells. During 1971-2008, one third of reported disease outbreaks form drinking water were linked to private wells. The complexity of water distribution has also increased; 6 million miles of polumg inside buildins support drinking water, sanitation, hygiene, cooling and heating needs in the US. Premise plumbing water quality can be compromised when water is stagnant or disinfectant concentrations are reduced, thereby promoting microbial pathogen grwoth and biofilm formation. Exposure to biofilm related pathogens can occur thourgh contact with, ingestion of, or aerosol inhalation of contaminated water form different sources, such as showerheads, hot tubs, building cooling towers or decorative fountains. Swimming in untreated recreational water venue (lakes, rivers, and oceans) can cause outbreaks predominantly linked to norovius., Siga toxin-roducing Escherichia coli, Cryptosporidium spp., and Shigella spp. Thsoe enteric pathogens can be introduced into untreated recreational water through human feces or movmit, stormwater runoff, seage or septic system malfunctions or animal waste and can then be transmitted to persons who ingest the contaminated water. See CDC

Bacteria: 

The most important bacterial gastrointestinal diseases transmitted through water are cholera, salmonellosis and shigellosis. These diseases are mainly transmitted through water (and food) contaminated with feces of patients. 

Types bacteria transmitted through water are the following. See Cabral

Campylobacter causes an estimated 1.5 million illnesses each year in the United States. People can get Campylobacter infection by eating raw or undercooked poultry or eating something that touched it. They can also get it from eating other foods, including seafood, meat, and produce, by contact with animals, and by drinking untreated water. Although people with Campylobacter infection usually recover on their own, some need antibiotic treatment. Campylobacter is a gram-negative, microaerophilic genus of bacteria of the family Campylobacteriacae. There are more than 20 species of Campylobacter, not all of which cause human illness. Approximately 90% of human Campylobacter illness is caused by one species, Campylobacter jejuni. Less common species, such as C. coli, C. upsaliensis, C. fetus, and C. lari, can also infect people. See CDC

E. coli strains isolated from intestinal diseases have been grouped into at least six different main groups, based on epidemiological evidence, phenotypic traits, clinical features of the disease and specific virulence factors. From these, enterotoxigenic (ETEC, namely O148), enterohemorrhagic (EHEC, namely O157) and enteroinvasive serotypes (EIEC, namely O124) are of outstanding importance and can be transmitted through contaminated water.

Legionella is the most implicated etiology in public water system outbreaks. Individual or private water system outbreaks assocaited with Legionella resulted in 8% cases, 92% hospitalizaiton and 100% deaths. MMWR, Mark 14, 2024, 73(1) “Surveillance of Waterborne Disease Outbreaks Assocaited with Drinking Water – United States, 2015-2020). 

Pseudomonas aeruginosa lives in the environment and can be spread to people in healthcare settings when they are exposed to water or soil that is contaminated with these germs. Resistant strains of the germ can also spread in healthcare settings from one person to another through contaminated hands, equipment, or surfaces. See CDC

P. aeruginosa is an aerobic gram-negative bacterium and P. aeruginosa is typified by motile, non-spore forming rods that are oxidase positive and lactose nonfermenters. P. aeruginosa is a member of the genus Pseudomonas, colloquially called the pseudomonads. The water-soluble pigments, pyocyanin and pyoverdin, give P. aeruginosa its distinctive blue-green color on solid media. The P. aeruginosa organism thrives in moist environments such as soil and water. It can be found in large numbers on fresh fruits and vegetables. Human colonization begins within the gastrointestinal tract, with subsequent spread to moist cutaneous sites such as the perineum and axilla. It forms smooth fluorescent green colonies at 42oC, with a characteristic sweet (grape-like) odor, making it easy to recognize on solid media in the laboratory. P. aeruginosa is an important plant pathogen, affecting lettuce, tomatoes, and tobacco plants. It can be found in fresh water environments (streams, lakes, and rivers), as well as sinks, showers, respiratory equipment, even contaminating distilled water. See Antimicrobe

P. aeruginosa can cause acute otitis externa (swimmer’s ear), folliculitis (hot tub rash) (1), and painful nodular lesions on the soles or palms (hot hand-foot syndrome) and is likely to be transmitted through contact with contaminated water in pools or hot tubs and not through person-to-person contact. P. aeruginosa is readily inactivated by disinfectants such as chlorine and bromine. Because of this, maintaining a minimum free chlorine concentration of at least 1 ppm in treated recreational water venues open to the public as recommended by CDC prevents waterborne transmission of most pathogens, including P. aeruginosa. Inadequately maintained disinfectant concentration can lead to proliferation of P. aeruginosa and buildup of biofilm on wet venue surface, scale, and sediment. Biofilm is a primarily polysaccharide matrix that is produced by microbial cells and in which bacteria are embedded; biofilm is difficult to remove and cannot be removed by gentle rinsing. Even when adequate disinfectant concentration is maintained, the extracellular matrix of the biofilm can protect P. aeruginosa and other pathogens from disinfectants. Among 987 treated recreational water–associated outbreaks reported to CDC for the period 1971–2021, 369 (37.4%) were linked to a hotel setting (i.e., hotel, motel, lodging, inn, or resort). (see Pseudomonas Infection Outbreak Associated with a Hotel Swimming Pool — Maine, March 2023)

–carbapenemase-producing carbapenem-resistant Pseudomonas aeruginosa (CP-CRPA) infections is challenging because of antibiotic resistance. CP-CRPA infections are highly transmissible in health care settings because they can spread from person to person and from environmental sources. (Cahill)

Vibrio are small, curved-shaped Gram-negative rods, with a single polar flagellum. Vibrios are facultative anaerobes capable of both fermentative and respiratory metabolism. Sodium stimulates growth of all species and is an absolute requirement for most. Most species are oxidase-positive and reduce nitrate to nitrite. Cells of certain species (V. cholerae, V. parahaemolyticus and V. vulnificus) have pili (fimbriae), structures composed of protein TcpA. TcpA formation is co-regulated with cholera toxin expression and is a key determinant of in vivo colonization. The incubation period for cholera is ca. 1–3 days. The disease is characterized by an acute and very intense diarrhea that can exceed one liter per hour. Cholera patients feel thirsty, have muscular pains and general weakness, and show signs of oliguria, hypovolemia, hemoconcentration, followed by anuria. Potassium in blood drops to very low levels. Patients feel lethargic. Finally, circulatory collapse and dehydration with cyanosis occurs. See Cabral

It is common practice in villages in Bangladesh to use cloth, frequently a flat, unfolded piece of an old sari, to filter home-prepared drinks. In laboratory experiments employing electron microscopy, it was found that inexpensive sari cloth, folded four to eight times, provides a filter of ≈20-μm mesh size, small enough to remove all zooplankton, most phytoplankton, and all V. cholerae attached to plankton and particulates >20 μm. Laboratory studies showed that sari cloth folded at least four times retained the V. cholerae cells attached to plankton, effectively removing >99% (>2 logs) of V. cholerae. See Colwell

Vibrio cholerae: (see also bacterial diseases)

Cholera is an acute diarrheal illness caused by infection of the intestine with Vibrio cholerae bacteria. People can get sick when they swallow food or water contaminated with cholera bacteria. The infection is often mild or without symptoms, but can sometimes be severe and life-threatening. About 1 in 10 persons will experience severe symptoms such as profuse watery diahrea, vomitting, thrist, leg cramps and restlessness. People can develop severe dehydration. The profuse diarrhea produced by cholera patients contains large amounts of the infectious Vibrio cholerae germ that can infect others if swallowed. This can happen when the bacteria get on food or into water. Caregivers should wash there hands thoroughly after handling handling feces.  See CDC

The cholera bacterium is usually found in water or in foods that have been contaminated by feces (poop) from a person infected with cholera bacteria. Cholera is most likely to occur and spread in places with inadequate water treatment, poor sanitation, and inadequate hygiene. See CDC

Only toxigenic strains of Vibrio cholerae serogroups O1 and O139 cause epidemics and are reportable as cholera. See Florida Health

Salmonella, a member of the family Enterobacteriaceae, include Gram-negative motile straight rods. Cells are oxidase-negative and catalase-positive, produce gas from D-glucose and utilize citrate as a sole carbon source. Salmonellae have several endotoxins: antigens O, H and V.

CDC estimates Salmonella bacteria cause about 1.35 million infections, 26,500 hospitalizations, and 420 deaths in the United States every year. Food is the source for most of these illnesses. Most people recover without specific treatment and should not take antibiotics. Antibiotics are typically used only to treat people who have severe illness or who are at risk for it.  Salmonella can be found in many foods, including sprouts and other vegetables, eggs, chicken, pork, fruits, and even processed foods, such as nut butters, frozen pot pies, chicken nuggets, and stuffed chicken entrees. Contaminated foods usually look and smell normal, which is why it is important to know how to prevent infection.See CDC

Salmonella is frequently present in surface water, an important source of water for irrigation. An increasing evidence indicates irrigation water as a source (or a vehicle) for transmission of Salmonella. This pathogen can survive in aquatic environments by a number of mechanisms, including entry into the viable but nonculturable (VBNC) state and/or residing within free-living protozoa. As such, assurance of microbial quality of irrigation water is critical to curtail the produce-related foodborne outbreaks and thus enhance the food safety. See Liu

Shigella are Gram-negative, non-sporeforming, non-motile, straight rod-like members of the family Enterobacteriaceae. Cells ferment sugars without gas production. Salicin, adonitol and myo-inositol are not fermented. Cells do not utilize citrate, malonate and acetate as sole carbon source and do not produce H2S. Lysine is not decarboxylated. Cells are oxidase-negative and catalase-positive. Members of the genus have a complex antigenic pattern, and taxonomy is based on their somatic O antigens.

Mycobacterium avium complex (Mac) consists of 28 serovars of two distinct species: Mycobacterium avium and Mycobacterium intracellulare. The importance of Mac organisms was recognized with the discovery of disseminated infection in immunocompromised people, particularly people with HIV and AIDS. Members of MAC are considered opportunistic human pathogens.

Helicobacter pylori has been cited as a major etiologic agent for gastritis and has been implicated in the pathogenesis of peptic and duodenal ulcer disease and gastric carcinoma. However, most individuals that are infected by this pathogen remain asymptomatic

A. hydrophila has gained public health recognition as an opportunistic pathogen. It has been implicated as a potential agent of gastroenteritis, septicemia, meningitis, and wound infections. It can play a significant role in intestinal disorders in children under five years old, the elderly, and immunosuppressed people. 

Viruses:

It is well known that bacteria are major causes of diarrhea transmitted through unsafe drinking water. What is less appreciated are viruses in these same drinking water sources and their impact on human health. Water-transmitted viral pathogens that are classified as having a moderate to high health significance by the World Health Organization (WHO) include adenovirus, astrovirus, hepatitis A and E viruses, rotavirus, norovirus and other caliciviruses, and enteroviruses, including coxsackieviruses and polioviruses. Water treatment utilities routinely assay for the presence of fecal coliforms in water supplies, but they do not assay for the presence of infectious viruses because it is either impossible or not feasible to detect or propagate infectious virus particles in a cost-efficient and timely manner. Despite these barriers, the United States Environmental Protection Agency (USEPA) is evaluating adenovirus, caliciviruses, enteroviruses, and hepatitis A virus for potential regulatory action. See Gall

Hepatitis: Waterborne or foodborne hepatitis caused by hepatitis A virus (HAV) and hepatitis E virus (HEV), has faeco-oral route of transmission. See Dutta 

Polio, or poliomyelitis, is a disabling and life-threatening disease caused by the poliovirus. Paralysis is the most severe symptom associated with polio, because it can lead to permanent disability and death. Between 2 and 10 out of 100 people who have paralysis from poliovirus infection die, because the virus affects the muscles that help them breathe.  Inactivated poliovirus vaccine (IPV) given as an injection in the leg or arm, depending on the patient’s age. Only IPV has been used in the United States since 2000. See CDC

Similar to other non-polio enteroviruses (NPEVs), PV is transmitted via the fecal-oral route and efficiently replicates in the intestinal tract. During PV infection, the virus is excreted from the human gut into the stool for ∼2 months. Although most PV infections are asymptomatic, patients can develop poliomyelitis following viremia in some cases, resulting in residual paralysis. Since the live oral poliovirus vaccine (OPV) was introduced in many industrial countries in the 1960s, polio epidemics have been successfully controlled. In 1988, the World Health Assembly resolved to eradicate polio by launching the Global Polio Eradication Initiative (GPEI). Large-scale OPV immunization resulted in a drastic reduction in the number of poliomyelitis cases. To date, the only countries where polio is endemic are Nigeria, Pakistan, and Afghanistan. See Yoshida

Diagnosis is usually based on repeated stool examinations but examination of duodenal fluid or biopsy material may also be necessary. Enzyme immunoassay or indirect immunofluorescence methods for direct detection of antigen or whole organisms in clinical specimens have also been developed. These tests are reported to be more sensitive than routine stool examination. See Wolfe

Protozoa:

Giardia: Giardiasis has a global distribution and it is a common cause of diarrhea in both children and adults and is transmitted via the fecal-oral route through direct or indirect ingestion of cysts. The laboratory diagnosis of Giardia spp. is mainly based on demonstration of microscopic cyst or trophozoite in stool samples but several immunological-based assays and molecular methods are also available for giardiasis diagnosis.  See Delavari Healthcare providers can order laboratory tests to identify Giardia germs in the stool (poop) of someone who is sick. Sometimes it can be difficult for doctors to know for sure if Giardia is making you sick. This is because people with a Giardia infection do not pass Giardia germs with every stool. Even when there are Giardia germs in their stool, there may not be enough for the laboratory to find and identify them. See CDC

Cryptosporidium parvum and Cryptosporidium hominis are obligate enteric protozoan parasites which infect the gastrointestinal tract of animals and humans. The mechanism(s) by which these parasites cause gastrointestinal distress in their hosts is not well understood. The risk of waterborne transmission of Cryptosporidium is a serious global issue in drinking water safety. Oocysts from these organisms are extremely robust, prevalent in source water supplies and capable of surviving in the environment for extended periods of time. Resistance to conventional water treatment by chlorination, lack of correlation with biological indicator microorganisms and the absence of adequate methods to detect the presence of infectious oocysts necessitates the development of consistent and effective means of parasite removal from the water supply. see Carey

–Transmission: Cryptosporidium parasites get into surface water sources, such as rivers and lakes, from the stool (feces) of infected animals or people. Public water systems that get their water from these surface water sources can contain Cryptosporidium oocysts (the egg-like form of the parasite). Filtration treatment will usually remove Cryptosporidium oocysts. Chlorine disinfection by itself is not effective. All Virginia public water systems that use surface water sources provide filtration treatment. In addition, in an effort to reduce health risks associated with Cryptosporidium, the Environmental Protection Agency (EPA) has promulgated the Long Term 2 Enhanced Surface Water Treatment Rule (LT2). LT2 requires that all water systems that obtain their water from surface water sources must monitor the raw (source) water for Cryptosporidium oocysts or indicator organisms. Monitoring results will indicate whether systems will be required to provide additional treatment to achieve effective Cryptosporidium reduction. See Virgina Department of Health

—-Recreational Water:

Recreational water can be classified as treated or untreated. Treated recreational water undergoes systematic treatment (e.g., disinfection or filtration) to maintain quality for recreational use and is typically in an enclosed and manufactured structure. In addition to pools and hot tubs, splash pads are treated recreational water venues. Splash pads can include single-pass splash pads in which treated tap water is circulated but does not undergo additional treatment within the splash pad. Untreated recreational water does not undergo systematic treatment to maintain quality for recreational use. Lakes, rivers, and oceans are untreated recreational water venues.

——Splash pads: Splash pads, also known as water playgrounds, interactive fountains, spray pads, spray parks, and wet decks, spray or jet water on users. Water can either be recirculated or pass once through the venue plumbing. In recirculating splash pads, after being sprayed or jetted, the water drains into a tank and is filtered and disinfected before being sprayed or jetted again. In single-pass splash pads, water circulates through the plumbing only once before draining, typically into a sewer system. During 1997–2022, public health officials from 23 states and Puerto Rico reported 60 waterborne disease outbreaks associated with splash pads. These reported outbreaks resulted in 10,611 cases, 152 hospitalizations, 99 emergency department visits, and no reported deaths. The 40 (67%) outbreaks confirmed to be caused, in part, by Cryptosporidium resulted in 9,622 (91%) cases and 123 (81%) hospitalizations. Two outbreaks suspected to be caused by norovirus resulted in 72 (73%) emergency department visits. See CDC

Cryptosporidium oocysts are common and widespread in ambient water and can persist for months in this environment. The dose that can infect humans is low, and a number of waterborne disease outbreaks caused by this protozoan have occurred in the United States, most notably in Milwaukee, Wisconsin, where an estimated 400,000 people became ill in 1993. See EPA

–Disinfection Measures: Even the lowest concentration of ammonia decreased significantly the viability of oocysts after 24 h of exposure. Increasing concentrations of ammonia increased inactivation rates, which ranged from 0.014 to 0.066 h−1. At the highest concentration of ammonia, a small fraction of viable oocysts still remained. Exposure to pH levels corresponding to those associated with the ammonia concentrations showed minimal effects of alkaline pH alone on oocyst viability. See Jenkins

Cyclosporiasis is infection with the protozoan Cyclospora cayetanensis. Symptoms include watery diarrhea with gastrointestinal and systemic symptoms. Diagnosis is by detection of characteristic oocysts in stool or intestinal biopsy specimens. Cyclosporiasis is caused by an obligate intracellular coccidian protozoa. Transmission is by the fecal-oral route via contaminated food or water. Cyclosporiasis has not yet been associated with commercially canned or frozen foods. This infection is most common in tropical and subtropical climates where sanitation is poor. Residents and travelers to endemic areas are at risk. Early reports of Cyclospora cayetanensis outbreaks in the US were attributed to imported raspberries from Guatemala. Subsequently, outbreaks of C. cayetanensis infection have followed ingestion of contaminated fresh vegetables including basil, snow peas, mesclun lettuce, and cilantro. In the summer of 2013, a multi-state outbreak involving hundreds of people in the US was attributed to ingestion of prewashed salad mixes  A 2018 multi-state outbreak was attributed to contaminated fresh vegetable trays. The life cycle of C. cayetanensis is similar to that of Cryptosporidium Crexcept that oocysts passed in stool are not sporulated. Thus, when freshly passed in stools, the oocysts are not infective, and direct fecal-oral transmission cannot occur. The oocysts require days to weeks in the environment to sporulate and, therefore, direct person-to-person transmission is unlikely. The sporulated oocysts are ingested in contaminated food or water and excyst in the gastrointestinal tract, releasing sporozoites. The sporozoites invade the epithelial cells of the small intestine, replicate, and mature into oocysts, which are shed in stool. See Merk Manual

Avian
 
Avian influenza virus (AIV): Avian influenaze viruses (AIV) are negative-sense isngle-stranded segmented genomes. They are encapsulated by envelopes containg the surface proteins hemagglutinin (HA) and neuraminidase (N) and are classified by 16 identified HA and ( NA subtypes, all of which occur in their reservoir hosts, free-flying waterfowl and shorebirds. The roles of birds as reservoire hosts in which viruses with pandemic potential can be amplified and trasnmited to humans have beocme a focus of itnerest with the emergence of HSN1 highly pathogenic AIV.
 
 
Poultry all over the world ahve been threatened since the appearance of highly pathogenic avian influenze viurs HSN1. The WHO has enoucraged the use of poultry vaccination policy together with biosecurity measures to counteract H5N1 outbreaks. High levels of hemagglutination inhibition antibodies and protection have been acheived using a DNA vaccine based on C3d molecule fused to HA in mice and enhanced chicken immunity by adminstiering a recombinant adenovial vector containing the HA H5 fused to chicken 154 has been acheived. (Pose, Veterminary Microbiology, (2001), 328-337). 
 
Adams (Molecular Immunoloy 46 (2009) 1744-1749) discloses that duck and chicken are important hosts of AIV, with distinctive response to infection. They examined the expression of cytokine genes in response to low pathogenic AIV H11N9 infection in PBMCs isolated from the blood of ckien and ducks. 
 
Infectious bronchitis virus (IBV): has been a continuing problem in poultry for more than 70 years. IBV cuases a highly contagious respiratory disease in chickens, resembles the recently described severe acute respirtory virus in pathogeneis and gehome oranization. It has been shown that the SARS in humans is caused by a coronavirus that resembles infectious bronchitis in transmission, pathogenesis and genome structure. Vaccines are available, but they are not effective long-eterm in controlling IBV infection, especially for variant strains. Genetic variations are ocmmon in new strains because of both point mutations and recombinants. CD8+ T cells are critical in controlling acute IBV infection. Adoptive transfer of T cells collected at 10 days post-infection protected syngenic chicks from clinical illness. Innate immunity may also be intstrumental in that chicken IFN-1 inhibits IBV replication in vivo. Local adminsitration of IFN-I also inhibited IBV associated respiratory illness. (Pei, Developmental and Comparative Immunology 29 (2005) 153-160). 
 
Horses
 
Recurrent airway obstruction (RAO): is a respiratory condition of horses that is characterized by bronchospasm, peribronchial cell infiltration, and accumulation of a predominantly neutrophilic exudate in the lumen of the small airways. Inflammation of the small airways in horses with RAO results from inhalation of airborne particles (mainly molds and fungi). Thus, control of environmental dust is very important to the treatment of horses with RAO. Treatment also commonly includes corticosteroids. Pentoxifylline (PTX) which is a methlxanthine derviative that is a nonselelctive inhibitor of phosphodiesterases (PDE) has also been reproted to improve respriatory function of RAO affected horses (Leguillette, AJVR, 63(3), 2002).
 
Viral respiratory infections: are common in horses and include herpesvirus type 4(EHV-4, rhinopneumonitis), equine influenza and equine viral arteritis. Symptoms include nasal discharge, submandibular lymphadenopathy, anorexia and cough (see Merck Manual, 2011).
 
Bacterial respiratory infections: such as pneumonia often accompany viral respiratory infections because the viral respirtatory infections destroy respiratory defense mechanisms. Secondary bacterail disease may result in mucosal bacterail infections (rhinitis and tracheitis).
 
Bovine (Cattle):
 Bacterial Infections:
 
–Mannheimia haemolytica: is the principla bacterium isolated from respiratory disease in feedlot cattle and is a significant component of enzootic pneumonia in all neonatal caovles. A commensal of the nasopharynx. M. haemolytica is an opportunist, gaining access to the lungs when host defesnes are compromised by stress or infection with respirtatory viruses of mycoplasma. Although several serotypes act as commensals, A1 and A6 are the most fequent isolates from pneumonic lungs. Potential virulence factors include iron-regulated outer membrane proteins and leukotoxin (Lkt). 
 
M. haemolytica is a gram-engative, non-motile, nons-spore-forming, fermentative, oxidase-postive, facultative anaerobic coccobacillus. It includes 12 capsular seriotypes. Both serotypes A1 and A2 colonize the upper respiratory tract of cattle and sheep. 
 
Viral Infections:

–Bovine Herpes virus Type-1 (BHV-1)/Bovine Respiratory Disease (BRD):  BHV-1, an alpah herpes virus, is an important etiological agent of respirtory and genitcal diseass in cattle. The resptiratory form of the disease spreads via aerosols and is characterized by rhinotracheitis, conjunctivities and development of bovine respitaory disease (BRD) complicated by secondary bacterial infections. The predisposition to bacterial complications by the virus is related directly to its cytolytic effect on the cells of nasla and tracheal mucosa apart from its immunosuppressive effects. The genital infection spreads via genital secretions, semen and foetal fluids. (Kaushik, US 2010/0196375). 
 
(Kaushik (US 2010/0196375) discloses a single chain variable fragmetn (scFv) that includes a light chain, a linker and a heavy chain variable region, that binds BHV-1 virus and methods for treating or netralizing BHV-1 infection. 
 
Rabbits:
Lethal rabbit virus, Rabbit Hemorrhagic Disease Virus type 2 (RHDV2) ontagious among rabbits, RHDV2 has been identified as the cause of death in several cases after tests conducted by the Washington Animal Disease Diagnostic Laboratory at Washington State University came back positive.  In 2019, the disease claimed the lives of numerous domestic and feral rabbits in Island and Clallam counties. Originally considered a foreign animal disease, eliciting immediate restrictions and emergency actions, RHDV2 is now regarded as a stable-endemic issue within Washington. 
 
Citrus:
 
Bacteria Candidatus Liberibacter asiaticus (CLas): is the etiological agent responsible for huanglongbing (HLB) disease in cittrus. The Asian citrus psyllid (ACP), Diaphorina citri (Hemiptera: Liviidae) is the vector of the bacterial CLas. HLB is the most destructive citrus disease worldwide, cuaisng fruit from infected tress to become small, misshapen and discolored with unpleasnt bitter and acidic flavor The damage caused by HLB is extensive, decreasing furit produciton by 57% in Florida alone form 2004-2019 and causing an estimated 1.7 billion in production losses between the harvest seasons of 2006-2007 and 2010-2011. The initial symptoms of the disease do not appear for months and at first resemble nutrient deficiencies, resulting in HLB infections remaining undiagnosed for long periods and providing stable reservoirs for teh pathogen. HLB is mianly transmitted by the ACP vector, but it can also be spread form tree to tree through grafting diseased branches. (Asban, “CRISPR-Cas9-mediated mutagenesis of the Asian Citrus Psyllid, Diaphorina citri” Gen Biotechnology, 2(4), 2023). 
 
The main method for reducing the spread of HLB among commercial groves includes remvoing infected trees serving as HLB reservoirs, planting certified healthy plants and applying insecticides to control D. citri vector populations. (Asban, “CRISPR-Cas9-mediated mutagenesis of the Asian Citrus Psyllid, Diaphorina citri” Gen Biotechnology, 2(4), 2023).
 
Asban, (“CRISPR-Cas9-mediated mutagenesis of the Asian Citrus Psyllid, Diaphorina citri” Gen Biotechnology, 2(4), 2023) disloses genetic based control methods similar to those used in other insect vectors of disease and agicultural pests such as Aedes aegypti and Drosophila suzukii. Asban showed CRISPR-Cas9 gene editing in D. citri using embryonic microinjection and ReMOT control. To ensure gene mofidicaiton, they targeted genes with visible mutatant phenotypes, whie (w) and kynurenine hydroxylate (kh). They dientified the locaiton of these genes in the G. citri geneome to design targeting gRNAs, developed and tested Cas9-RNP delivery methods into embryos and females and validated the phenotypic and genotypic changes upon gene disruption. first they idnetified the genomic sequences for w and kh by comparing it with the known protein sequences of the Drosophila melanogaster w and kh using tBastn on the latest version of teh D. citri genome available in the citrusgreening.org platform. 
 
 
 

Stroke occurs when the blood flow to a part of the brain is suddenly blocked by occlusion (ischemic stroke, responsible for about 90% of strokes). The acute death of brain cells is caused by reduced delivery of oxygen. Within the ischemic core zone, most of the affected cells are neurons, because they show the highest vulnerability to oxygen deprivation. Surrounding the ischemic core zone, there is an area of moderately ischemic brain tissues called penumbra where surviving cells are exposed to secondary deleterious phenomena, such as excitotoxicity, spreading depolarization and inflammation. Thus the prime goal of neuroprotection is to rescue the penumbra. Clincially, depending on the part of the brain that is affected, strokes can result in weakness or paralysis of the arms, legs and/or facial muslces, loss of vision or speech, and imparied walking.

The two most common forms of ischemia (deficiency of oxygen in a part of the body causing metabolic changes) are cardiovascular and crebrovascular. Cardiovascular ischemia, in which the body’s capacity to provide oxygen to the heart is diminished, is the leading cause of illness and death in the US. Crerebral ischemia is a precursor to cerebrovascular accident (stroke) which is the third leading cause of death in the US. Bar-Or (US 7,449,338)

Signs and Symptoms : 

Timely receipt of appropriate treatments for stroke requires prompt recognition of stroke signs and sumptoms and activaiton of EMS. The five major signs and symptoms of stroke include 1) sudden severe headache; 2) sudden loss of vision in one or both eyes, 3) sudden weakness in an arm, a leg, or the face, 4) sudden confusion, trouble speaking, or understanding, and 5) sudden trouble walking, dizziness, or loss of balance or coordination.

Full-blown strokes are often preceded by transient ischemic attachs (TIA)

Pathological mechanisms/Risk factors: 

The continum of ischemic disease includes (1) elevated blood levels of cholesterol and other blood lipids; (2) subsequent narrowing of the arteries, (3) reduced blood flow to the body organ (as a result of arterial narrowing), (4) cellular damage to an organ caused by a lack of oxygen and (5) death of organ tissue caused by sustained oxygen depreivation. (3-5) above are collectively referred to as “ischemic disease” while (1-2) are considered its precursors.

Risk factors for ischemic heart disease indclude being over age 50, smoking, diabetes mellitus, obesity, high blood pressure, elevated low density lipoproteins, high cholesterol and strong family history of cardiac disease.

Diagnosis:

It is known that immediately folloiwng an ischemic event, proteins such as creatine kinase (CK),serum glutamic oxalacetic transaminase (SGOT) and lactic dehydrogenase (LDH) are released, and these proteins have been used for evaluating the occurrence of past ischemic heart events (US 4,492,753).  

Bar-Or (US 7,449,338) teaches  a method of testing for the existence of ischemia based on detecting the existence of an alteration of the serum protein albumin which occurs folloiwng an ischemic event.

Treatment: 

Early treatment is very important with stroke. Among persons with onset of stroke, less than half arrived at the hosptial within 2 hours of symptom onset. Rapid removal of a thrombus (i.e., bloot clot) after ischemic stroke can greatly reduce the risk of the loss of brain fnction. 

— TPA (issue plasminogen activator): is the only treatment approved by the FDA for use with ischemic stroke patients and is only approved for use within 3 hours of symptom onset. Patients treated with tPA are 30%-50% more likely to have good functional outcomes than those who do not receive tPA. However, intravenous recombinant tissue plasminogen activator (rtPA) is associated with increased risk of intracerebral hemorrhage. 

–A CT scan is a crucial component of optimal stroke care for all stroke patients. The National Institutes of Neurological Disorders and Stroke recommends that stroke patients receive an initial CT scane within 25 minutes of hospital arrival.

–Mechanical removal: Blood clots can also be mechanically removed using a system called Mechanical Embolus Removal in Cerebral Ischemia (MERCI®). Ultrasound may also be used to enhance the effectivenss of the tPA or to physically remove the thrombus. Magnetci partciles either conjugated to biomolecules which allows specific attachment to thrombus tissue (US 12/403,124) or which can be directed to the thrombus and disrupt it with the assistance of a magetic wave (see Drug Delivery) have also been used. 

Complications from Stroke:

Thromboysis (dissolution of blood clots) relies upon the administration of exogenous plasinogen activators that lyse fibrin. However, significant risks include uncontrolled bleeding. The most feared complication of thromobytic therapty is symptomatic intracranial hemorrhage (SICH). 

Clopidogrel bisulfate sold as Plavix was introduced in the U.S. in 1998.

Hemorrhagic stroke accounts for about 15% of all strokes but is associated with a disproportionate degree of morbidity. Studies have indicated that inflammatory processes may be involved in exacerbating brain injury after the hemorrhagic even (Hua y, J. Nuerosurg. 200, 1016-1022). 

There are two main types of hemorrhagic strokes: (1) intracerebral hemorrhage and 2. subarachnoid hermorrhage. 

Intracerebral Hemorrhage (ICH)

Intracerebral hemorrhage (ICH) is the second most common and deadliest form of stroke carrying a mortality rate of 30-50% which has not improved over the last two decades. Moreover, ICH imparts some form of disability in close to 90 of its survivors.

Risk Factors: The most common etiology of ICH is hypertension.

Complications: include haematoma expansion (HE), perihaematomal oedema (PHE), intraventricular extension of haemorrhage (IVH) with hydrocephalus, seizures, venous thromboembolic events (VTE), hyperglycaemia, increased blood pressure (BP), fever, and infections. Complications such as HE, IVH with obstructive hydrocephalus, and hyperglycaemia are major predictors of increased ealry mortality and adverse outcome during the hyperactue phase of ICH.

Etiology:

1. Role of complement system: 

(i) Inhibitors of C3 and C5: Complement C3 is an important factor causing brain damage following ICH in mice. However, another study reported that neurological deficits and brain edema were worse in complement C5 deficient mice. These differing results indicate that different complement factors have different effects on brain injury after ICH, that is, either beneficial or harmful. C5 deficient mice fail to form C5a fragments and member attack complex (MAC), but complement C3 deficient mice fail to form C3a, C3b, C5a and MAC (Yang, “the role of complement C3 in intracerebral hemorrhage-induced brain injury” J. Cerebral Blood Flow & Metabolism (2006), 26, 1490-1495).

Lambris (US13/059482) discloses complement inhibotrs which reduce or prevent C3a and C5a formation, thereby treating intracerebral hemorrhage. In a preferred embodiment, the inhibitor is a C3 inhibitor which not only prevents the formation of C5a but also C3a. Examples of C3 inhibitors used are compstatin or their analogs. 

(ii) inhibitors of C3aR and C5aR: Lambris (US13/059482) discloses that inhibitors of C3aR and C5aR improved recovery (reduced brain edema and imprvoed nuerological outcome) in a mouse model for ICH. 

Treatment: Treatment options for ICH are mostly supportive. Elevation of the head to 20-30 degrees and avoidance of pain and fever could minimize any rise in ICP. Medical measures such as hyperventilation and the use of analgesia, sedatives, and osmotic diuretics are designed to lower ICP before placement of an ICP monitor or any definitive neurosurgical intervention such as craniotomy or ventriculostomy.

Subarachnoid Hemorrhage

A subarachnoid hemorrhage is bleeding into the space (subarachnoid space) between the inner lyaer (pia mater) and middle layer (arachnoid mater) of the tissue covering the brain (meninges). The most common cause is rupture of an anuerysm (bulge) in an artery. Usually, rupture of an artery causes a sudden, severe headache, often followed by a brief loss of consciesness. Computed tomography, sometimes a spinal tap and angiography are done to confirm the diagnosis. Drugs are used to relieve headache and to control blood presure and surgery is done to stop the bleeding. 

See also Drug Delivery of anti-thrombotic agents.

Each year, about 795,000 persons in the U.S. experience a stroke. There are 2 major types of stroke: ischemic stroke and hemorrhagic stroke.

In the normal or healthy states, an equilibrium exists between fibrin formation (coagulation) and fibrin dissolution (fibrinolysis). However, when this hemostatic process is impaired, coagulation and fibrinolysis are pathologically expressed as thrombosis and hemorrhage, respectively. The clinical manifestations of pathological thrombosis or thrombotic disease are extremely diverse and include disseminated intravascular coagulation (IC), deep vein thrombosis (DVT), arterial and venous thrombosis. Thromboeembolism and thrombotic complications of other vascular disease (e.g., atherosclerosis) can result in occlusion of major arteries leaidng to organ ischemia and the life threatening conditions such as crebrovascular accidt (stroke), myocardial infarction, etc. (Gargan, 5,837,540).

Blood clots when thrombin cleaves two pairs of small peptides from fibringoen to yeild fibrin monomers (Matsueda, 4,916,070).

Ischemic Stroke (see outline)

Hemorrhagic Stroke: See outline

Pathology

Atherosclerotic plaque: progresses in discrete stages, entailing multiple episodes of rupture and healing that ultimately culminate in a complete obstruction, leading to stroke or an acute heart attack. Microdeposits of fibrin are the hallmark of the unstable lesion. Numerous cellular and molecular processes play a role including macrophages and other inflammatory cells which secrete matrix metalloproteinases (MMPs) that can dissolve fibrous omponents, and large lipid cores that induce prothrombotic tissue factor and destabilize lesions by distributing stress to rupture prone regions. 

Treatment:

ELIQUIS (NDA 202155) relates to drug products containing the active ingredient apixaban in a tablet composition. Apixaban is in the drug class Factor Xa inhibitors (a type of anticoagulant) and is used to lower the risk of stroke and to prevent deep vein thrombosis (DVT). Factor Xa inhibitors work by blocking the activity of clotting factor Xa. ELIQUIS is used to treat nonvalvular atrial fibrillation and blood clots. The study includes ELIQUIS because it was one of the twelve top grossing drugs of 2017.

Thrombosis is the formation, development or presence of a blood clot (thrombus) in a blood vessel. It is the most common severe medical disorder.  The most fequent example of arterial thrombosis is coronary thrombosis, which leads to occlusion of the coronary arteries and often to myocardial infarction (heart attack). The standard therapy is adminsitration of a thromboytic protein by infusion.

Another important example of arterial thrombosis is cerebral thrombosis

Venous thrombosis is a frequent complication of surgical procedures such as hip and knee athroplasties.

Mechanisms of Action/Pathogenesis

Role of complement: Studies have shown a role of complement in procoagulant pathways. For example, interception of C5a and C5aR results in distinct changes in pro/antifibrinnoytic proteins and in the induciton of tissue factor (TF) in endothelial cells and monocytes. Ritis (J. Immunology, 2006, 177, 4794-4802) also show that antiphospholipid Ab-induced complement activation and downstream signaling via C5a receptors in neutrophils leads to the inudction of tissue factor (TF), a key initiating component of the blood coagulation cascade. Inhibition studies using the complement inhibitor compstatin showed that complement activation is triggered by antiphospholipid syndrome (APS) IgG and leads to the induction of a TF dependent coagulant activity. Blockage using a selective C5a receptor antagonist and stimulation of neutrophils wiht recombinant human C5a also showed that C5a and C5aR mediate the expression of TF in nuetrophils. 

Thrombus associated diseases:

Thrombus associated diseases are vascular conditions that develop due to the presence of a clot.

Abdominal Aortic Aneurysm (rupture of an abdominal aortic aneurysm (RAAA)): is a lethal event in 90% of patietns. In hospital mortality rates of 10-70% account for a large proportion of these deaths and are due primarily to multiple organ failure after successful repair.

Boyd (“a CD18 monoclonal antibody reduces multiple organ injury in a model of ruptured abdominal aortic aneurysm, 1999) discloses that a CD18 m antibody reduces multiple organ injury in a model of ruptured abdominal aortic aneurysm.

Acquired thrombotic thrombocytopenic purpura: is a rare, life threatening autoimmune blood clotting disorder.

Cablivi (sold by Sanofi), a humanized, 259 aino acid, 27.78 kDa bivalent nanobody produced in E. coli that binds to von Willebrand factor, a key protein in hemostasis, which in turn inhibits the itneraction of von Willebrand factor with blood platelets, preventing platelet adhesion and hence the clotting characteristic of the condition, has been approved in Europe for treatment. (Gary Wash “Biopharmaceutical benchmarks 2018” Nature Biotechnology, 36(12), 2018)

Deep-vein thrombosis (DVT): is a condition in which blood clots form in the deep blood vessels of the legs and groin. These clots can block the flow of blood from the legs back to the heart and sometimes a piece of a clot is detached and carried by the bloodstream through the heart to a blood vessel, where it lodges and reduces, or blocks the flow of blood to a vascular tissue. This is called an embolism. If the clot lodges in pulmonary blood vessel (see below) it can be fatal.

Pulmonary embolism: In the US alone an estimated 600k patients suffer from PE’s each year. Many of these cases go undetected and many of these patients later die due to complications associated with the disease.

Thrombus: is a circumscribed blood solidification that forms in arteries or veins by intravascular clotting. A typical example of an arterial thrombosis is that of the coronary arteries. If a thrombus detaches from the vessel wall, it can be carrierd by the blood stream which can obstruct a downstream smaller vessel. The brain supplying aerteries are a typical example of thromboembolisms in arteries. 

Ischemic Stroke (see outline)

Hemorrhagic Stroke: See outline

Treatment

Anti-thrombotic agents are those agents that inhibit or reduce blood clot formation and/or stimulate thromboysis (thrombus dissolution). They include aspirin, protaglandin E1, selective thromoxane A2 inhibitors, selective thrombin inhibitors, platelet receptor GPIIb/IIIa blockers, streptokinase, heparin, complement inhibitors and kistrin. (Lipton, US 6,503,947).

Annexins: have shown anticoagulant activity in several in vitro thrombin dependent assays. Allison (US 2006/0105952) discloses methods for preventing arterial or venous thrombosis by adminnistering to a subject a modified annexin protein.

Intravenous recombinant tissue plasminogen activator (rtPA) is the only treatment for acute ischemic stroke that is approved by the FDA. The earlier it is adminsitered the better.

Factor Xa inhbitors:

–Apixaban (Eliquis): is an anticoagulant medicaito used to treat and prevent blood clots and to prevent stroke in people with novalvular atrial defibrillation through direclty inhibiting factor Xa. It is used as an anlternative to warfarin to prevent blood clots following hip or kee replacement and in those with a histoyr of prior clots. 

–Rivaroxaban (Xarelto): is an anticoagulant medication (blodo thinner) used to treat nad prevent blood clots. Specifically it is used to reat deep vein thrombosis and pulmonary emboli and to prevent blood clots in atrial fibrillation. Rvaroxaban appears to be as effective as warfarin in preventing strokes and embolic events in patients who are classified as moderate to high risk. It inhbitors both free and bound Factor Xa in the prothrombinase complex. It is a selective direct factor Xa inhibitor with an onset of action of 2.5-4 hours. 

Causes of Acute Liver Failure:

Chronic infection with hepatitis C virus (HCV) is known to cause acute liver failure.

Alcohol-induced liver disease: 

Drug Induced Liver Disease (DILI): accounts for about 13% of cute liver failure in the US and is the 3rd most common cause of acute liver failure.

Mechanisms of Action

Developement of autoantibodies: 

–Cytochrome P450 2E1 (CYP2E1) is a 493 amino acid enzyme involved in the monooxygenation of drugs and other xenobiotic agents. It has been reported that autoantibodies to CYP2E1 eptiopes contributes to the development of hepatic autoimmune diseases. For example, autoantibodies to CYP2E1 have been identified in persons with drug induced liver injury (DILI). A type of DILI developed develops in susceptible individuals following adminsitration of halogenated volatile anesthetics. Oxidative metabolism of the anesthetic produces trifluoroacetylchloride (TFA) which is a reactive metabolite that can covalently bind to and alter native liver proteins. The TFA-protein complexes, known as drug haptens, are novel autoantigens or hapten autoantigen complexes (neoantigens) capable of eliciting allergic or autoimmune resposnes. A second type of DILI is alcohol induced liver diseases where individuals chronically exposed to alcohol also develop autoantibodies to CYP2E1. Chronic viral infections are also known to induce autoimmunity directed to CYP2E1. For example, chronic infection with HCV is known to induce autoimmune reacions. Individuals with chronic HCV expressed decreased levels of CYP2E1 as well as CYP2E1 autoantibodies. (Njoku (13/203402) discloses a CYP2E1 Gly113-Leu133 epitope that contributes to the development of hepatic autoimmune diseases. T and B cells specific for the Gly113-Leu133 epitope mediate an autoimmune response that contributes to the devleopment of hepatic autoimmune diseases. Methods for using the polypeptide for identifying a mammalain subject at resik of developing hepatic autoimmune disease are also provided. 

Susceptible individuals who develop anesthetic-induced DILI have elevated levels of CYP2E1 specific IgG4 autoantibodies. In constrast, exposed susceptible individuals who develop CYP2E1 specific IgG1 autoantibodies remain healthy. Accordingly, pathogenesis in hepatic autoimmune disease is assocaited with emergence of IgG4 autoantibodies and IgG4 autoanitbodies that are specific for the Gly113-Leu133 epitope of CYP2E1 can be used for diagnosing a pateint with hepatic autoimmune diasease. 

FDA Approved Drugs

Drugs that treat schizophrenia are called antipsychotics. The first antipsychotic drug, chlorpromzaine was discovered by accident in the ealry 1950. Subsequent research showed that chlorpromazine’s antipsychotic properties were due to its antagonism of dopamine receptors in the brain. That finding resulted in the development of other typical antipsychotics, which treat positive symptoms but not negative symptoms and have a number of problematic side effects, including extrapyramidal symptoms (“EPS”), tardive dyskinesia, prolactin elevation (hyperprolactinemia), and sudden decrease in blood pressure (orthostatic hypotension).

Researchers discovered clozapine in the early 19601. It was the first “atypical” antipsychotic, in that it had a diminished propensity to cause EPS and was useful for treating both positive and negative symptoms of schizophrenia. However, Clozapine had serious potential side effects including orthostatic hypotension, frank hypotension, and agranulocytosis (a life threatinging decrease in white blood cells). Due to those side effects clozapine was withdrawn from clinical trails in the 1970s. The FDA did finally approve clozpine in 1990, but only for treatment resistant or treatment intolerant patients, subject to regorous blood testing.

Risperidone: In 1994, the FDA approved risperidone, the first post-clozpine atypical antipsychotic. Risperidone is a medication that works in the brain to treat schizophrenia. It is also known as a second-generation antipsychotic (SGA) or atypical antipsychotic. Risperidone rebalances dopamine and serotonin to improve thinking, mood, and behavior. Risperdal, the brand name for Risperidone, is a second-generation antipsychotic (SGA) drug used to treat schizophrenia and bipolar disorder. Sometimes, the drug gets subscribed to those with autism, dementia, or obsessive-compulsive disorder. Developed by Johnson and Johnson subsidiary Janssen-Cilag, the FDA approved the drug in December 1993. 

Starting in 2010, Johnson & Johnson became the subject of thousands of lawsuits by men alleging that Risperdal use caused them to experience a condition known as gynecomastia or growth of excessive breast tissue. This change is said to be due to elevated prolactin levels caused by taking risperidone. There is research that suggests a link between Risperdal and increased prolactin levels. See Forbes

Since then the FDA has approved seven other atypical antipsychotics: olanzapine (1996), quitiapine (1997), ziprasidone (2001), aripiprazole (2002, paliperidone (2007), asenpaine (2009) and iloperidone (2009). Although clozpine remains the “gold standard” with respect to efficacy, the other atypical antipsychotics are considered at least as effective as typical antipsychotics for treating positive symtoms while also treating negative symptoms and causing fewer EPS side effects.

In 2002, the FDA approved Abilify® which has the active ingredient aripiprazole. Abilify® is marketed by Otsuka Pharmaceutical Co., Ltd. not only for the treatment of schizphrenia but also bipolar disorder, irritability associated with autistic disorder in pediatric patients, and as an add-on treatment for depression. It has been commercially successful. In 2009, its sales were $3.3 billion.

Brexpiprazole (Rexulti): is a medication that has similar effects to two other atypical antipsychotics, cariprazine (Vraylar) and aripiprazole (Abilify) but brexpiprazole does not have approval in the United States for treating bipolar mania. Past studies suggest that brexpiprazole is an effective adjunctive treatment for major depressive disorder and schizophrenia. The active drug in Rexulti is brexpiprazole. This drug belongs to a class of medications called atypical antipsychotics. (A medication class is a group of drugs that work in a similar way.) Rexulti is currently only available as a brand-name medication. 

Drugs in Clinical Trial

Current antipsychotic medicines rely on the same primary pathway and approach of inhibiting D2 dopamine receptors, and frequently 5HT-52A serotonin receptors, and are often used by physicians to address a wide range of psychiatric conditions, including schizophrenia and bipolar disorder, among others. However, these drugs have many side effects such as weight gain. Investigators have recently been working with different neurotransmitters such as acetylcholine, located in the cholinergic pathway. Within the cholinergic pathway, acetylcholine interacts with a type of receptor called the muscarinic receptor. There are five distinct muscarinic receptors, M1-M5, found in the brain as well as various peripheral tissues. Muscarinic receptor agonists emerged in the 1990s as a promising new approach for treating psychosis and cognitive impairment. The link between muscarinic receptor stimulation in the central nervous system (CNS), particularly the stimulation of M1 and M4 receptors, and the reduction of symptoms of psychosis and improvement in cognition, has been well studied and is supported by research from preclinical studies and clinical trials. However, the successful development of a therapy targeting muscarinic receptors has been limited by undesirable side effects that are believed to arise primarily as a result of stimulation of muscarinic receptors in peripheral tissues. Recently, Karuna Therapeutics has been investigating therapy targeting muscarinic receptors which do not have these adverse side effects. Their lead drug KarXT (xanomeline-trospium) is the lead candidate, currently being evaluated in Phase 3 clinical trials as both a monotherapy and adjunctive therapy for the treatment of schizophrenia, as well as for the treatment of psychosis in Alzheimer’s disease.

Natural Products

Sodium benzoate may be beneficial as an add-on therapty (1 gram/day) in schizophrenia. 

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