BACTERIAL PATHOGENS OF HUMANS INTRODUCTION Medically important bacteria may be classified into five main groups that include gram-positive, gram-negative, acid fast, spiral and cell wall deficient bacteria. Note: 1. Morphology, Growth characteristics, Virulence (pathogens' invasiveness, intoxication and 1 hypersensitivity owing to genetic or biochemical or structural features), infective dosages, Pathogenicity (the ability of bacteria to cause disease colonization characteristics in a and relating host), disease to each organism discussed. 2. Also note the overlapping causative agents of typical infectious diseases and the organs or body parts commonly affected. 3. The most common sites of microbial entry are: (1) mucosal surfaces 2 comprising the respiratory, ear canal, alimentary and genitourinary tracts; (2) the skin or the conjunctiva in the case of eye infections. 4. Aetiology of bacterial diseases is compounded by the need to differentiate between the the “good” and the “bad” bacteria. Diseases such as: Bacterial meningitis, Urinary vaginosis, Bacterial tract Bacterial pneumonia, infection (UTI), Bacterial gastroenteritis, and Bacterial skin infections (Impetigo, Erysipelas, 3 and Cellulitis) have multiple aetilogies. Also note that bacteria can cause multiple aetilogies. 5. Avoidance of innate host defence mechanisms including but not limited to barriers such as mucous, secretions (lysozyme, interferons e.t.c.), complement system, acidity, Phagocytic and inflammatory responses. Note: Complement is a set of proteins circulating in the blood stream which, 4 on activation by the presence of microbes complexes or antibody-antigen attract phagocytes, enhance phagocytic ability and form a membrane attack complex which can kill gram-negative bacteria. GRAM POSITIVE AND NEGATIVE COCCI 5 Pyogenic Cocci (various pus-producing spherical bacteria) Gram-positive cocci Staphylococcus aureus, Streptococcus pyogenes and Streptococcus pneumoniae, Gram-negative cocci Neisseria gonorrhoeae meningitidis. STAPHYLOCOCCUS 6 and N. Staphylococcus aureus, S. epidermidis or S. albus and S. saprophyticus are three clinically important members of staphylococcus species. S.aureus is the most staphylococcal virulent of species It characteristically produces coagulase enzyme which enables it to coagulate plasma. S. saprophyticus is a pathogen of the urinary tract. Staphylococcus epidermidis lives on the skin and mucous 7 membranes (normal flora). S. epidermidis is rarely a pathogen and probably benefits its host by producing acids on the skin that retard the growth of dermatophytic fungi. Staphylococcus aureus occur normally on mucous membranes. S. aureus cause: Boils (pimples), wound infections, pneumonia, osteomyelitis, septicemia, food intoxication, and toxic shock syndrome. S. aureus is the leading cause of nosocomial infections by 8 Gram-positive bacteria. Also, it is usually resistant to penicillin and many other antibiotics. Streptococcus and Enterococcus Streptococci are gram-positive cocci often seen growing in pairs or chains. They are non-sporing facultative aerobes which may occasionally have capsules. Enterococci, have similar characteristics as streptococci and were formerly classified as Streptococci. Enterococci differ from Streptococci in 9 their ability to grow on bile salt containing media. Streptococci can be described as haemolytic or non haemolytic. The haemolytic streptococci may have α (green colouration) or β haemolysis (colourless) haemolysis. Streptococci also have carbohydrate antigens in their cell envelops that give different reactions to antibodies in agglutination tests, and provide a basis for classification known as the Lancefield system of classification, 10 such as Lancefield Groups A, B, C, D up to G. Streptococcus pyogenes cause suppurative diseases and toxinoses, autoimmune or allergic diseases. S. pyogenes is the main streptococcal pathogen causes tonsillitis or strep throat. Streptococci also invade the skin to cause localized infections and lesions, and produce toxins that cause scarlet fever and toxic shock. Sometimes, as a result of an acute 11 streptococcal infection, anomalous immune responses are started that lead to diseases like rheumatic fever and glomerulonephritis, which are called post-streptococcal sequelae. Streptococci are sensitive to penicillin and the other beta lactam antibiotics. Streptococcus pneumoniae is the most frequent cause of bacterial pneumonia in humans. It is also a frequent cause of otitis media (infection of the middle ear) and meningitis. The bacterium 12 colonizes the nasopharynx and from there gains access to the lung or to the eustachian tube. If the bacteria descend into the lung they evade engulfment by alveolar macrophages if they possess a capsule which somehow prevents the engulfment process. Encapsulated strains are able to invade the lung and noncapsulated strains, which are readily removed by phagocytes, nonvirulent. 13 are Note that pneumonia may be caused by various bacteria as shown in the Table below Organism Predisposing factor Symptoms to infection Streptococ Older patients Sudden cus or patients onset pneumoni with various pleuritic ae underlying diseases prior pain, fever, or rusty sputum, cold 14 hospitali- sores; or sation of any Pneumonia kind. in the chronic bronchitic Staphyloc Long term occi use of aureus glucocorticoi ds or pneumonia following influenza 15 Haemophi Acute lus or chronic influenzae inflammation of the airways i.e. chronic or acute bronchitis Klebsiella Predisposing Thick pneumoni disease eg viscous ae alcoholism, purulent red diabetics; sputum, hospitalisatio pneumothor 16 n, Mechanical ax on X-ray ventilation Moraxella Associated catarrhali with s pneumonia in older adults, long of history cigarette smoking, underlying chronic obstructive 17 pulmonary disease lung or cancer and malnutrition. Mycoplas Associated ma with Non productive pneumoni pneumonia in cough, ae older adults pharyngitis in young adult, ambulant 18 despite positive chest X-ray Legionella Being a Non pneumoph middle ila aged productive male, cough, smoking, confusion, exposure to diarrhoea, air conditioning or hotel shower 19 Mycobacte Immunosuppr Upper lobe rium ession consolidatio tuberculos n, is lymphadeno pathy, Chlamydi Associated a with pneumoni pneumonia in ae older persons Chlamydi Association a psittaci with birds 20 hilar Group B streptococci (S. agalactiae) are a frequent cause of peripartum fever. The organisms easily colonise infants delivered vaginally by mothers are carriers of the bacteria. They are major causes of neonatal sepsis and meningitis. In neonatal sepsis the neonate patients demonstrate may typically respiratory distress, lethargy, and hypotension as symptoms. 21 Groups C and G streptococci cause infections similar those of Group A. These include pharyngitis, cellulitis and soft tissue infections, pneumonia, bacteraemia, endocarditis and septic arthritis Group D streptococci (Enterococci) E. faecalis and E. faecium, the most significant pathogens of the enterococci are more associated with infections in patients who are elderly or debilitated, patients in whom the balance of normal 22 flora has been altered by antibiotic treatment or patients in whom the mucosal or epithelial barrier has been disrupted for example by catheterization. In these patients they may be causative agents for urinary tract infections and nosocomial bacteraemia. They are also frequent causes of endocarditis, liver abscesses, infectious complications of biliary surgery, and diabetic foot ulcers 23 Anaerobic streptococci (Peptostreptococci) Peptostreptococci (P. magnus, P. micros, P. asacharolyticus) are normal commensals of mucosal surfaces of mouth, lower gastrointestinal and female genital tract. They cause mixed infections with these other anaerobic organisms when a mucosal barrier of the skin is compromised by surgery, trauma, tumour and necrosis. 24 ischemia or NEISSERIAE The Neisseriae cause gonorrhea and meningitis. Neisseriaceae is a family of Gram-negative bacteria which are small cocci usually seen in pairs. Most neisseriae are normal flora or harmless commensals of mammals living on mucous membranes. In humans they are common residents of the throat and upper respiratory tract. Two species are primary pathogens of man, Neisseria gonorrhoeae and meningitidis. 25 Neisseria Neisseria gonorrhoeae causes sexuallytransmitted disease and may be asymptomatic such that an infected mother can give birth and unknowingly transmit the bacterium to the infant during its passage through the birth canal resulting in neonatal ophthalmia, which may cause blindness. For this reason an antimicrobial agent is usually added to the newborn eye at the time of birth. 26 Neisseria meningitidis is an important cause of bacterial meningitis, an inflammation of the meninges of the brain and spinal cord. Other bacteria that cause meningitis Haemophilus include influenzae, Staphylococcus aureus and Escherichia coli. Meningococcal meningitis differs from other causes in that it is often responsible for epidemics of meningitis. It occurs most often in children aged 6 to 11 months, but it also occurs in older children and in adults. 27 LISTERIA MONOCYTOGENES Listeria monocytogenes is a Grampositive rod-shaped bacterium. It is the agent of listeriosis, a serious infection caused by eating food contaminated with the bacteria. The disease affects primarily pregnant women, newborns, and adults with weakened immune systems. The two main clinical manifestations are sepsis and meningitis. Meningitis is often complicated by encephalitis. 28 Microscopically, Listeria species appear as small, Gram-positive rods, which are sometimes arranged in short chains. Flagella are produced at room temperature but not at 37°C. Pathogenesis Listeria monocytogenes is presumably ingested with raw, contaminated food. An invasin secreted by the bacteria enables the listeriae to penetrate host cells of the epithelial lining if the immune system is 29 compromised. Listeria monocytogenes multiplies not only extracellularly intracellularly, after but within also macrophages phagocytosis, or within parenchymal cells which are entered by induced phagocytosis. The bacteria macrophages first and appear then spread in to hepatocytes in the liver. The bacteria stimulate a CMI response that includes the production interferon, of TNF, macrophage gamma activating factors and a cytotoxic T cell response. 30 Listeria are able to penetrate the endothelial layer of the placenta and thereby infect the fetus. Haemophilus influenzae. Haemophilus influenzae is a small, nonmotile Gram-negative Haemophilus influenzae bacteria. requires preformed growth factors that are present in blood, specifically X factor (i.e., hemin) and V factor (NAD or NADP). In the laboratory, it is usually 31 grown on chocolate blood agar which is prepared by adding blood to an agar base at 80oC. Pseudomonas aeruginosa. P. aeruginosa strains produce two types of soluble pigments, the fluorescent pigment pyoverdin and the blue pigment pyocyanin. The latter is produced abundantly in media of lowiron content and functions in iron metabolism in the bacterium. Pyocyanin (from "pyocyaneus") refers to "blue 32 pus", which is a characteristic of suppurative infections caused by Pseudomonas aeruginosa. Resistance to Antibiotics The bacterium is naturally resistant to many antibiotics. It can create biofilms which are impervious to therapeutic concentrations of Pseudomonas carries antibiotics. antibiotic resistance plasmids. Only a few antibiotics are effective 33 against Pseudomonas aeruginosa, including fluoroquinolones, gentamycin and imipenem. Cystic fibrosis patients eventually become infected with Pseudomonas aeruginosa. Bordetella pertussis and Whooping Cough B. pertussis produces a variety of substances with toxic activity in the class of exotoxins and endotoxins. It produces the pertussis toxin which mediates both the colonization and 34 toxemic stages of the disease. PTx is an A-B exotoxin. The A subunit is an ADP ribosyl transferase. The B component binds to specific carbohydrates on cell surfaces. PTx is transported from the site of growth of the Bordetella to various susceptible cells and tissues of the host. Following binding of the B component to host cells, the A subunit is inserted through the membrane and released into the cytoplasm. The A subunit then transfers the ADP ribosyl moiety of NAD to the membrane-bound 35 regulatory protein Gi that normally inhibits adenylate cyclase resulting in cough paroxysm. Lipopolysaccharide: Bordetella pertussis possesses lipopolysaccharide (endotoxin) in its outer membrane. The lipopolysaccharide is alternative form of Lipid A which is called Lipid X. Lipid X causes activation of complement, fever and hypotension. Lipid X, but not Lipid A, is pyrogenic. 36 E. coli Diseases Neonatal Meningitis E. coli strains invade the blood stream of infants from the nasopharynx or GI tract and are carried to the meninges. Intestinal Diseases Caused by E. coli As a pathogen, E. coli is best known for its ability to cause intestinal diseases. Five classes (virotypes) of E. coli that cause diarrheal diseases 37 are now recognized: enterotoxigenic E. coli (ETEC), enteroinvasive E. coli (EIEC), enterohemorrhagic E. coli (EHEC), enteropathogenic E. coli (EPEC), and enteroaggregative E. coli (EAEC). Each class falls within a serological subgroup and manifests distinct features in pathogenesis. Enterotoxigenic E. coli (ETEC) 38 ETEC may produce a heat-labile enterotoxin (LT) that is similar to cholera toxin. Enteroinvasive E. coli (EIEC) EIEC closely resemble Shigella in their pathogenic mechanisms and the kind of clinical illness they produce. Enteropathogenic E. coli (EPEC) 39 EPEC induce a profuse watery, sometimes bloody, diarrhea. Enteroaggregative E. coli (EAEC) The distinguishing feature of EAEC strains is their ability to attach to tissue culture cells in an aggregative manner. These strains are associated with persistent diarrhea in young children. They resemble ETEC strains in that the bacteria adhere to the intestinal mucosa 40 and cause non-bloody diarrhea without invading or causing inflammation. Enterohemorrhagic E. coli (EHEC) EHEC are recognized as the primary cause of hemorrhagic colitis (HC) or bloody diarrhea, which can progress to the potentially fatal hemolytic uremic syndrome (HUS. There are many serotypes of this E. coli strain but only those that have been 41 clinically associated designated as with EHEC. HC are Of these, O157:H7 is the prototypic EHEC and most often implicated in illness worldwide. EHEC infections are mostly food or water borne and have implicated undercooked ground beef, raw milk, cold sandwiches, water, unpasteurized apple juice and vegetables Vibrio cholerae 42 Cholera is a severe diarrheal disease. Transmission to humans is by water or food. The clinical description of cholera begins with sudden onset of massive diarrhea. The patient may lose gallons of protein-free fluid and associated electrolytes, bicarbonates and ions within a day or two. This results from the activity of the cholera enterotoxin which activates the adenylate cyclase enzyme in the intestinal cells, converting them into pumps which 43 extract water and electrolytes from blood and tissues and pump it into the lumen of the intestine. This loss of fluid leads to dehydration, anuria, acidosis and shock. The watery diarrhea is speckled with flakes of mucus and epithelial cells ("rice-water ") and contains enormous numbers of vibrios. The loss of potassium ions may result in cardiac complications and circulatory failure. Untreated cholera frequently results in high mortality rates. 44 Treatment of cholera involves the rapid intravenous replacement of the lost fluid and ions. Following this replacement, administration of isotonic maintenance solution should continue until the diarrhea ceases. If glucose is added to the maintenance solution it may be administered orally, thereby eliminating the need for sterility and iv. administration. By this simple treatment regimen, patients on the brink of death seem to be miraculously cured and the 45 mortality rate of cholera can be reduced more than ten-fold. Cholera Toxin Cholera toxin activates the adenylate cyclase enzyme in cells of the intestinal mucosa leading to increased levels of intracellular cAMP, and the secretion of H20, Na+, K+, Cl-, and HCO3- into the lumen of the small intestine. The net effect of the toxin is to cause cAMP to be produced at an abnormally high rate which stimulates mucosal cells 46 to pump large amounts of Cl- into the intestinal contents. H2O, Na+ and other electrolytes follow due to the osmotic and electrical gradients caused by the loss of Cl-. electrolytes in The lost H 2O and mucosal cells are replaced from the blood. Thus, the toxin-damaged cells become pumps for water and electrolytes causing the diarrhea, loss of electrolytes, and dehydration that are characteristic of cholera. 47 Salmonella and Salmonellosis Salmonella are the cause of two diseases called salmonellosis, and enteric fever (typhoid), resulting from bacterial invasion of the bloodstream, and acute gastroenteritis, resulting from a foodborne infection/intoxication. Antigenic Structure Somatic (O) or Cell Wall Antigens Surface (Envelope) Antigens 48 Flagellar (H) Antigens Shigella and Shigellosis Shigellae are Gram-negative, nonmotile, non-spore forming, rodshaped bacteria, very closely related to Escherichia coli. Shigellosis Shigellosis is an infectious disease caused by various species of Shigella. People infected with Shigella develop diarrhea, fever and stomach cramps 49 starting a day or two after they are exposed to the bacterium. The diarrhea is often bloody. Shigellosis usually resolves in 5 to 7 days, but in some persons, especially young children and the elderly, the diarrhea can be so severe that the patient needs to be hospitalized. Reiter's syndrome Persons with diarrhea usually recover completely, although it may be several months before their bowel habits are 50 entirely normal. About 3% of persons who are infected with Shigella flexneri may subsequently develop pains in their joints, irritation of the eyes, and painful urination. This condition is called Reiter's syndrome. Hemolytic Uremic Syndrome (HUS) Hemolytic uremic syndrome (HUS) can occur after S. dysenteriae type 1 infection. Convulsions may occur in children; the mechanism may be related to a rapid rate of temperature elevation 51 or metabolic alterations, and is associated with the production of the Shiga toxin. The Shiga Toxin The Shiga toxin, also called the verotoxin, is produced by Shigella dysenteriae and enterohemorrhagic Escherichia coli (EHEC), of which the strain O157:H7 has become the best known. Mechanism of Action 52 The toxin acts on the lining of the blood vessels, the vascular endothelium. The B subunits of the toxin bind to the cell membrane. The A subunit interacts with the ribosomes to inactivate them. The A subunit of Shiga toxin is an Nglycosidase that modifies the RNA component of the ribosome to inactivate it and so bring a halt to protein synthesis leading to the death of the cell. The vascular endothelium has to continually renew itself, so this killing of cells leads to a breakdown of the 53 lining and to hemorrhage. The first response is commonly a bloody diarrhea. This is because Shiga toxin is usually taken in with contaminated food or water. Clostridium perfringens C. perfringens 54 Clostridium perfringens, which produces a huge array of invasins and exotoxins, causes wound and surgical infections that lead to gas gangrene, in addition to severe uterine infections. Clostridial hemolysins and extracellular enzymes such as proteases, lipases, collagenase and hyaluronidase, contribute to the invasive process. Clostridium perfringens also produces an enterotoxin and is an important cause of food poisoning. Usually the organism is encountered in improperly sterilized 55 (canned) foods in which endospores have germinated. Gas gangrene Gas gangrene generally occurs at the site of trauma or a recent surgical wound. The onset of gas gangrene is sudden and dramatic. About a third of cases occur on their own. Patients who develop this disease in this manner often have underlying blood vessel disease (atherosclerosis or hardening of the arteries), diabetes, or colon cancer. 56 Gas gangrene is marked by a high fever, brownish pus, gas bubbles under the skin, skin discoloration, and a foul odor. It can be fatal if not treated immediately. Clostridium difficile C. difficile Clostridium difficile causes antibioticassociated diarrhea (AAD) and more serious intestinal conditions such as 57 colitis and pseudomembranous colitis in humans. These conditions generally result from overgrowth of Clostridium difficile in the colon, usually after the normal intestinal microbiota flora has been disturbed by antimicrobial chemotherapy. In the hospital and nursing home setting, C. difficile infections can be minimized by careful use of antibiotics, use of contact precautions with patients with known or suspected cases of disease, and by implementation of an 58 effective environmental and disinfection strategy. Clostridium tetani C. tetani Clostridium tetani is the causative agent of tetanus. The organism is found in soil, especially heavily-manured soils, and in the intestinal tracts and feces of various animals. The organism produces 59 terminal spores within a swollen sporangium giving it a distinctive drumstick appearance. Although the bacterium has a typical Gram-positive cell wall, it may stain Gram-negative or Gram-variable, especially in older cells. Tetanus is a highly fatal disease of humans.The disease stems not from invasive infection but from a potent neurotoxin (tetanus toxin or tetanospasmin) produced when spores germinate and vegetative cells grow after gaining access to wounds. The 60 organism multiplies locally and symptoms appear remote from the infection site. Pathogenesis of tetanus Most cases of tetanus result from small puncture wounds or lacerations which become contaminated with C. tetani spores that germinate and produce toxin. The infection remains localized, often with only minimal inflammatory damage. The toxin is produced during 61 cell growth, sporulation and lysis. It migrates along neural paths from a local wound to sites of action in the central nervous system. The clinical pattern of generalized tetanus consists of severe painful spasms and rigidity of the voluntary muscles. The characteristic symptom of "lockjaw" involves spasms of the masseter muscle. It is an early symptom which is followed by progressive rigidity and violent spasms of the trunk and limb muscles. Spasms of the pharyngeal 62 muscles cause difficulty in swallowing. Death usually results from interference with the mechanics of respiration. Clostridium botulinum C. botulinum C. botulinum is a large anaerobic bacillus that forms subterminal endospores. It is widely distributed in 63 soil, sediments of lakes and ponds, and decaying vegetation. Pathogenesis of Food-borne Botulism In food-borne botulism, the botulinum toxin is ingested with food in which spores have germinated and the organism has grown. The toxin is absorbed by the upper part of the GI tract in the duodenum and jejunum and passes into the blood stream by which it 64 reaches the peripheral neuromuscular synapses. The toxin binds to the presynaptic stimulatory terminals and blocks the release of the neurotransmitter acetylcholine which is required for a nerve to simulate the muscle. Bacillus anthracis and Anthrax The anthrax bacillus, Bacillus anthracis, was the first bacterium shown to be the cause of a disease. In 65 1877, Robert Koch grew the organism in pure culture, demonstrated its ability to form endospores, and produced experimental anthrax by injecting it into animals. Bacillus anthracis is Gram-positive, sporeforming rod. The bacterium can be cultivated in ordinary nutrient medium under aerobic or anaerobic conditions. Genotypically and phenotypically it is very similar to Bacillus cereus. Anthrax 66 Gastrointestinal anthrax is similar to cutaneous anthrax but occurs on the intestinal mucosa. As in cutaneous anthrax, the organisms probably invade the mucosa through a preexisting lesion. The bacteria spread from the mucosal lesion to the lymphatic system. Intestinal anthrax results from the ingestion of poorly cooked meat from infected animals. Gastrointestinal anthrax is rare but may occur as explosive outbreaks associated with ingestion of infected animals. Intestinal 67 anthrax has an extremely high mortality rate. Bacillus cereus is a normal inhabitant of the soil, but it can be regularly isolated from foods such as grains and spices. B. cereus causes two types of food-borne intoxications (as opposed to infections). One type is characterized by nausea and vomiting and abdominal cramps and has an incubation period of 1 to 6 hours. It resembles Staphylococcus aureus food poisoning in its symptoms and incubation period. 68 This is the "short-incubation" or emetic form of the disease. The second type is manifested primarily by abdominal cramps and diarrhea with an incubation period of 8 to 16 hours. Diarrhea may be a small volume or profuse and watery. This type is referred to as the "long-incubation" or diarrheal form of the disease, and it resembles food poisoning caused by Clostridium perfringens. In either type, the illness usually lasts less than 24 hours after onset. 69 The short-incubation form is caused by a preformed, heat-stable emetic toxin, ETE. The mechanism and site of action of this toxin are unknown, although the small molecule forms ion channels and holes in membranes. The longincubation form of illness is mediated by the heat-labile diarrheagenic enterotoxin Nhe and/or hemolytic enterotoxin HBL, which cause intestinal fluid secretion, probably by several mechanisms, including pore 70 formation and activation of adenylate cyclase enzymes. Corynebacterium diphtheriae Diphtheria is an upper respiratory tract illness characterized by sore throat, low fever, and an adherent membrane (called a pseudomembrane on the tonsils, pharynx, and/or nasal cavity. Diphtheria toxin produced by C. diphtheriae, can cause myocarditis, polyneuritis, and other systemic toxic 71 effects. A milder form of diphtheria can be restricted to the skin. Pathogenicity 1. Invasion of the local tissues of the throat, which requires colonization and subsequent bacterial proliferation. The bacteria produce several types of pili. 2. Toxigenesis:The diphtheria toxin causes the death eucaryotic cells and tissues by inhibition protein synthesis in the cells. 72 Toxigenicity Two factors have great influence on the ability of Corynebacterium diphtheriae to produce the diphtheria toxin: (1) low extracellular concentrations of iron and (2) the presence of a lysogenic prophage in the bacterial chromosome. The repressor is activated by iron, and it is in this way that iron influences toxin production. High yields of toxin are 73 synthesized only by lysogenicbacteria under conditions of iron deficiency. Mycobacterium tuberculosis and Tuberculosis Tuberculosis TB infection means that MTB is in the body, but the immune system is keeping the bacteria under control. The immune system does this by producing macrophages that surround the tubercle bacilli. The cells form a hard shell that 74 keeps the bacilli contained and under control. Most people with TB infection have a positive reaction to the tuberculin skin test. People who have TB infection but not TB disease are NOT infectious, i.e., they cannot spread the infection to other people. These people usually have a normal chest xray. TB infection is not considered a case of TB disease. Mycobacterium bovis is the etiologic agent of TB in cows and rarely in 75 humans. Humans can also be infected by the consumption of unpasteurized milk. Atypical mycobacteria which include mycobacteria demonstrating unique properties like growth temperatures, pigment production when grown in either light (photochromogens) or darkness (scotochromogens) or rapidity of growth. Examples include M. kansasii, (photochromogenic) M. avium and M. intracellulare, (non pigmented 76 mycobacteria commonly associated with pulmonary and extrapulmonary infections in HIV patients) and M. chelonei, which are fast growing. Cell Wall Structure The cell wall structure of Mycobacterium tuberculosis deserves special attention because it is unique among procaryotes, and it is a major determinant of virulence for the bacterium. The cell wall complex contains peptidoglycan, but otherwise it 77 is composed of complex lipids. Over 60% of the mycobacterial cell wall is lipid. The lipid fraction of MTB's cell wall consists of three major components, mycolic acids, cord factor, and wax-D. Resistance to anti-TB drugs can occur when these drugs are misused or mismanaged. Examples include when patients do not complete their full course of treatment; when health-care providers prescribe the wrong 78 treatment, the wrong dose, or length of time for taking the drugs; when the supply of drugs is not always available; or when the drugs are of poor quality. Multidrug-resistant tuberculosis (MDR TB) is TB that is resistant to at least two of the best anti-TB drugs, isoniazid and rifampicin. These drugs are considered first-line drugs and are used to treat all persons with TB disease. 79 Extensively drug resistant TB (XDR TB) is a relatively rare type of MDR TB. XDR TB is defined as TB which is resistant to isoniazid and rifampin, plus resistant to any fluoroquinolone and at least one of three injectable second-line drugs (i.e., amikacin, kanamycin, or capreomycin). Because XDR TB is resistant to first-line and second-line drugs, patients are left with less effective treatment options, and cases often have worse treatment outcomes. 80 Both MDR TB and XDR TB are more common in TB patients that do not take their medicines prescribed, regularly or who or as experience reactivation of TB disease after having taken TB medicine in the past. Persons with HIV infection or other conditions that can compromise the immune system are at highest risk for MDR TB and XDR TB. They are more likely to develop TB disease once infected and have a higher risk of death from disease. 81 Actinomycetes and related bacteria The actinomycetes are relatives of tuberculosis and diphtheria but are not pathogenic. Actinomycetes show branching and filament formation. Many of the organisms can form spores, but they are not the same as endospores. Branched forms resemble molds. Actinomycetes such as Streptomyces have a world-wide distribution in soils. They are important in aerobic decomposition of organic compounds 82 and have an important role in biodegradation and the carbon cycle. Actinomycetes are the main producers of antibiotics in industrial settings, being the source of most tetracyclines, macrolides (e.g. erythromycin), and aminoglycosides (e.g. gentamicin, etc.). 83 streptomycin, Spirochaetes (Spiral bacteria) These are spiral shaped bacilli. With the exception of a few, they generally cannot be cultivated in the laboratory. They are classified into three clinically important classes. 84 Borrellia, which are relatively large motile spirochaetes exemplified by B. vicenti and Leptotrichia buccalis and B recurrentis. B. vicenti and Leptotrichia buccalis are known causative agents for Vincents angina while B recurrentis is associated with relapsing fever. Lyme disease was first recognized in the US. Lyme outbreak and the onset of illness occur during summer and early fall suggested that the transmission of the disease was by an arthropod vector. 85 The etiologic agent is Borrelia burgdorferi. Treponema, which are relatively thinner and more tightly coiled than Borrelia. Typical pallidum examples and T. are Treponema pertenue, which respectively cause syphilis and yaws. Leptospira: These are finer and more tightly coiled than the Treponemes. They are classified as a single species of 86 Leptospira interrogans. Many of its available serotypes (over 130) are pathogenic and include icterohaemorrhagiae which L. causes Weil’s disease and L. canicola which causes lymphocytic meningitis. Obligate Intracellular Gram-negative bacteria Small bacteria that require intracellular environment easily for growth and are not cultured in 87 diagnostic laboratories. Important members of the group include: Clamydias of which Clamydia trachomatis, (causative agents for eye disease, urethritis and cervicitis and lymphogranuloma venereum). C. psittaci (causative agent for psittacosis – an uncommon respiratory infection) and C. pneumoniae (causative agent for an atypical pneumonia). 88 Rickettsiae and coxiellae: Rickettsiae are obligate intracellular gram negative bacteria with preference for vascular endothelium. Rickettsial diseases are associated with petechial (vasculitic rash) and multi-organ disease. Coxiella is a related genus that causes acute disease (atypical pneumonia), and chronic disease (infective endocarditis) 89 Cell-wall deficient bacteria Mycoplasmas are a group of bacteria that lack a cell wall. Pathogenic important typically pneumoniae species of mycoplasmas include Mycoplasma and Ureaplasma urealyticum. They are not stained by gram stain reagents and are also resistant to the effects of β-lactam antibiotics because of their lack of cell wall. They cause atypical pneumonia, upper respiratory tract infections and central nervous system complications. 90 Most isolates are sensitive Erythromycin and Tetracycline. 91 to