Infection Sample Answers - UCD Medical Society


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Infection Sample Answers - UCD Medical Society

  1. 1. Describe infections caused by Staphylococcus Aureus. (2009 Resit) (2008 Resit)<br />Staphylococcus Aureus is a facultatively anaerobic, gram positive coccus that is responsible for many staph infections. It is part of the skin flora, found in the nose and skin and around 20% of the population are long-term carriers of the bacterium species. <br />Numerous other infections are caused by this highly virulent species. It is a common cause of invasive infections. Superficial infections include folliculitis, impetigo, wound infection, cellulitis and abscesses, and deeper infections such as osteomyelitis, septic arthritis and pneumonia. Haematogenous infections include septicaemia, and metastatic infections such as endocarditis, meningitis and pneumonia. <br />Staph Aureus is very virulent and achieves its pathogenicity by incorporating many factors. Cell surface proteins, such as Protein A bind to the Fc region of IgG, preventing opsonisation and activating local complement. Enzymes also play an important role - Coagulase, converts fibrinogen to fibrin, creating a wall of fibrin around the bacteria which protects it against phagoytosis. Other enzymes include hyaluronidase, staphylokinase, deoxyribonuclease, lipase, protease and catalase. <br />Staph Aureus is responsible for many toxigenic infections. Staphylococcal food poisoning, caused by enterotoxin of Aureus inoculated in food causes nausea, vomiting and abdominal pain. Staphylococcal Scalded Skin Syndome is most common in neonates and young children, and is caused by the epidermolytic toxin present in Aureus. It causes erythema of the skin and bullae formation, often with spontaneous bullae rupture and cleavage of the epidermis. Toxic Shock Syndrome (TSS) is one of the most serious staph infections, and is caused by the TSS toxin in Aureus. It causes fever, hypotension, multiorgan damage and an erythematous rash with desquamation. It has a very rapid onset and has a mortality of 3-6%. <br />As mentioned above, extracellular products such as TSS toxin can cause catastrophic effects on the body. These three ‘superantigens’ are particularly pathogenic, because they stimulate T-cells non-specifically by binding with high affinity to MHC II receptors of monocytes and macrophages. This complex is recognised by Tcells and initiates dramatic cytokine liberation, which can be very harmful to body tissues. Other extracellular products of S Aureus include haemolysins and Panton Valentine Leucocidin, which forms pores in cell membranes. <br />Diagnosis of a staph infection is by laboratory investigation. Specimins can be taken from pus, sputum, faeces or nose swab, and a gram stain test performed – S Aureus is gram positive, so will be purple in colour. Blood cultures are performed on blood agar, and colonies appear golden yellow and in irregular clusters. Coagulase tests are positive. An antibiotic sensitivity test also indicates which antibiotic will be most effective – there is increasing incidence of resistance in staph species, with some S Aureus strains being resistant to methicillin (MRSA) so it is important to treat appropriately. <br />Treatment is usually determined by the antibody sensitivity test. Flucloxacillin is a common choice because it is B-lactamase stable, but is not effective against MRSA. Vancomycin (a glycopeptide) is usually the drug of choice for MRSA.<br />Describe infections caused by Staphylococcus Epidermidis. Discuss organism and host factors that predispose to these infections. (2009)<br />Staphylococcus Epidermidis is a faculatively anaerobic gram positive coccus that is part of normal skin and mucous membrane flora. It is usually non-pathogenic, but can cause disease in immunocompromised patients, and it is most frequently associated with nosocomial infection involving patients with in-dwelling foreign bodies. It is becoming increasingly resistant to multiple antibiotics, with 80-90% penicillin resistant, and 60-80% methicillin resistant. <br />Staph Epidermidis has a unique pathogenic profile. It is the most common cause of polymer-associated infections. The bacteria adhere to biomaterials (such as the plastic catheter or prosthetic valve) by producing a ‘slime’ of polysaccharides and surface proteins, called biofilm. It is a multilayer of cell clusters embedded in amorphous extracellular material. This material protects the bacteria against host defence mechanisms and antibiotics. <br />Host factors are very important in epidermidis infections. Firstly, epidermidis infections are almost exclusive to patients with an indwelling foreign body or device. The most common device is an IV catheter. There are several ways of bacterial colonisation – direct inoculation during implantation of the device, breakage in the skin at the point of catheter entry can allow the entry of bacteria (which are part of the skin flora), and migration along the inner lumen of catheters. Urinary catheters pose the same problem. <br />Epidermidis causes septicaemia by infecting catheters, prosthetic heart valves and pacemakers, ventriculoatrial shunts and valvular prostheses. Peritonitis and ventriculitis are also caused by indwelling bodies, in particular CSF shunts. Epidermidis is also the most common cause of early prosthetic valve endocarditis.<br />Patients who become infected with Epidermidis strains are also often immunocompromised and are therefore unable to fight this normally non-pathogenic micro-organism. <br />Diagnosis of Staph Epidermidis is by laboratory investigation. Specimens reveal gram positive cocci in clusters. Blood cultures on blood agar reveal white colonies (incomplete haemolysis), coagulase negative and catalase positive tests. <br />Treatment involves removal of the indwelling offending device – catheter/valve etc. Treatment with antibiotics is required to kill the infection. Staph Epidermidis is becoming increasingly resistant to many antibiotics which leaves very few options. Vancomycin is often the antimicrobial of choice. <br />Compare infections caused by Staphylococcus aureus to those caused by Staphylococcus epidermidis. Discuss organism and host factors that account for these differences. (2007)<br />Staphylococcus Aureus and Epidermidis are both facultatively anaerobic, gram positive cocci that are part of normal skin flora in humans. <br />Staph Aureus is coagulase positive and produces golden colonies in clusters on blood agar. Infections are usually of acute onset and are treated with antibiotics. <br />Infections caused by aureus are varied and range in severity – from superficial skin infections such as folliculitis, impetigo, cellulitis and abscesses, to deer infections like osteomyelitis and septic arthritis. Infections can also be spread haematogenously, and Aureus is a common cause of septicaemia, and metastatic infections including endocarditis, meningitis and pneumonia.<br />These infections are caused by the wide range of virulence factors produced by the bacteria. Cell surface proteins like Protein A cause opsonisation (and hence protection) of the bacteria by binding to the Fc portion of IgG. Enzymes play an important role in pathogenesis. Coagulase (both bound and free) causes the conversion of fibrinogen to fibrin, which forms a coat around the bacterium, preventing its phagocytosis. Other enzymes include catalase, hyaluronidase, lipase, protease, deoxyribonuclease and staphylokinase. <br />Extracellular products (toxins) can produce devastating effects also. TSS toxin causes toxic shock syndrome, enterotoxin causes food poisoning and epidermolytic toxin causes Scalded Skin Syndrome. Other toxins such as haemolysin and Panton Valentine Leukocidin are also used by Aureus to increase its virulence. <br />Host factors that cause infection are less notable, but the clever use of the host’s defence system in pathogenicity allows for rapid infection, eg opsonisation preventing phagocytosis. The superantigens (TSS toxin, enterotoxin and epidermolytic toxin) cause their devastating effects by inducing cytokine proliferation and cascades. It binds to the MHC II on monocytes and macrophages which activates Tcells in the vicinity (up to 20% of the bodys Tcell reserve), causing massive cytokine production and attack, which can damage the body tissues. <br />Staphylococcus Epidermidis is coagulase negative and produces white colonies on blood agar (incomplete haemolysis). Infections are usually more subacute and have a long latent period. <br />Epidermidis infections are most commonly polymer associated nosocomial infections. They almost always occur as a result of an indwelling foreign body – most commonly an IV catheter, but can be any form of prosthesis including valves, shunts and vascular prostheses. Epidermidis is the most common cause of early stage prosthetic valve endocarditis. Septicaemia is usually caused by catheters, prosthetic valves, shunts and vascular prostheses. Ventriculitis and peritonitis can also occur as a result of an infected shunt. <br />The presence of the indwelling foreign body in the host is the most important factor in terms of staph Epidermidis infection. The pathogenicity of this micro-organism is quite unique. The bacteria adhere to biomaterials (ie plastic etc) by producing a ‘slime’ of polysaccharide and surface proteins, called biofilm. It is a multilayer of cell clusters embedded in amorphous extracellular material. The material protects the bacteria from the host’s defences and from antibiotics. <br />In an IV catheter there are many ways the bacteria can gain access to the body. It can occur by direct inoculation when inserting the catheter. Because epidermidis is part of the skin flora, it can enter the body by the breakage in the skin at the catheter’s point of entry. The bacteria can also migrate along the inner lumen of the catheter to gain entry. Prosthetic valves and other devices usually receive the bacteria by haematogenous spread and growth occurs. <br />It is important to note also that staph aureus is a highly virulent bacteria, and therefore often infects healthy hosts, whereas staph epidermidis is usually relatively non-pathogenic and hosts are usually immunocompromised and/or have an indwelling foreign body.<br />Both Aureus and Epidermidis are becoming increasingly resistant to antibiotics. For some of the most resistant strains Vancomycin is the drug of choice.<br />Describe infections caused by Pseudomonas Aeruginosa. Discuss organism and host factors that predispose to these infections. (2008)<br />Pseudomonas Aeruginosa is an aerobic bacteria found as normal skin flora and in the human gastrointestinal tract. It is a gram negative bacillus that cannot ferment glucose, is oxidase positive and produces distinctive pigments of blue or green when cultured. <br />Pseudomonas is an opportunistic pathogen – the patient must be immunocompromised for infection to occur. Common infections include UTIs (12.5% of nosocomial), wound infections (especially post-surgical) and burns infections. Respiratory tract infections in ventilated patients (eg CF patients) and endocarditis are also caused by pseudomonas. Septicaemia caused by pseudomonas has an almost 100% mortality in immunocompromised patients.<br />Pathogenically, pseudomonas needs a significant break in the skin or first line of defence for infection to occur. Attachment is via mucoid exopolysaccharide pili and alginate, which bind to receptors in the body. The mucoid produced reveals more receptors and protects the bacterium from the body’s defences. In CF patients there are increased receptors for alginate producers – makes them more susceptible to infection. Once attachment occurs, pseudomonas induces causes destruction of tissue. This may be by chronic inflammation, induced by endotoxin LPS in the cell wall, or by extracellular products. Exotoxin A inhibits protein synthesis by inhibiting elongation factor 2. Exoenzyme S is also produced. Elastase has proteolytic activity that can cause necrosis, haemorrhage and tissue destruction and invasion. Pseudomonas can also produce cytotoxins and haemolysins. <br />In terms of host factors, the patient must usually be severly immunocompromised or have a significant skin break for infection to occur. Most pseudomonas infections occur in a hospital setting so prolonged nosocomial stay increases the risk. Pseudomonas can also dwell on most surfaces so hygiene is of extreme importance, especially in hospitals when using invasive equipment. Eg. Catheter, scalpels etc.<br />Pseudomonas is highly antibiotic resistant. Special antibiotics have been developed to fight pseudomonas, including penicillins Carbenicillin, ticarcillin and pipercillin, and cephalosporin Cefazidine. These are usually administered with an aminoglycoside such as Gentamycin. Fluoroquinolones and Carbapenems are also used. <br />Discuss treatment and antimicrobial prophylaxis of infective endocarditis. (2007)<br />Describe how you would investigate a patient with suspected infective endocarditis. Comment on diagnostic tests and criteria. (2008)<br />Discuss the investigation and treatment of infective endocarditis. (2008 Repeat)<br />Discuss the investigation and treatment of native valve endocarditis. (2009)<br />Infective endocarditis is an infection of the endocardium, on or around the valves. It is caused by the formation of non-infected thrombus on abnormal endothelial surface. Secondary infection of the thrombus with bacteria transiently present in the bloodstream leads to proliferation of bacteria on the thrombus, and the formation of a vegetation on the endothelial surface.<br />The incidence of IE is 3.6/100,000 and it has a mortality of 11-26%. Incidence is greater in males than females and 50% of cases are in patients aged over 60. <br />Predisposing factors include<br /><ul><li>Structural heart disease (congenital, mitral valve prolapsed, degenerative)
  2. 2. Previous history of IE (recurrence of 3-9%)
  3. 3. Prosthetic valve
  4. 4. IVDU
  5. 5. Rheumatic heart disease
  6. 6. Vascular instrumentation –stent, catheter, fistula
  7. 7. Ulcerative colonic lesions
  8. 8. HIV</li></ul>Investigation<br />If IE is suspected, blood cultures are taken immediately. If the patient is acutely unwell, three sets are taken from different entry points in one hour. If the patient appears stable, the sets should be taken across a 24 hour period. A blood culture ‘set’ consists of one aerobic and one anaerobic to cater for different types of bacteria. <br />Once the bloods have been sent to the lab, the patient will be put on empiric antimicrobial therapy. In an acute presentation, Staphylococcus aureus is the most common causative agent, so Flucloxacillin and Gentamycin are the drugs of choice. If the presentation is more subacute, it is more like to be caused by Viridians streptococci, so Benzylpenicillin and Gentamycin are administered. If the patient has an intracardiac prosthesis, penicillin allergy or if the suspected agent is MRSA, a combination of Vancomycin, Rifampicin and gentamycin is administered.<br />Patients with suspected endocarditis must have an echocardiogram. A transthoracic (TTE) is an uninvasive method, whereby the ultrasound is taken over the chest wall. However, the view provided is sometimes insufficient for diagnosis, particularly in very obese patients and those with COPD. Sensitivity is also low for smaller lesions, and only has a detection rate of around 60%. A trans-oesophageal echo is much more sensitive (80-90% detection) – a probe is passed down the oesophagus to around the level of the heart and so it provides a more accurate reading. However it is reserved for more high risk patients (eg those with a previous history of IE or with a prosthetic valve) because it is more costly and invasive.<br />If the patient has a history of ulcerative colonic lesions, or blood culture results indicate Strep Bovis is the causative agent, a colonoscopy is required to check for ulcerative lesions eg a tumour or IBD. <br />When the blood culture results are available, they are not always definitive. 5-10% of IE is ‘culture negative’. This can be due to antibiotics administered before the cultures were taken, or the organisms are difficult to grow or require prolonged incubation. The HACEK group, Bartonella, Brucella, Chlamidia and Coxiella Burnetti all fall under this latter category, and may require serology, histology or PCR techniques to provide confirmation.<br />Diagnosis<br />The Duke criteria is used for diagnosis of IE. A definitive diagnosis is often difficult in IE, and requires 2 major, one major and 3 minor or 5 minor criteria. Possible diagnosis of IE requires one major and one minor criterion, or three minor criteria. <br />Positive blood cultures is the first major criterion. This means a typical organism (ie S aureus or viridians strep) from 2 or more cultures, or Coxiella Burnetti from one culture. The second major criterion is a positive echocardiogram for IE (a positive oscillary intracardiac mass), or a new valvular regurgitation. <br />Minor criteria consist of a predisposing heart condition, IVDU, a temperature greater than 38C, vascular features including emboli, immunological features such as Roth spots or glomerulonephritis, and microbiological evidence, such as serology. <br />Management<br />Treatment and management of IE is by a multidisciplinary team, from cardiology, microbiology and cardiothoracic surgery. Patients are administered empirical antibiotics, as mentioned above, after blood samples are taken. An antibiotic sensitivity test is used to determine the most effective specific antibiotic, and thus the treatment is adjusted accordingly. <br />Antibiotics are must be at a high dose to kill the bacteria – immune cells cannot penetrate the vegetation because it is avascular, so a high dose is required via IV to ensure penetration of AB by diffusion. Antibiotics are used synergistically for max effect (eg. A cell wall inhibitor and gentamycin). A prolonged course of antibiotics is required to ensure that any bacteria that remain dormant are also killed. Usually the course is 4 weeks IV for a native valve, and 6 weeks for a prosthetic valve. The use of antibiotics may require monitoring (eg. Gentamycin can cause kidney damage). <br />Treatment may also involve valve repair (to remove the vegitiation) or complete valve replacement with a prosthesis. Ideally, the surgeon must clear up the infection first but this is not always possible, so complications sometimes arise with immunocompromised patients undergoing surgery. Surgery is usually only performed if absolutely necessary – if there is heart failure due to valve dysfunction, if there is an intracardiac complication, if the treatment with antibiotics is ineffective (as in fungal endocarditis) or if there is local problems, including perivalvular extension of the infection.<br />Prevention<br />Only patients with high risk cardiac conditions, such as a previous IE, prosthetic valves or surgical shunts, use prolonged prophylaxis. Patients in the high risk category will be administered antimicrobial prophylaxis prior to any major or minor dental procedures (this is because strep viridians is a common cause of IE and is part of the mouth flora, which could cause transient bacteraemia and cause IE). Other procedures including GI, GU, gynaecological or respiratory often require prophylactic treatment. <br />Patients at high risk of IE are also advised to practice good dental hygiene to prevent infection.<br />What are the common organisms causing urinary tract infection? Discuss the investigation and treatment of urinary tract infection. (2008 Resit)<br />Describe the virulence factors that enable bacteria to cause urinary tract infections. (2007)<br />Discuss the laboratory diagnosis and treatment of acute pyelonephritis. (2009 Resit)<br />Urinary tract infections are classified according to site of infection. Upper UTI involves infection of the kidneys, presenting clinically as pyelonephritis, pyelitis or a renal/perinephric abscess. Lower UTIs are those confined to the bladder (cystitis), the urethra (urethritis) and prostate (prostatitis). <br />A wide range of microorganisms cause UTIs and they vary according to whether the infection is obtained in a domicillary or nosocomial setting. Uncomplicated domicillary infections are most commonly caused by E.Coli (80%). Staphylococcus Saprophyticus causes 10-15% and the remainder is by Klebsiella, Proteus mirabilis and other gram negative bacteria. <br />Nosocomial infections have a different profile, and this is largely due to the change in flora in hospitals, and the presence of very virulent bacteria and immunocompromised patients. E.Coli is responsible for 50%, Pseudomonas Aeruginosa causes 12.5%, and enterococci cause 15%. Proteus and Klebsiella each cause 7.5%. Nosocomial infections are frequently complicated UTIs – where the infection is in the presence of functional/anatomical abnormalities and altered host defence.<br />Investigation of a UTI is by laboratory diagnosis. Specimens used are urine samples – midstream urine sample (MSU) is the most common, but catheter urine withdrawn from the draining tube can also be used. Suprapubic aspiration of urine directly from the bladder or early morning urine samples can also be used. The sample must be examined within 2 hours of collection. <br />Microscopic examination of the urine from a patient with a UTI usually contains bacteria. This is cultured to determine the causative agent and so treat appropriately. Quantitative culturing of bacteria can be diagnositic, if there is >100,000 CFU (colony forming units) per ml of urine it indicates infection. However, lower counts are sometimes seen in males, and in gram positive and yeast infections. Red blood cells and white cell casts are usually present also. The presence of squamous epithelial cells indicates the specimen is contaminated. Diagnostically, white blood cells in the urine greater than 10cells/mm3 is considered abnormal (pyuria). <br />UTI diagnosis can also be made by dipstick analysis. A leukocyte esterase test indirectly tests for pyuria. Bacteria produce nitrate reductase, which converts nitrate in the urine to nitrite, so a Nitrite test is performed to test for the presence of bacteria. <br />Asymptomatic bacteruria is the presence of significant bacteruria without symptoms of infection. It is usually not serious, but must be treated if the patient is pregnant, a renal transplant recipient, or has a planned surgery or instrumentation. <br />Treatment varies according to the severity of the infection. Acute uncomplicated cystitis is treated with a 3day course of antibiotics (or 7 days for pregnant women, diabetics or those who are symptomatic for longer than 3 days). Usual antimicrobials are co-trimidazole, fluoroquinolones, B-lactams or nitrofurantoin. For complicated infections and mild pyelonephritis, a 10-14 day oral dose of fluoroquinolones is usually recommended. Severe pyelonephritis requires IV gentamycin + fluoroquinolones, ampicillin or third generation cephalosporin, followed by oral therapy of the same antimicrobials after symptoms subside – usually total treatment is 14 days. <br />For a urinary tract infection to occur, the bacterial virulence must overcome the host’s defence mechanisms. There are several ways bacteria achieve this. <br />Most gram negative and gram positive bacteria have pili/fimbriae on their surfaces. Pili are hairlike projections that attach to other cells, such as mucosal or endothelial cells, allowing colonisation of the urinary tract. Different types of pili exist even within bacterial species. For example, in EColi, there are Type 1 pili which attach to receptors on cells, and then pass out in the urine – these cause cystitis. P-Pili attach to the wall of the bladder and may ‘climb’ up to the kidney, causing pyelonephritis. <br />Polysaccharide capsules allow bacteria to evade phagocytosis, because the capsule is slippery and fragile. Haemolysins produced by bacteria are exotoxins which cause lysis of red blood cells. Urease is an enzyme that splits urea, increasing the pH of the urine. This causes calcium and minerals to precipitate out of the urine and produce calculi – this nidus of infection causes obstruction of the urinary tract and parenchymal destruction – which can lead to complicated UTIs. <br />Flagella on the bacterial cell surface allow motility – bacteria can chemotactically ‘swim’ toward nutrients and possibly even away from harmful substances, evading attack. IgA proteases break down IgA antibodies, once again evading the immune response. However, many of these virulence factors (pili, flagella, capsule) are in fact antigenic, and cause immune reaction. They can also be used as the targets for antimicrobial therapy. <br />Discuss the investigation and treatment of acute haematogenous osteomyelitis. (2008)<br />Osteomyelitis is an infection of the bone. Infection can occur directly, often when there is compound fracture of a bone that breaks through the skin and bacteria enter, or it is surgically induced. Haematogenous infection is when the infection is carried in the bloodstream - often primary lung infection with streptococcus pneumoniae can cause osteomyelitis.<br />Acute haematogenous osteomyelitis refers to an infection that occurs over days or weeks. In children, the most common site of infection is in the metaphysis of long bones, and in adults it is in the vertebral bodies. These sites of infection have a greater vascular flow than other bones, which makes them more susceptible to blood-borne infection. <br />Transient bacteraemia reaches the bone (eg metaphysis) and bacteria replicate. Inflammation within the metaphysis can lead to a small haematoma (dilated vessels). This causes vascular obstruction and the bacteria settle and multiply, forming a medullary abscess. <br />Symptoms of acute osteomyelitis are often ambiguous – in children it usually presents as a high fever with poorly localised pain. Pseudoparalyisis in the infected leg, and after some time overlying soft tissue swelling can be detected. In adults it usually presents as back pain in the lumbar region and tenderness of the vertebrae. It may or may not present with fever. This makes it a difficult diagnosis to make, because there are many possible causes for these somewhat non-specific symptoms. <br />Diagnosis is usually made in the laboratory. Blood cultures are always taken in the case of unexplained pyrexia, but these are not always positive. Common infectious agents in children are Staph Aureus and coagulase negative staphylococci (especially in prosthetic bones), and Haemophillus Influenzae. In adults the most common agents are once again Staph Aureus and strep pyogenes. Special patient groups may have unusual bacteria – eg Diabetic (ulcer associated) may be polymicrobial, IVDU may be infected with pseudomonas, Salmonella may cause osteomyelitis in people with sickle cell anaemia, and in immunocompromised patients fungal infections are sometimes seen. <br />Needle aspiration may be required from the bone if the blood cultures are not definitive, especially in adults. An X-Ray is not a very useful form of diagnosis because the changes are slow to form, and if it is detectable on X-ray it may be too late to save the bone. <br />The treatment course is immediate for children, but for adults biopsy must be proven before treatment can commence. Usually the treatment of choice is Benzylpenicillin (2.4g) and Flucloxacillin (2g) administered via IV every 6 hours. If these drugs are contraindicated, Teicoplanin (12mg/kg) can be substituted. If gram –ve agents are suspected, Ciprofloxacin can be added and if H.Influenzae is suspected Cefuroxime can also be added. <br />IV administration of the drugs for 14-21 days is recommended (depending on the response to treatment), and the treatment should be continued orally for 3-4 weeks afterward. <br />List the types of skin infection which require admission to hospital. Describe the clinical presentation, laboratory diagnosis and treatment of one of these infections. (2009)<br />Serious skin infections involving the dermis and deeper layers of the skin must be admitted to hospital for treatment. Infections include cellulitis, necrotising fasciitis and myonecrosis. <br />Necrotising fasciitis is a rare but often rapidly fatal skin/soft tissue infection. It involves the superficial fascial layers, usually in the extremities or the abdomen. It can be a progression from cellulitis or may start ab initio. It is said to be caused by ‘flesh eating bacteria’ because the bacteria literally disintegrate the flesh. <br />It presents clinically as erythema and pain in the limb. Sometimes it can present with a very high fever. Usually swelling of the tissue appears within a few hours, and some systemic signs such as vomiting can sometimes present. <br />There are two types of necrotising fasciitis. Type 1 is less rapidly fatal, and is polymicrobial, often caused by anaerobes of the Clostridium variety. It is most commonly seen in diabetics – it may start as a simple skin scratch where the area becomes infected and the skin begins to break down. There is often little to suggest serious injury in this case so clinical suspicion is important.<br />Type 2 is more rapidly fatal and may present with no predisposition or history of trauma to the limb. It is caused by a single organism – usually Strep Pyogenes, but can also be caused by S.Aureus and other bacteria. Destruction of the tissue is caused by the bacteria releasing exotoxins, eg SPE. <br />Diagnosis is made both clinically and in the laboratory. If the disease has progressed, the tissue can appear necrosed. Examination of specimen or blood will reveal the causative microorganism and determine the course of treatment.<br />Treatment usually requires first surgical debridement and removal of the necrosed tissue, because it can lead to gangrenous destruction of the limb and mynecrosis. Treatment with antibiotics is also necessary to kill the infection. Usually a penicillin (eg Benzlypenicillin) and clindamycin or metronidazole for anaerobic bacterial coverage. Treatment with hyperbaric oxygen is sometimes used to kill anaerobic organisms. <br />Untreated, necrotising fasciitis has a very high mortality of over 75%. With corrective surgery and antibiotic treatment mortality is significantly reduced and prognosis good with limb prosthesis.<br />Why are inpatients susceptible to hospital acquired infections? Describe one such infection in detail. (2008)<br />Hospital acquired – or nosocomial – infections are those that are not present or incubating at the time of admission, but develop during hospitalisation. 5-10% patients admitted to hospital develop a nosocomial infection, and they are responsible for 3% of all hospital deaths and 1% of all deaths. Rates of infection are highest in bigger hospitals and in specialised units such as the ICU. <br />Inpatients are susceptible to infection for a number of reasons. Firstly, the reason for their admission may make them predisposed to infection – any illness can cause a weakness in the immune system, and by that token all patients can be considered immunocompromised in some way. Therefore they may not be able to fight off infection as they usually would. <br />Instrumentation is a major problem for nosocomial infection spread. Any breakage in the skin is a breach of the body’s first line of defence against pathogens – therefore every catheter and every line inserted into the patient’s skin could potentially be contaminated and cause infection. IV catheters are particularly implicated in hospital acquired infections, especially by Staphylococcus epidermidis. Similarly urinary catheters are responsible for 80% of nosocomial UTIs. Hygiene is of utmost importance for all healthcare workers to prevent the spread of infection. Because pathogens are spread easily, either directly from person-person, by aerosol, inoculation, or by common vehicle, any instruments in a hospital that are not sterilised is potentially carrying a whole range of pathogens that could cause serious illness in an immunocompromised patient. <br />Diagnostic and therapeutic procedures, such as tracheal intubation or a trans-oesophageal echocardiography that are invasive can introduce bacteria into the body. Intubation bypasses the air-filtering system of cilia in the upper respiratory tract, and large particles that are usually filtered are aspirated into the lungs, which can cause respiratory tract infections, including pneumonia and chronic lung infections.<br />The use of broad spectrum empirical antibiotics is one of the most notable causes of hospital acquired infections. These antibiotics kill bacteria that are sensitive – weaker, less resistant strains – and pave the way for the colonisation of more resistant strains of bacteria that are not easily treated. Hospitals are a hub of resistant bacteria for this reason, and a patient is far more likely to encounter the more resistant strains in the hospital than in the community. <br />Immunosuppressive treatments, such as treatment for autoimmune disorders or chemotherapy, suppresses a patient’s immune system, making them more susceptible to infection, and especially susceptible to opportunistic infections. These infections arise when the normal body flora is either killed and more pathogenic bacteria can thrive instead, or when normal flora becomes pathogenic in the immunocompromised state. <br />Finally, inpatients are exposed to a wider range of dangerous pathogens in a hospital – and furthermore, pathogens interact with other pathogens, increasing their virulence and producing more resistant strains of bacteria. It is estimated that up to one third of HAI are preventable by simple hygiene techniques and increased awareness. <br />Urinary tract infections are the most common hospital acquired infections (30-40%). 80% are caused by instrumentation (ie catheter) and 5-10% is caused by GI or GU surgery. In the hospital, 50% are caused by EColi, 12.5% caused by pseudomonas, 15% by enterococci, and Klebsiella and Proteus are each responsible for 7.5%. <br />Usually the organisms are endogenous – due to the patient’s own flora – or they can be exogenous, where they have been picked up from the hospital environment. The factors mentioned above lead to increased susceptibility to infection.<br />Write short notes on... Measles. (2008) (2009 Resit)<br />Measles is a highly infectious virus of the Morbillivirus genus. It is an RNA enveloped virus of helical symmetry with only one serotype. It is sensitive to detergents, acid labile (ineffective between 5-9pH) and rapidly inactivated by heat and light. It has surface proteins haemagluttinin, fusion protein and matrix protein; and structural proteins nucleoprotein, large protein and phosphoprotein. <br />Measles spreads via aerosol droplets or through respiratory secretions. It is highly contagious, with one case infecting a further 17-20 people. Inoculation of the respiratory tract leads to local replication, followed by lymphatic spread and viraemia. This leads to wide dissemination of the virus to all tissues including the conjunctivae, respiratory tract, the UT, small bloodvessels, the lymphatic system and the CNS. The virus infected cells and immune cells produce the characteristic erythematous maculopapular skin rash.<br />The virus has an incubation period of 10-14 days, followed by a prodromal stage for 2-4 days, consisting of malaise, fever, coryza, conjunctivitis and Koplik’s spots. It is sometimes also accompanied by a mild respiratory tract infection such as a cough. This stage is then followed by the rash which lasts 5-6 days. The virus is infectious from the prodromal stage until 3-4 days after the rash onset. <br />The most serious complication is encephalitis. Acute measles post-infectious encephalitis has an incidence of 1/1000-5000 and has a 15% mortality rate. Subacute sclerosing panencephalitis is much more rare at 1/100,000, and has a high mortality. Other complications include secondary bacterial infections of the resp tract, otitis media, giant cell pneumonia, diarrhoea and rarely seizures. <br />Diagnosis of measles is usually clinical. The presence of Koplik’s spots on the oral mucosa is diagnostic. Laboratory diagnosis consists of serum or saliva culture and identification of measles specific IgM.<br />In Ireland the incidence has greatly declined since the MMR vaccine was introduced in 1988. It is administered at 15months and again aged 4-5. <br />Write short notes on... Rubella. (2008 Resit) (2009)<br />Rubella is a moderately infectious virus of the Togavirus genus. It is a ssRNA enveloped virus of icosahedra symmetry. It is rapidly inactivated by chemical agents, low (acidic) pH, UV light and heat. Humans are the only hosts and the most common age for infection is 4-9. <br />Transmission occurs by respiratory droplet inhalation. The virus replicates in the nasopharynx and regional lymphnodes causing primary viraemia. The virus spreads to systemic tissues then causing secondary viraemia. It has an incubation period of around 14 days. The prodromal stage is usually subacute, but some may symptoms including upper resp tract infections, low grade fever, arthralgia and lymphnode swelling, and the characteristic erythematous maculopapular rash. The virus is infectious 7 days before to 4 days after the appearance of the rash. <br />Complications are usually mild – such as arthralgia. Thrombocytopaenia purpura, encephalitis, neuritis and orchitis are very rare complications. The most serious effect of Rubella is the infection of a pregnant woman leading to congenital rubella syndrome. The earlier in the pregnancy the infection occurs the greater the extent of foetal damage. If infected in the first trimester, up to 85% children will be affected, with apparent anomalies or anomalies that will develop later. The classic defects caused by rubella are IUGR, congenital heart defects, deafness, cataracts and mental retardation. <br />Diagnosis is usually either clinical or by serology. Rubella specific IgM are detectable for 4-8 weeks after infection – screening for antibodies is the best way to determine if a person has been subject to the virus. Virus isolation is not usually performed because it is difficult (need to have the right cells to culture it in, and is only useful for diagnosing the congenitally acquired disease. <br />Infection with the virus confers lifelong immunity. Similarly vaccination with the MMR vaccine at 15months and 4-5 years confers immunity. It is contraindicated in pregnancy because it is a live virus. <br />Write short notes on... Candida Albicans. (2008) (2009) (2009 Resit)<br />Candida Albicans is a form of yeast fungus that is part of the normal flora habituating the GI tract and GU tract of females. It is a single celled organism that replicated by budding. It can cause cutaneous, mucosal and invasive infections. <br />The yeast prefers warm moist areas, and therefore can infect the axilla, groin and perineum, and sometimes the nail bed. It usually presents clinically as a localised erythematous macular rash. It is diagnosed by taking skin scrapings and examined microscopically. Treatment for a skin infection is a topical azole, and for a nail infection an oral azole. <br />Mucosal infections usually present as discrete white patches on the mucosal surface, and most commonly infect the oral cavity and the vaginal mucosa. Sometimes the oesophageal mucosa can also become infected, but usually only in HIV patients. A swab is taken, and examined by microscopy and cultured. It is treated with fluconazole, either oral or topical.<br />Invasive conditions can be either focal or disseminated. They usually only affect very immunocompromised patients, because humans have a very high intrinsic immunity to yeasts, and systemic infections by a yeast are quite rare. A systemic infection may present as a bloodstream infection, which is often related to a line or cannula in a hospital setting. It can also present as endocarditis, hepato-splenic disease or by intra-abdominal collections. Diagnosis is by gram stain – the organism is large, purple and round or oval, sometimes with budding. The yeast is culturable on most media, and a chromogenic media identifies the strain of Candida. Candida Albicans has a positive germtube test. <br />Treatment for an invasive albicans infection is oral or IV fluconazole. <br />Short notes on... Aspergillus. (2008 Resit)<br />Aspergillus is a mould or filamentous fungus that is acquired from decaying vegetation. Moulds consist of individual cells joining end-to-end forming hyphae by atypical extension. A group of hyphae forms a mycelium. Moulds replicate by asexual reproduction forming sporangia, which then release spores. Inhalation of these spores is the most common route of infection.<br />Allergic Bronchopulmonary Aspergilliosus is a hypersensitivity reaction of the airways, usually in susceptible immunocompromised patients such as those with CF or asthma. Symptoms are a dry wheeze, cough, shortness of breath and fever. Aspergillus antibody detection is used to diagnose the condition, and it is treated with Itraconazole and steroids.<br />An aspergillioma is a clump of fungus or ‘fungus ball’ that forms in the lung cavity. It can cause obstruction of the airways and cause infection, and must be treated or removed. <br />Invasive Aspergilliosus is most commonly caused by Aspergillus Fumigatus, a fungus which is normally non-pathogenic. In immunocompromised patients it gains acces to lung periphery and multiplies. It can cause serious problems by damaging and penetrating the blood vessels, causing thrombosis, vessel occlusion and tissue necrosis. Diagnosis is made by culturing specimens and aspergillus antigen detection. A CT of the thorax can also be useful in identifying the source of the infection.<br />It is treated with Amphotericin B, but has a poor prognosis if it has invaded into the bloodstream. <br />Give a brief overview of the anti-bacterial agents that interfere with bacterial cell wall synthesis. (2007)<br />Bacterial cell walls are good targets for anti-bacterial agents because humans do not have cell walls, so toxicity is therefore usually quite low. Cell wall synthesis inhibitors are often used synergistically with other anti-microbial agents to potentiate their affect. <br />Beta-lactam antibiotics inhibit cell wall synthesis by three mechanisms<br /><ul><li>Inhibiting the synthesis of cell wall component peptidoglycan
  9. 9. Inhibiting the transpeptidation enzyme that cross links cell wall components
  10. 10. Inactivating the inhibitor of autolytic enzymes in the bacteria – therefore causing cell lysis</li></ul>There are four families of B-lactam antibiotics. They are called B-lactams because of the presence of the B-lactam ring in their structure. <br />I. Penicillins<br />Penicillins were the first discovered and therapeutically used antimicrobial. They are bactericidal, but sensitive to B-lactamase. Administration is by oral, IV or intramuscular. It’s absorbtion is decreased with food and with an acidic pH. It is widely distributed across all tissues and body fluids, it crosses the placenta, and bone and blood-brain-barrier when they are inflamed. It is metabolised and excreted by the kidneys. Side <br />Side effects include hypersensitivity reactions, GIT disturbances, neurotoxicity (seizures, hallunciation, coma), platelet dysfunction, elevated LFTs, granulocytopaenia and haemolysis. It is widely used clinically, and is usually the first line of defence for most bacterial infections, unless it is contraindicated. Penicillins are quite broad spectrum, and most gram –ve and +ve bacteria are sensitive to them. It is used in skin infections (impetigo, cellulitis), in strep throat, UTIs, STIs, gangrene, diphtheria. It is also affective against Haemophillis Influenza and pseudomonas aeruginosa. <br />Examples of penicillins include Penicillin, Amoxicillin, and newer generations such as Carbenicillin and Pipercillin. <br />II. Cephalosporins<br />Cephalosporins are another group of B-lactams and they are relatively B-lactamase resistant. They contain a target for B-lactamase that does not allow bacterial cleavage of the B-lactam ring. Cephalosporins are bactericidal, can be administered orally, IV or intramuscularly and also have a wide distribution. Third generation Cephalosporins can cross the BBB when it is not inflamed and there therefore very useful against meningitis. Most are excreted unchanged in the urine, only some are metabolised in the liver. Side effects include local phlebitis, GIT and hypersensitivity reactions and neurotoxicity at very high concentrations. They can also cause hepatotoxicity and nephrotoxicity in the form of allergic interstitial nephritis. <br />Cephalosporins are used clinically when the bacterium is of unknown origin – for example in meningitis. If there is suspected meningitis, third generation cephalosporins are usually immediately administered after a lumbar puncture. They are also used in mixed infections, ones that involve anaerobes in particular, and in surgical prophylaxis. Third generation cephalospoirns are used against B-lactamase producing bacteria and in gram –ve meningitis. <br />Examples include Cefalexin, Cefachlor and Ceftriaxone. <br />III. Carbapenems such as Imipenem are broad spectrum B-lactamase antibiotics. They are administered by IV and have a wide distribution, but do not cross the uninflammed BBB. They are metabolised in the kidney by enzyme Dihydropeptidase and have similar side effects to other B-lactams. They are used clinically against G- and G+ aerobes and anaerobes.<br />IV. Monobactem antibiotics such as Aztreonnam, are relatively resistant to most B-lactamase producing bacteria, but are only effective against G- aerobic rods (eg EColi, proteus, klebsiella, pseudomonas). They are administered by IV and excreted renally. Side effects are similar to other B-lactams, and also include elevated liver function tests and an increased risk of superinfection with G+ organisms. <br />The other major family of cell wall synthesis inhibitors are the Glycopeptides. Glycopeptides work by inhibiting the release of cell-wall building blocks, inhibiting peptidoglycan synthesis, and leaving a backlog of precursor molecules. They are bactericidal against most G+s and is also effective against MRSA, however they are bacteristatic against Streptococci, who appear to be resistant to cell death. They are administered by IV, because they are not absorbed from the GIT (although they can be used to sterilise the GIT against Clostridium difficile pre-operatively if taken orally). <br />Side effects include hypersensitivity, local phlebitis, rash and fever. Ototoxicity and nephrotoxicity are rare. They are used clinically to treat pseudomembranous colitis, staph infections in patients who are allergic to penicillin and endocarditis. <br />Use of glycopeptides is limited to reduce the risk of bacterial resistance developing. They are usually reserved for very serious infections and are therefore very expensive. <br />Examples include Vancomycin and Teicoplanin. <br />Other cell wall inhibitors that are not commonly used include Bacitracin, which inhibits the dephosphorylation of lipid carrier, but is highly toxic and only used topically. Cycloserine is a structural analog of D-alanine, which is a precursor of peptidoglycan and is taken into the molecule, rendering peptidoglycan non-functional and causes the breakdown of the cell wall. Cycloserine is used to treat TB.<br />Give a brief overview of the anti-microbial agents that interfere with bacterial protein synthesis. (2008)<br />Bacterial protein synthesis is similar to human protein synthesis, but the difference in ribosomal subunits used allows this process to be exploited by anti-microbials with minimal toxicity. Humans have 60s and 40s subunits, whereas bacteria use 30s and 50s subunits. Proteins are a necessity for survival of bacteria, so inhibiting their production essentially kills the bacteria. <br />Two agents affect protein synthesis at the 30s subunit – Aminoglycosides and Tetracyclines. <br />I. Aminoglycosides<br />Aminoglycosides are bactericidal antibiotics that bind to the 30s on the ribosome, and cause alteration in the codon-anticodon recognition. This leads to misreading of DNA, and the ‘wrong’ DNA is incorporated, forming a non-functional protein. Penetration into the bacterial cell requires the use of oxygen dependent active transport, and so aminoglycosides are not very useful against anaerobes. Aminoglycosides are usually prescribed with a B-lactam or other cell wall inhibitor to potentiate their action – if the cell wall is broken, the aminoglycoside can easily access the ribosomes and cause their affect.<br />Aminoglycosides are administered orally or by IV, they have limited distribution - they do not cross the BBB, cells, eyes or secretory fluids, but can access joints and pleura and cross the placenta. They are metabolised and excreted through the kidneys.<br />Aminogycosides are most useful against G- aerobic bacteria, but can be used against G+ also. As mentioned, they are usually treated along with a B-lactam. Side effects include hypersensitivity and GIT disturbances, nephrotoxicity, ototoxicity and neurotoxicity. <br />The most commonly used drug from this category is GENTAMYCIN. <br />II. Tetracyclines<br />Tetracyclines inhibit protein synthesis by competing for the A site on the 30s of the ribosome – this means the protein produced is truncated and non-functional. Tetracyclines are bacteristatic and require active transport to gain access to the bacterial cells interior. Administration is oral or by IV. It is important to note that if taken orally, the drug binds to metals in the stomach, so absorption is decreased in the presence of milk, antacids and iron. It is widely distributed across body fluids, and excretion is unchanged in the bile and kidney. Minocycline (synthetic) is metabolised in the liver. <br />Tetracyclines have a wide range of uses, against G+ and G- bacteria. It can be used in chlamidial, rickettsial, mycoplasmic infections, and also against cholera and plague. Minocycline can be used to treat adult acne, and demeclocycline is used to treat SIADH, by inhibiting the binding of ADH in the renal tubules.<br />Side effects can involve GIT irritation and vitamin B deficiency. Chelation of calcium can lead to calcium deposition in the teeth and bones causing staining and hypoplasia and so is not recommended in children and pregnant women. Photosensitivity, dizziness and nausea have also ben reported. Very high doses can cause bone marrow suppression, anaemia and nephrotoxicity. <br />Tetracyclines used clinically include tetracycline, minocycline, demeclocycline and doxycycline. <br />Six drugs work by taking their effect on the 50s subunit – chloramphenicols, macrolides, lincosamides, fuscidic acid, streptogrammin and oxalizidonones<br />I. Chloramphenicols<br />These bind to the 50s subunit and inhibits transpeptidation, so it only inhibits bacterial protein synthesis because this process is not used in human protein synthesis. They can be administered orally or by IV, have a fast and complete absorption and a wide distribution (it crosses the BBB). They are metabolised by the liver (90%) and excreted by the kidneys.<br />Chloramphenicols are broad spectrum, working against G- and G+ and Rickettsiae. They are mostly bacteristatic, but are bactericidal against H.Influenza, N.Meningitidis and Strep. Pneumoniae. Their use is confined to serious infections to reduce the incidence of resistance. They can be used in H.Influenza, meningitis, bacterial conjunctivitis and typhoid fever. Side effects include bone marrow suppression, Grey Baby syndrome, hypersensitivity and GIT. <br />II. Macrolides. <br />Macrolides bind to the 50s subunit and inhibits protein production by inhibiting translocation and blocks access to the A site. It can be bactericidal or bacteristatic, depending on the organism. <br />Erythromycin is most effective against G+, spirochaetes, mycoplasma and legionella, but can be used in G- infections also. Azithromycin is more effective against H.Influenza and legionella and can also be used to treat toxoplasmosis gondii by killing the cysts. Clairythromycin is used against H.Influenza, mycobacterium, leprosy and lyme disease. <br />They can be administered orally, and erythromycin is sometimes given via IV. They have a wide distribution but do not cross the BBB or synovial fluid. They are metabolised in the liver (clairythromycin is converted to an active metabolite here by p450 system), and excreted in the bile. <br />Side effects include GIT, hypersensitivity, cholestatic jaundice and opportunistic infections of GIT and vagina. <br />III. Lincosamides<br />Lincosamides such as Clindamycin also inhibit translocation of the 50s subunit, and blocking the A site. These are administered orally, have a wide distribution but do not cross the BBB and are excreted in the bile and urine. Mild side effects include GIT and inflammation of the colon. They are used in G+ cocci infections – serious staph infections, staph conjunctivitis and anaerobic bacteria.<br />IV. Fusidic Acid<br />Fusidic Acid drugs such as sodium fusidate also inhibit translocation at the 50s subunit. They are administered orally, have a wide distribution and are excreted in the bile. They have mild side effects of GIT and jaundice. They are narrow spectrum Abs, and can only be used against osteomyelitis, serious staph infections and to treat staph conjunctivitis. <br />V. Streptogrammin eg. Quinupristin<br />These antibiotics use the 50s subunit, block tRNA attachment and cause premature peptide release. They are administered by IV and metabolised by the liver. Side effects include phlebitis, arthralgia and myalgia. <br />VI. Oxalizidonones eg. Linezolid<br />These bind the 50s subunit, blocking initiator tRNA. They are administered orally or by IV, metabolised in the liver and kidneys and excreted renally (30-60% unchanged). Side effects include thrombocytopenia, GIT, rash and dizziness. <br />Quinupristin and Linezolid are used synergistically at smaller doses to reduce toxicity. They are reserved for serious infections and are very expensive. Uses include MRSA, VRE, penicillin-R strep pneumonia, skin and soft tissue infections to prevent sepsis and for Nosocomial pneumonia. <br />Write short notes on... Fluoroquinolones. (2009) (2009 Repeat)<br />Fluoroquinolones are bactericidal nucleic acid synthesis inhibitors. They work by inhibiting DNA gyrase topoisomerase II, causing inhibition of the negative supercoil of DNA and inhibition of transcription and translation. The damage to the DNA causes gaps in the DNA strands, which induces repair process. The repair enzymes try to patch the DNA back together, but the processes are uncoordinated, causing the breakdown of DNA, causing irreversible damage to the bacterium and death. Resistance to fluoroquinolones is due to reduced uptake and enzyme affinity, either by mutated enzymes or mutated gyrase.<br />They are administered orally or by IV. Absorbtion from the GIT may be hindered by the presence of aluminium or magnesium, which binds to the drug. Distribution is wide, with preferential perfusion to the kidney, prostate and lung. Some agents including ofloxacin cross the BBB with 90% of the plasma concentration of the drug. Fluoroquinolones are metabolised in the liver, and inhibit the P450 system, and are excreted in the urine. <br />Side effects are usually rare and mild, with GIT and hypersensitivity, arthropathy, CNS headaches and dizziness. Rarely encountered side effects include renal impairment, HT or photosensitivity. It is important to not the drug interaction with theophylline – ciprofloxacin inhibits the p450 system and thus can induce theophilline toxicity. <br />The most commonly used fluoroquinolone is Ciprofloxacin. This is a broad spectrum gram –ve antimicrobial, which also works against H.Influenza, N.gonnorrhoea and pseudomonas. It is most commonly used in complicated UTIs, pseudomonas incfections including otitis media, in gonorrhoea ‘the clap’ and can also be used in anthrax poisoning. <br />Other agents include levofloxin, norfloxacinm ofloxacin.<br />Write short notes on... Sulphonamides. (2009)<br />Sulphonamides are bacteristatic nucleic acid synthesis inhibitors that work by inhibiting nucleotide synthesis. Nucleotides are the precursors of DNA (the bases), and sulphonamide is a structural analogue of PABA, which is required for the synthesis of folic acid in bacteria. Sulphonamides compete with PABA for the enzyme dihydropteroate synthetase, inhibiting the synthesis of folate, which is then converted to folic acid by dihydrofolate reductase. Folic acid is then used as a precursor molecule for bacterial DNA. Inhibition of this pathway causes bacteriostasis as it cannot replicate or produce proteins. <br />Sulphonamides are administered orally, by IV or intramuscularly and are well absorbed. They have a wide distribution, crossing the placenta and BBB. They are hepatically metabolised and excreted by the kidneys. Side effects include GIT, headache, depression, cyanosis, bone marrow suppression, anaemia, hypersensitivity and photosensitivity, hepatitis, crystalluria, StevensJohnson Syndrome, kernicterus, and they also increase the activity of warfarin, so can cause haemorrhage. <br />Sulphonamides are broad spectrum and can be used against G+ and G- bacteria, as well as against chlamidial infections and malaria. <br />Sulphonamides are used most commonly in conjunction with Trimethoprim, which is a folate antagonise. It competes for the dihydrofolate reductase enzyme mentioned previously to inhibit production of folic acid. Because these two drugs work on the same bacterial pathway, lower doses can be administered which reduces the side effects. They are used together against UTIs, respiratory tract infections, especially Pneumocystitis Carinii in AIDS patients. <br />Write short notes on... Metronidazole. (2009 Resit)<br />Metronidazole is a nucleic acid inhibitor that binds to DNA, and preventing nucleic acid synthesis by damage via toxic oxygen products. It is bacteriostatic, and is well absorbed and distributed, eliminated in the urine mostly unchanged. It is used to treat sepsis in bacteroides sp., pseudomembranous colitis by clostridia so, and to treat oral infection by fusobacterium sp. Side effects include GIT disturbance, rashes and urticaria. Most notably, metronidazole causes a disulfram-like effect with alcohol, as it inhibits alcohol and aldehyde dehydrogenase, causing nausea and vomitting.<br />Describe the ways by which antimicrobial resistance can be controlled. (2007)<br />List the factors that have contributed to the development of antimicrobial resistance. (2009)<br />Antimicrobial resistance is the method by which microorganisms become stronger, more resistant to treatment and more difficult to kill. Resistance can be natural, for example gram negative bacteria can sometimes have natural resistance because of their cell walls, or it can be acquired. <br />Acquired resistance can be vertically inherited – where genetic mutations occur naturally as the organisms divide. The less resistant organisms are killed by the immune system or by antimicrobial drugs, and those who have a genetic alteration that makes them more resistant survive. This is called selective pressure. Alternatively, and more clinically significantly, horizontal evolution can occur. This is where bacteria pass on resistance to each other, either inter or intra-species. After transmission of the resistance genes (usually carried on plasmids), the genes are incorporated into the organisms DNA and resistance is carried. <br />Horizontal resistance is associated with the over-use or inappropriate use of antibiotics. Antibiotics administered at a low dose will not kill a pathogen, and the pathogen will see the antimicrobial as a threat, and develop resistance to it. Similarly, orally administered drugs have a reduced bioavailability after absorption from the GI tract, which is effectively the same as administering a low dose. Treatment for insufficient amount of time may not kill the bacteria, and allows it to develop resistance after treatment has stopped. Controlling the use of antimicrobials is one of the most important and efficient methods of controlling resistance. This applies to healthcare practitioners, who must choose an appropriate empiric antimicrobial agent, and adjust the drug according to an antibiotic sensitivity test. Patients must also be aware of correct practice when taking antibiotics – they must finish the course at the correct dosage for the right amount of time, and should never share medication or keep it in case of re-infection. <br />Animals are a constant source of antimicrobial resistance. Animals in the food chain are often given medication inappropriately – animals given drugs to treat an infection should not be allowed into the food chain until there is no trace of the drug in its system. Farmers often give livestock prophylactic antibiotics if one or two animals in the group are infected. This is both unnecessary, and causes increased resistance. Antimicrobials were once used as growth promoters, but this practice is now illegal. The incidence of VRE in broiler chickens in Denmark has been reduced from 80 to 5% since this law was introduced. Animal infections with resistant organisms have the potential to enter the food chain and be acquired by humans. This may include pathogens, such as salmonella, VRE and campylobacter, or non-pathogenic species that can transfer resistance to pathogenic organisms, such as enterococci, increasing their resistance. The DAFF have published a list of guidelines for vets including guidelines on animals entering the food chain after antimicrobial therapy, and the process of random testing to monitor residues in animals and meats. <br />Usually the most resistant organisms are found most commonly in hospitals. Hospitals have a susceptible population of immunocompromised individuals, and a pool of resistant organisms. Resistance is spread easily in hospitals – either directly, from person-person contact, or indirectly, by infection spreading to contaminated clinical equipment or a contaminated environment. Insufficient bed capacity, and shared rooms with crowded conditions are perfect for microorganisms to spread easily from sick person to sick person. Interaction with different bacteria allows easy spreading of resistance genes. Furthermore, the poor handwashing compliance and poor equipment cleaning allows the resistance to spread even more easily. To control the spread of resistance, stricter measures are required to improve handwashing after every patient, to isolate patients or put patients in cohort wards and improved cleaning of the environment and clinical equipment, and the use of personal protective equipment of gloves and masks etc to ensure healthcare workers are not carrying infectious pathogens. <br />Surveillance and education of the public and doctors are important to increase awareness of the danger of antimicrobial resistance.<br />Briefly review the mechanism of action of Antiviral drugs. (2008)<br />Antiviral drugs target three pathways in the replication and spread of viruses. <br />Agents that inhibit the replication of the viral genome include Acyclovir and Ribavirin.<br />Acyclovir is converted to monophosphate by thymidine kinase and converted to triphosphate in the host cell. It inhibits DNA polymerase by competing with endogenous molecules and terminating the nucleotide chain. After incorporation into the chain it interferes with DNA replication with the formation of truncated or non-functional proteins. Acyclovir is used most commonly by HSV 1 and 2, varicella zoster and CMV. Gancyclovir has a similar method of action and is used against CMV and retinitis. <br />Ribavirin and Tribavirin are both guanosine analogues. They inhibit the replication of the viral genome by blocking the synthesis of dGTP, inhibiting viral RNA polymerase and therefore inhibiting replication. It is a broad spectrum antiviral and can be used against DNA and RNA viruses. Common uses include infections caused by respiratory syncytial virus, Influenza A and B, Hepatitis C and Lassa fever.<br />Amantadine and Rimantidine are inhibitors of viral uncoating. They block H+ ion channels, which are M2 transmembrane proteins. This prevents the fusion of the viral membrane with the endosome membrane, it prevents the assembly and release of new virions at the cell surface, and it prevents the acidification of virus containing vesicles, preventing their uncoating. It is used against Influenza A but is not useful against H1N1 because of viral resistance.<br />Finally, Oseltamivir (tamiflu) is a prodrug, activated in the liver, that inhibits viral release – it inhibits neurominidase by blocking its active site, which inhibits the release of budded virus from the cell. It is used to treat influenza A and B, and as a prophylactic measure against these viruses also. <br />Briefly review the mechanisms of action of antifungal agents. (2007) (2008 Resit) (2009 Resit)<br />Briefly review the mechanisms of action of antifungal agents and their therapeutic uses. (2009)<br />Fungi are eukaryotic organisms, more similar to human cells than other microorganisms, so targeting fungi specifically can be a challenge for the pharmaceutical industry. Nevertheless there are several sites of action that can be exploited. <br />Fungi have a rigid cell wall – Echinocandins such as caspofungin and micafungin inhibit cell wall synthesis by inhibiting Beta-glucan synthase. It irreversibly inhibitis 1,3 B-glucan synthase and is therefore fungicidal. It is a broad spectrum antifungal with little direct human toxicity. <br />Polyenes such as Amphotericin B are large cyclic macrolide molecules. They bind ergesterol with very high affinity, forming a pore which causes the loss of K+ and macromolecules. Ergesterol is the fungal equivalent to cholesterol in the cell membrane, and has a much higher affinity for ergesterol than cholesterol. It is a broad spectrum antifungal used to treat systemic infections caused by aspergillus, candida and Cryptococcus. However it is associated with a wide range of side effects, with over 80% patients experiencing renal toxicity. <br />Azoles are synthetic fungistatic agents that take effect on the cell membrane. Ketonazole inhibits fungal P450 3A enzymes, converting lanosterol to ergesterol causing altered membrane fluidity, disrupted membrane enzymes and inhibits replication. It also inhibits the transformation of candida yeasts into hyphae in the body. Fluconazole is a bistriazole with similar affects. Azoles are used to treat a wide range of fungal infections, both superficial and systemic. Side effects include hepatotoxicity, endocrine effects and drug interations involving the P450 system.<br />Griseofulvin is a narrow spectrum fungistatic agent that interacts with microtubules, disrupting mitosis and thus inhibiting nuclear division. It is used orally to treat prolonged nail and skin infections as it is selectively taken up into keratin. It induces the CYP450 system, so drug interactions are an important side effect.<br />Flucytosine is a synthetic narrow spectrum agent used to treat yeast and cryptococcal meningitis. Cytosine is converted into 5-fluorouracil and inhibits DNA synthesis by inhibiting thymidylate synthetase. It requires cytosine permease to enter the cell. Side effects are mild, and it is associated with increasing resistance. <br />Finally Allylamines inhibit fungal squalene epoxidase – decreased ergesterol synthesis leads to squalene in the cell which is fungicidal. <br /> <br />