Mild to moderate pain is an unspecific definition of pain, would prefer that we all used some sort of visual acuity scale (from last lecture) to quantify everything precisely—mild to moderate would fall between 0 and 5 on one of those scales. The mainstays of our analgesic therapy are found in the box on this page. Acetaminophen is known as Tylenol. Ibuprofen is generic for Advil and Motrin. Naproxen is known as Alleve, over the counter. You can see by the nomenclature that the ‘-prophens’ are related to a chemical class. How do they differ? Which one will be suitable for mild to moderate pain? . Always consider starting on the low end of the anti-inflammatory agents before prescribing a narcotic agent like hydrocodone which is an ingredient in Vicodin.
In dental pain, Celebrex (single doses of 200 and 400 mg) is comparable to naproxen sodium 550mg, and ibuprofen 400 mg in terms of duration of analgesia. “Well, that’s odd” you may think, “…if Celebrex is not significantly superior, but merely comparable to conventional NSAIDs, why prescribe Celebrex or Vioxx, both of which are very expensive?” A very good question indeed, my friend! The trick is in selectively inhibiting COX-2, not COX-1. COX-1 inhibition hurts the gut; you increase the risk of GI ulceration and bleeding. So the reason that Vioxx and Celebrex emerged was not for superior analgesic effects, but for GI safety.
When we compare Vioxx and Celebrex, renal and vascular safety with vioxx is compromised due to dose-related peripheral edema and hypertension. As a result of this fact, the FDA took a hard look at chronic Vioxx dose at 50mg. There is more significance of cardiovascular problems with chronic use. As dentists, we’d only prescribe vioxx for 5 days for acute pain. We’re being careful not to promote these drugs too much in the clinic until there are more comparative studies.
“An evaluation of flurbiprofen, aspirin, and placebo in postoperative oral surgery pain”
There are dose related effects related to Flurbiprofen (a Flurinated Ibuprofen) with respects to pain relief. Two aspirin tablets (650 mg) beats the placebo, but is metabolized and its effects are gone in 6-8 hours. Flurbiprofen at 25mg is similar to aspirin, but if you double the dose of flurbiprofen, it jumps way up in effective pain relief. If you double the dose again, it only increases pain relief just a bit. So the lesson here is that if you double a dose it doesn’t necessarily double the effectiveness of a drug,
A salicylate derivative, diflunisal (brandname dolobid= “dolo” as in dolor, which means pain, and “bid” meaning 2x/day… so given 2x/day for pain…clever). We see that aspirin (650 mg) peaks analgesic effects at about 2.5 hours. Diflunisal is clearly superior to aspirin, but rarely prescribed anymore because it is now available generically and hence is not advertised anymore. It’s a case of pharmaco-economics.
This compares acetaminophen (1000mg) and a placebo and naproxen (440mg; known otc as Alleve). Acetaminophen, already at a maximum daily dose, peaks quickly and drops off rapidly. Naproxen has superior analgesic power and lasts longer. So if you tell the patient to take Alleve 2x/day, it beats out acetaminophen. So don’t be a chump and over-prescribe drugs that aren’t as good as some others… use the drugs that are appropriate!
(codeine is an opiate derivative)
-codeine at 60mg is not effective for dental pain
-acetaminophen alone (600mg) beats codeine even though its not a COX-1/COX-2 inhibitor.
THUS, codeine alone is not superior to acetaminophen, BUT when the two are combined (codeine + acetaminophen, as in Tylenol III) we have increased analgesia as compared to either product alone.
Caffeine has no analgesic power. It’s usually present in analgesic combinations above 30 to 65mg. Some pts are very sensitive to caffeine and show tachycardia and nervousness. So if you prescribe caffeine as an adjunct to other therapies (as in Excedrin migraine, which contains acetaminophen, aspirin AND caffeine).
Etodolac (Lodine) is widely promoted in dental conferences, because the manufacturers are looking for a dental use. It’s approved for dental analgesia, but not as popular as ibuprofen. There are differences in indications between all these drugs . Ketorolac is the only injectable NSAID available right now, approved only for acute pain. After intra-muscular injection, there is a prescription for 3 days oral Ketorolac. Ibuprofen can be used for fever, pain, arthritis, dysmenorrhea. Same with aspirin. Same indications with naproxen, plus gout and ankylosing spondylitis
Does pretreatment with an NSAID before a dental procedure reduce the extent and severity of post-surgical or post-extraction pain and inflammation? Is the time course of the pain and inflammation less if an NSAID is given one hour pre-surgery?
To answer,we see that both pre- and post-operative ibuprofen dosages are essentially the same in analgesia effectiveness. Some oral surgeons argue that pre-dose ibuprofen modifies the time course of post-extraction inflammation and swelling. As far as analgesia though, it doesn’t mean that they will come out of surgery with no pain.
Because of duodenal ulcers or gastric ulcers. Aspirin accelerates the risk of GI ulceration. If a pt has an ulcer, these NSAIDs are absolutely contraindicated!
It is important that dentists know dosages along with regimens. It is important to understand the term “analgesia”, which is “a state of not feeling pain although the pt is fully conscious.” Lidocaine is a local anesthetic (LA), NOT an analgesic. Pain must be precisely defined, this is an area that the medical/dental profession is not adept at.
The (JCAHO) standards provide that “Pain is considered the fifth vital sign” and that the intensity of pain should be recorded on a patient’s record along with temperature, pulse, respiration, and blood pressure. Dentists should asses pain just as they do other vital signs like bp, hr, etc.
Patients won’t refer to the type of pain, only “it hurts”. You must determine if it is inflammatory, traumatic, trauma related, etc. The choice of an analgesic depends on the type of pain; if inflammatory, use a non-steroidal anti-inflammatory analgesic, if its neuropathic, you must use an entire different analgesic. Most dental related pain is traumatic, related to tissue injury.
For many of us, “mild, moderate, severe” is the way we quantitatively identify pain. This is not really adequate to describe pain, it should be based on a more exact scale such as the visual analog scale (VAS) to be described later.
We also must talk about acute vs. chronic pain; acute pain includes a duration of the regimen, many of the drugs we will discuss are approved for “acute pain in adults, no longer than 3-5 days therapy”. Whereas chronic pain lasts day after day, month after month, so managing that kind of pain requires a different strategy. So we must be able to manage the different types of pain.
There are pain patterns involving the central nervous system. The thalamus and CNS are the origin of pain in some cases. Most pain that you’ll see in dentistry is from peripheral origins—something happens to peripheral tissues, mediators are released and activate pain receptors, and the pt perceives the pain via a central mechanism. Some pain is of vascular origin, such as migraine headaches—to treat these we use analgesics that affect vascular tissue. We don’t call anti-migraine drugs analgesics, because they act on the physiology of the vasculature.
Many pts seen in practice or clinic are being treated for arthritis. If a pt is taking a good heavy dose of anti-inflammatory for their arthralgia and come in for a dental procedure, do they already have effective analgesia? The need to prescribe analgesia may be affected when a pt is taking drugs for chronic arthritis.
Evaluating analgesics vs. placebo effects is important. Sometimes a placebo such as a sugar pill (or any pill with no active ingredient) is given during clinical trials to test the effectiveness of an analgesic vs the psychological effects associated with a fake treatment (the placebo). It is unethical for anyone to prescribe a placebo unless you’re doing a study, and in that case you’ve got to get all kinds of clearance from ethics committees, etc.
Pain is mediated by many pathways. Chemical mediators of pain and drug targeting include prostaglandins (PGE1, PGE2), which cause dental pain, inflammation, and fever. There are other mediators that could be effected by a particular drug strategy, but overwhelmingly the peripheral acting agents are modifying the production of theses chemical mediators which precipitate pain.
Pain pathways are well known. Peripheral nerves to the spinal cord to the ascending tracts to the thalamus and ultimately pain is perceived in the sensory cortex (homunculus). The distribution of pain in the sensory cortex is well represented in the neck, tongue and oral cavity. So the central pathway becomes essential and for many patients analgesics must block the central pathway. Remember, blocking a peripheral nerve with lidocaine is not considered analgesia, licocaine is a local anesthetic NOT an analgesic.
There is an emotional aspect of pain, commonly manifested as depression associated with a chronic pain (such as chronic lower back pain). Thus, anti-depressants are common adjuncts in the treatment of long-term pain. The limbic system is the origin of pain’s emotional component.
Approximately 50% of prescription drugs are also available over the counter (otc). A prescription is good if you want to really control the pain because you can prescribe a specific dose, regimen, etc. If a pt calls with residual pain after, for example, an extraction, it’s ok to tell them to just take some ibuprofen or other otc analgesics. There is now some concern about otc drug abuse.
The DEA regulates the classification of narcotic drugs, we’ll say a lot about schedule II, III, and IV analgesics in the future. The typical schedule II analgesics are those that have addiction liabilities (ie. Codeine and morphine). Schedule III and IV are less addictive. There is talk about changing the classification of Vicodin from schedule III to II, because of the potential for abuse. Schedule II drugs need special triplicate forms for prescriptions. Vicodin is one of the most heavily abused drugs in medicine and dentistry and is the number one cause of dentists losing their license for drug “misdirection”, either using it themselves or over-prescribing it.
For therapeutic decision making, the clinician must know the nature and severity of pain, the best indicated class of analgesics, contraindications, doses and dose regimens, and drug interactions.
Although there are a variety of views on the subject, there is no reason to think that former heroin or narcotic users would need a different amount of analgesic. However, former substance abusers may have different levels of tolerance as to local anesthetic administration. These are unresolved issues, however.
There are known drug alternatives for the management of pain, such as acupuncture, hypnosis, etc.
-Alveolar osteitis “dry socket”
-Maxillary sinusitis “teeth hurt in maxilla”
-Trigeminal neuralgia: this requires a very special strategy
-Burning mouth/ lip syndrome: some patients have this burning sensation
-TMJ
-Myofascial
-Oral cancer pain: must be managed with narcotics! Its been found that physicians have been under prescribing analgesics for painful conditions such as cancer—the courts side with the patient on this.
-Mandibular fracture
-Post-tooth extraction pain: often used as a pain model to evaluate an analgesic against a placebo
-Central pain: “Causalgia” burning pain often accompanied by trophic skin changes, due to injury of a peripheral nerve.
-Heterotopic pain
-Lancinating pain
-Terebrating pain: “boring” type of pain (like a bore being driven into your skull, not boring as in “lecture is boring”)
This is an old scale, which has never caught on in dentistry. Words are not assigned to the VAS, but it goes by numbers and is quantitative. “Mild, moderate, severe” are not accurate terms. The choice of a drug should depend more on a quantitative scale, such as the VAS. In this system, the clinician can chart the amount of pain that a person is in and it can be normalized to help with clinical studies. Mean VAS scores may be plotted before, during and after analgesic therapy, vs variables such as time post medication (or placebo), or vs dose of drug (as seen in the handout). So the VAS can help us to determine that CP99 is not in clinical use, because it is not much better at analgesia than a placebo.
There are other scales using the same idea, for instance an increasing degree of sad faces can help a child to tell you how much pain he or she is in; also there are color gradation scales for people who understand that better.
NOXIOUS STIMULI TISSUE INJURY OR INFLAMMATION OR EXCESSIVE HEAT OR EXCESSIVE PRESSURE RELEASE OF MEDIATORS (PG, BK, HIST. ENDORPHINS, LT, SUBSTANCE P, etc.)
-prostaglandins are the most important in pain, PGE1 and PGE2 cause inflammation.
COX-2 Inhibitors: inhibit cyclooxygenase of the number 2 isoform, thereby inhibiting prostaglandins and thromboxanes from forming so pain and fever and inflammation are not produced. (This is contrasted with non-specific COX inhibitors such as Advil and Aspirin, which inhibit other cyclooxygenases as well).
Although the textbook shows it as cyclooxygenase, there are really 2 isoforms! The prostaglandins that cause problems are PGE1 and PGE2. Prostacyclins (PGI2) are mostly involved with vascular control (vasodilator and anti-platelet substance) and not really involved with pain. Thromboxane is inhibited by aspirin, which has an anti-platelet effect. So when we’re talking about pain, we’re talking about blocking PGE1 and PGE2 by inhibiting the cyclooxygenase; drugs like aspirin and advil are not blocking the prostaglandin receptor, but instead are blocking the production of the mediator by inhibiting the rate-limiting-enzyme.
In 1985 it was found that there are more than one cyclooxygenase. COX-1 is always present in all tissues, it is “constitutive” (always there). The COX-2 enzyme is inducible, once COX-2 is induced it produces prostaglandins pain and inflammation. So to treat pain, it is best to inhibit COX-2. Many OTC drugs (aspirin, advil, etc) are not specific and so there are other effects on the platelet, etc. besides just analgesia effects.
COX-2 specific inhibitors currently available are celecoxib (Celebrex) and rofecoxib (Vioxx). These are heavily advertised drugs. Whenever you see a suffix –coxib, think of a COX-2 specific inhibitor.
Peripherally acting analgesics inhibit the synthesis and/or release of prostaglandins. This is a good way to determine drugs like aspirin and ibuprofen (peripherally acting) from codeine (centrally acting). With severe pain, we want to block central perception. So drugs like morphine and codeine bind to specific receptors in the CNS called opiate receptors, and thus act as agonistic activity on the receptor site.
When we’re talking about central pathways, we’re talking about drugs that effect the transmission of pain from the spinal cord up through the thalamic nuclei, etc. This is to be distinguished from peripheral nerve blocks, from local anesthetics—this is NOT analgesia. Analgesics do not interfere with nerve conduction!!!
Central acting agents modify pain by working on the higher CNS centers by blocking the perception of pain, or they may act on the limbic system to alter the emotional, or interpretation of pain response.
CNS analgesics DO NOT block pain fiber nerve transmission, block peripheral pain receptor(s), or act as local anesthetics.
Pain receptor(s) may be stimulated by touch, heat/cold, pain mediators, prostaglandins, substance P.
Bacteria
Streptococcus Pneumoniae (i.e.: pneumococcal pneumonia) is the most common. More than 80 serotypes identified but 14 capsular types are most common to cause disease. Accounts for 80% of all pneumonia cases.
Predisposing factors: impaired secretory clearance of URT.
Pathogenesis: a) aspiration of URT secretions causes infection b) pneumococcal multiplication in alveolar spaces causes outpouring of oedema fluid, leukocytes, and RBCs c) bacterial + complement products stimulate chemotaxis of neutrophils but S. pneumoniae has capsular antiphagocytic properties + prevents complement lysis (i.e.: protective mechanism) d) consolidation occurs due to coagulation of exudates e) antibodies to capsular polysaccharide produced, bind to wall, activate complement opsonisation increases efficiency of phagocytosis by macrophages and neutrophils e) healing occurs after macrophages removed debris.
Clinical features: rapid onset of fever, pleuritic chest pain, chills, cough, sputum (rust colour).
Diagnosis: a) large numbers of lancet shaped gram +ve cocci arranged in pairs in conjunction with macrophages + neutrophils in sputum smears b) positive blood cultures confirmatory, but only 30% of pneumonia patients become bacteremic c) pleural fluid obtained by thoracocentesis, gram stain + culture for bacteria.
Treatment: penicillin G but resistance is spreading so use 3rd generation cephalosporin. Vancomycin if resistance spreads.
Prophylaxis: polyvalent vaccin containing capsular polysaccharides from 14 most virulent strains.
Pyogenic cocci: Staph aureus, Strep pyogenes etc. Usually these are 2nd to infections that depress immune system or introduction of infectious agents directly into blood stream by IVDU.
Diagnosis: sputum, blood, pleural fluid culture + identification
Treatment: antimicrobial therapy is targeted at cause of pneumonia gained from culture + identification.
Gram negative bacilli: Haemophilus influenzae (except type B), Klebsiella Penumoniae, Pseudomonas aeuroginosa (main pathogen in CF patients), E. coli, Leigionella Pneumophila. Gram –ve bacillary pneumonia accounts for about 10% of all cases of pneumonia.
Predisposing factors: alcoholics, IVDU
Diagnosis: culture + identification. If you want to differentiate between organisms that colonise the URT and organisms that have caused the pneumonia then do a aseptic: transtracheal or transthoracic aspirates & transbronchoscopic lung biopsy specimens.
Treatment: Selection of antimicrobial agents are based on the results of susceptibility tests of isolated organisms. Cephalosporins + aminoglycosides used initially. Quinolones used to treat P. aeuroginosa + Proteus species.
Mycoplasma pneumoniae, Leigionella sp, Chl pneumoniae + psittaci + tracomatis, Coxiella Burnetti (Q fever), , Influenza: in order of incidence all cause atypical pneumonia syndrome. These organisms are hard to grow in laboratory agar media (unlike Strep, Haemophilus, Staph – which are easy to grow in such media). Diagnosis: antigen detection methods. Treatment: not susceptible to beta lactams (penicillin, cephalosporins) so use macrolides (erythromycin + roxithromycin) + tetracyclines.
Viruses
Most often viruses cause interstitial pneumonitis. Common aetiologic agents include:
RSV (most common in children: < id="rqo6130" face="Wingdings"> bronchiolitis, 4-5 yrs bronchopneumonia), adenovirus (1, 2, 3, 5 - children), parainfluenza virus (types 1, 2, 3 - children) , influenza A (most common in adults) & B
Less common aetiological agents include:
Herpes virus, rhinoviruses, rubeola virus, echoviruses, corona viruses, coxsackie viruses.
Predisposing factors: age (elderly, very young) + immunological status (underlying disease affecting CMI, hospitalised patients)
Transmission: droplet inhalation (coughing + sneezing). Most prominent in winter + spring due to “population closeness”.
Pathogenesis: a) URT cells are infected by viruses b) spreads to other lung areas via infected secretions by URT, or by haematogenous + lymphatic spread.
Diagnosis:
Influenza A virus: WBC count > 10, 000m3
RSV: WBC are not specific, but CXR shows bilateral bronchopneumonia
Adenovirus: WBC count > 30, 000m3
Rubeola pneumonia (measles): CXR shows interstitial pneumonia
Treatment: most cases supportive only. But sometimes: RSV ribavirin
Fungi
Pneumocystis carinii: major cause in immunocompromised patients (esp. AIDS). Approximately half of AIDS patients develop Pneumonocystis carinii pneumonia.
Diagnosis: Demonstration of P. carinii in lung. Bronchoalveolar lavage samples preferred but if –ve then use transbronchial biopsy specimens. Silver stains reveal multinucleated cysts.
Treatment: trimethoprim-sulfamethoxazole is preferred, if intolerable then use pentamidine. Prophylaxis with medication is recommended in immunocompromised patients.
General Points about the respiratory system
The respiratory system is divided into upper and lower zones. Above the larynx, the respiratory system contains normal flora. Part of the normal flora may be disease-causing organisms, but they are often carried as normal flora (i.e.: if some organisms from here are taken and put somewhere else in the body, then they might cause disease).
The respiratory system is exposed to air; hence it has many defence mechanisms against infective organisms. The lower respiratory tract has macrophages which can be mobilised in case of infection. The upper respiratory tract has functional cilia, which act to remove mucus from the tract. If there is any impairment in these defences, then there is incidence of infections (i.e.: smoking impairs ciliary function – therefore mucus is stagnant and provides a favourable environment to infection).
Nomenclature
Pneumonia: infections involving the lung parenchyma and air spaces, often showing consolidation. Cause: typically bacterial Strep Pneumoniae.
Bronchitis: infections of the bronchial mucosa WITHOUT involvement of lung parenchyma (if involved, then we called it Bronchopneumonia)
Pneumonitis: interstitial inflammation caused by viral infections or toxic compounds.
Lobar pneumonia: infection of lung parenchyma within anatomic boundaries of a lobe. Cause: Strep Pneumoniae, Klebsiella Pneumonia (not common).
Aetiological agents lung infections
Broadly speaking pneumonia can be caused by: bacteria, virus, fungi, parasites. Some organisms can cause disease in healthy individuals (i.e.: Mycoplasma pneumoniae, Strep. Pneumoniae), some organisms cause disease in immunocompromised individuals (i.e.: Pneumocystis carinii), other organisms cause disease in young children where immune system is imcompletely developed (i.e.: respiratory syncytial virus).
Questions
Describe the general properties of Pox viruses?
Describe the Various genre of Pox viruses?
Describe the Orthopoxviruses that exist, including the disease/signs they cause?
Describe the Parapoxviruses and the diseases/signs they cause?
Describe the Unclassified Pox virus, including the disease/signs they cause?
How would you diagnose and prevent this disease?
Poxviruses are 300nm in size, enveloped, have a brick shape and are resistant to drying. They can be seen under the light microscope. Smallpox and molluscum contagiosum are the only two which do not have animal reservoirs, whereas others occur from zoonoses. The three main genre are the orthopoxvirus, paropoxvirus, and unclassified pox viruses. Belong to the first genre are: Variolla major, Variolla minor, Vaccinia virus, Monkey pox, and Cow pox. The 1st 2 cause severe and mild small pox respectively. The 3rd one is a virus used to immunise against small pox. Monkey pox causes disease which is different but not distinguishable from small pox, and the last one causes vesicular lesions in man. The parapoxvirus genre contains: Milker’s nodules virus and Orf viruses. The former causes isolated lesions in man, and the latter causes lesions in arm and forehand, which usually spontaneously heal. The unclassified genre is concerned with: molluscum contagiosum – and this causes lesions in skin axilla + trunk. It is spread by contact and STD. Diagnosis is clinical, and also presence of viral inclusions in lesion isolates. Treatment is spontaneous healing, along with cryotherapy. Prevention is via small pox vaccine. Virus not destroyed in case outbreak due to bio terrorism.
Pharyngitis: 50% caused by viruses, and 50% of bacteria of which, most important is Strep pyogenes & Group A beta-haemolytic streptococci. Next most important is: EBV (pharyngitis, lymphadenitis, fever & rash)Symptoms: malaise, fever, headache, sore throat. White exudate visible in the pharynx and tonsils are enlarged. Treatment: Penicillin G for 10 days continuous (bacterial cause).
Acute laryngitis vs Chronic laryngitis: former: viral syndrome, latter: investigate for malignancy
Croup (laryngotracheobronchitis): Parainfluenzae virus Type I – usually in children
Otitis media (middle ear infection): The middle ear is connected to the nasopharynx. URT infections may cause otitis media. The mucous membranes become inflamed and you get fluid build up infection settles in. Cause: RSV complication, Group A streptococci, Haemophilus influenza, Strep. Pneumoniae etc.
Epiglottiditis: inflammation of the epiglottis. This is a rapidly progressing cellulitis of the supraglottis structures sometimes leading to total airway obstruction. Cause: Haemophilus Influenza type B. Clinical features: usually childhood illness, great difficulty breathing, cant swallow and drools. Must not do a throat swab because potential total airway obstruction, unless someone present to intubate. Treatment: 3rd generation cephalosporins + intubation. Vaccination is available, so not common at present day.
Questions
Describe the general properties of a Human papilloma virus?
Describe the transmission routes for the two main types of warts (what are these)?
What happens when you get infected?
Give examples of types of warts presented associating them with a particular type of the virus?
How would you diagnose Human papilloma virus?
How would you treat and prevent it?
The human papilloma virus is approximately 45nm in size, icosahedral non-enveloped virus. It causes warts of two types: skin + genital. The former is transmitted via direct contact with contaminated material whilst the latter is only transmitted via sexual intercourse. Now it is said that there are about 60 different types present, belonging to about 16 groups. A type is considered to be different compared to another type if it contains < id="r88n59" face="Wingdings"> plantar warts, Type 2 common warts (hand etc), Type 6, 11 genital warts, Type 16, 18, 31 cervical carcinoma. Incubation period is usually about 1-20 months, average being 2-3 months. Remember each type causes a particular set of pathological entities hence diagnosis is usually by the appearance of the lesion, sometimes excision of lesion and histological examination is necessary. You can also radiolabel probes and put it into the host cells containing the viral nucleic acid. Treatment is via topical application of agents such as: glutaraldehyde, or lactic or salicyclic acid. Genital warts are treated by applying podophyllin. Prevention is relatively easy, stay away from contaminated sites and also use safe sex practices. Virus vaccines are now being developed for HPV 16, 18, 6, 11.
Questions
Describe the general properties of adenoviruses, including their life cycle?
What infections and diseases can be caused by adenoviruses?
How would you diagnose adenoviruses?
Gastroenteritis is one of the diseases, how does this occur elaborate?
Adenoviruses are 70nm, DNA, icosahedral non-enveloped viruses that contain penton fibres + knobs. > 40 serotypes have been identified and they all have the same group antigen. They replicate in epithelial cells, and are transmitted via the respiratory system and/or faecal oral route. Common infections from adenoviruses include: respiratory tract infections (i.e.: pharyngitis, acute respiratory disease and pneumonia in infants) + eye infections. Rarely it causes meningoencephalitis and haemorrhagic cytitis. Diagnosis is made via isolating virus in culture and identifying distinctive inclusion bodies within 2-20 days. You can also use serological tests for the group antigen present on every serotype. A rapid latex agglutination test is used for faecal virus. The virus is also said to multiple in the GIT causing adenoviral gastroenteritis (type 40-41-42). Basically it can cause vomiting, watery diarrhoea, and a mild fever. Incubation period is between 8-10 days, and duration of symptoms is usually 9-12 days. Note that adenoviruses are “slow ticking” viruses, meaning they are very persistent.
If the infection reaches a threshold level (i.e.: virulence is high, and dose is high) and eludes the innate arm of the immune response, then adaptive immunity is activated. This occurs as a result of antigen presentation to naïve T cells at the lymph nodes, which get activated and then travel to the site of infection to elicit a response (cell mediated), or antigen may remain in the lymph nodes, activating B cells for antibody production (humoral). What determines whether a T or B cell response is initiated? That depends on the type of cytokines produced by the innate immune response.
The innate immune response involves a variety of protective/effective mechanisms including:
Epithelial barriers offering physical and mechanical barriers
Chemical factors: in response to microbes, macrophages and other cells secrete cytokines that mediate many of the cellular reactions of innate immunity (i.e.: inflammatory cytokines IL1, IL6, IL8, IL12, TNF-a). These activate vascular endothelium, lymphocytes, chemotactic factor & acute phase protein production. This causes chemoattraction of lymphocytes site of infections.
Natural killer cells go to site of infection and kill intracellular microbes by killing the infected cell.
Phagocytes such as: neutrophils, basophils, eosinophils, macrophages all play a role in recognising and ingesting microbes for intracellular killing.
Complement pathway: these are membrane associated proteins (proteolytic enzymes) that play three major roles: 1) opsonisation (C3b), 2) breakdown products act as chemoattractants, 3) forms MAC that punches holes in microbial cell membrane.
These mechanisms provide an effective strategy against microbial infections, but they do not provide long last immunity nor memory. These mechanisms are immediate and control the infection while the adaptive response is being formed.
Infections can be intracellular or extracellular. Intracellular infections can be within the cytoplasm or within vesicles, which are located in the cytoplasm. Examples of the former: viruses, Chlamydia, rickettsia, listeria etc. Examples of the latter: mycobacteria, salmonella, listeria, Legionella etc. How does the body control the infections within the cytoplasm? This is done mainly via CD8 T cell activation and differentiation into CTLs that directly kill the infected cell, NK cells that respond by directly killing the infected cells as well. How does the body control the infections that are within vesicles? T cells recognise these cells and then kill them, CD4+ cells get activated and produce cytokines that activate macrophages and B cells (which produce antibodies and kill infected cell). NK cells kill the infected cell but also produce a macrophage activating cytokine – IFN-γ.
Extracellular infections can occur in interstitial places, blood, and lymph. Some examples of pathogens that do this are: viruses, protozoa, fungi, Helminths, bacteria etc. The main way the immune response reacts to this sort of infection is by humoral immunity (antibody protection), phagocytosis and neutralisation. Extracellular infections can also occur within epithelial surfaces. Many examples of microbes cause this (i.e.: candida, strep, staph etc). Ig A antibodies are produced in immunity, and inflammatory cells are recruited to the site of infiltration.
The innate response occurs within 0-4 hours, where preformed mediators are released, this recruits and activates the effector cells (i.e.: NK, phagocytes, complement, acute phase proteins etc) – as a result – these results migrate to the site of infection in an activated form and remove the infectious agent. After this (4-96 hrs) – if the infection is still present, then more recruitment of inflammatory cells occurs and more chemical mediators are secreted. These cells recognise the infectious agent and get activated – and as a result increased inflammation results and the infectious agent is removed. After 96 hours, the antigen may make its way (i.e.: APCs present it to them) to the lymph nodes. It is then recognised by naïve T cells, which are activated after the following occurs: T cells recognise ligands on APCs, TCR recognises MHC-associated peptide antigens, CD4/CD8 co receptors recognise MHC molecules, adhesion molecules strengthen binding of T cells to APCs, costimulation provided by APCs. This cause’s clonal expansion, where T lymphocytes begin to proliferate + differentiate, resulting in expansion of antigen specific clones. CD4+ helper T cells may differentiate into effector cells that secrete cytokines mainly to activate macrophages and B lymphocytes & CD8+ T cells may differentiate into CTLs that kill infected cells expressing the antigen. This results in removal of infectious agent. But memory is preserved after this. So in the event of a re-infection, preformed antibody and memory T cells recognise the antigen – rapid expansion and differentiation into effector cells occurs – together they remove the infectious agent.
Bacteria can be gram +ve or gram –ve. Gram +ve bacteria are opsonised and phagocytosed. Gram –ve bacteria are opsonised and undergo lysis by the complement mechanism. Intracellular bacteria are killed by macrophage activation by T cell derived cytokines, and also CTLs directly killing the infected cell. If the bacteria is non-invasive, then a humoral response (antibody production) is enough to neutralise the toxin.
Antibody
Humoral immunity is mediated by antibodies. Antibodies prevent infection by blocking the ability of microbes to invade host cells. These can be done by interfering with the microbe’s ability to attach to the host tissues. Antibodies have the following functions: neutralise infectivity and pathogenicity of toxins by binding to them and interfering with their functions, opsonise microbes therefore promoting phagocytosis, activate the classical complement pathway (stimulate inflammation / MAC). The alternate pathway does not require antibody to be activated (immediate response).
Extracellular bacteria
Extracellular bacteria are first (0-4hrs) handled by the innate immune response. Macrophages and other cells secrete cytokines and chemokines that attract inflammatory cells to the site of infection. Alternate complement pathway is activated. This causes an immediate inflammatory response which keeps the bacteria in check before other processes take over. The adaptive immune response takes over, and this involves antibody production due to B cell activation plasma cells, and cytokines released due to CD4+ T cells activated + CTLS from CD8+ T cells being activated. The antibodies produce further induce classical complement pathway activation. Therefore together they attack the bacteria.
Intracellular bacteria
Cell mediated immune response take control of this type of bacteria. The bacteria can be located within vesicles in cells, or within the cytoplasm itself. Intracellular bacteria residing in vesicles within phagocytes are removed by activated phagocytes. This activation is provided by CD4+ T cells, production of cytokines etc. CD8+ T cells on the other hand differentiate into CTLs and directly kill the infected cell (bacteria within cytoplasm of cell) thus eliminating the infection.
The innate immunity prevails again initially, with the activation of macrophages and inflammatory cells.
For elimination of fungi, the innate arm of the immune response is more efficient. The innate response involves: chemotactic factors, chemokines and other chemicals that lure inflammatory cells to the site of infection, macrophages erode the infection. Adaptive immunity is complex. T cells get activated, and secrete macrophage activating cytokines, activated macrophages phagocytose the fungal infection. Meanwhile, differentiated B cells produce antibodies to fungal toxins. Spores produced by fungi bind to IgE – this degranulates the mast cell – histamine is released. Histamine vasodilates vessels, increase fluid flow – wash out spores.
For most of these intracellular infections – the immune response is not efficient enough to eliminate the infection totally – but only achieves this partially. Thus, infection is controlled not eliminated. Innate immunity is useless, so adaptive immunity is of paramount importance.
Protozoans
Antibody acts as an opsonising agent, so that phagocytosis can occur. CD4+ T cells secrete cytokines activating macrophages and B cells. CD8+ T cells differentiate to CTLs and produce cytotoxic T cell effects. Th1 cytokines deal with intracellular parasites whilst TNF-a controls parasitic infection, but can be harmful when produced in large amounts. Granulomas formed to wall off infection – prevent spread.
Helminths
Antibody is very important here, i.e.: IgA inhibits attachment, IgG serves as an opsonin. For tissue parasites, complement fixation via IgA and IgM important (i.e.: they activate complement pathway). IgE causes mast cell degranulation – this increases fluid flow and expulse Helminths from GIT. Eosinophils accumulate at site of infection – mediate ADCC (antigen dependent cellular cytotoxicity).
Bacteria
Bacteria can vary their antigenic material known as antigenic variation – i.e.: E.coli. Avoidance of complement mediated damage:
1) outer capsule of microbe not penetrable
2) outer surface configuration does not allow C3b binding,
3) diversionary structures (decoy cytokine receptors, or antibody binding to diversionary structure doesn’t do anything),
4) produce enzymes that degrade complement products,
5) resistance to MAC forming + inserting,
6) secreting decoy proteins so complement binding is diverted from binding to bacteria.
Resistance to phagocytosis:
- phagocytosis requires chemotaxis, but toxins repel/prevent chemotaxis therefore phagocytes don’t come near infection,
- bacteria may have outer coats that inhibits phagocytosis (i.e.: Pneumococcus),
- inhibit phagolysosome fusion and escape from vesicles of phagocytes into cytosol.
Viruses
Antigenic drift (influenza), blocking complement system (i.e.: HSV produces C3b binding protein and augments decay of C3bBb), immunosuppressive cytokines (Epstein Barr virus), cytokine receptor homologue (Vaccinia, CMV), inhibits antigen processing pathway (i.e.: CMV), infects immune cells.
Parasites
Sequestered in a particular anatomical position so difficult access, avoids phagocytosis, antigenic variation – avoids recognition, it somehow has same surface antigens of host so immune system thinks its also part of host, suppresses immune system, lymphocytoxic factor, release spores that can mop up any antibody.
General Properties
Staphyloccus species are usually round in appearance, are gram positive organisms and do not have endospores. They usually grow in clusters resembling a grape bunch hence the derivative of the name – staphyle. The organisms are facultatively anaerobic meaning they can either be aerobes or anaerobes. They grow between 18-40ºC in a wide variety of media. 16 of the 32 species colonise humans.
Classification
Staphlycocci are classified as a subcategory of Micrococcaceae. The other subcategories are: Micrococcus, Stomatococcus mucilaginosis.
The most medically significant variants of the Staphylcoccus species is: aureus, epidermidis & saprophyticus (discussed in tutorial).
Staph. Aureus (Murray 3rd Ed. 175)
The colonies of Staph aureus are usually golden in colour, due to the carotenoid pigments formed during the growth. It is also the only species that produces the enzyme coagulase, and is also clumping factor positive (i.e: this is bound coagulase, binds fibrinogen, converts to insoluble fibrin – this causes the aggregation process).
Carriage
The crux of the matter is – this organism is bloody common in the general population, and is more common in the hospitalised population. Organism is most found in one’s genital areas.
Virulence Factors (Murray 3rd Ed. Pg 175)
This organism has numerous virulence factors which can be broken up into broad categories. You do not need to know each and individual toxins, but a categorical view will be presented a little later.
Capsule: inhibits chemotaxis and phagocytosis, inhibits proliferation of mononuclear cells. Facilitates adherence to catheters and synthetic material.
Coagulase: See above for the function of this enzyme.
Clumping factor: See above for the function of this substance
Protein A: binds to Fc portion of IgG, therefore prevents antibody action
Lipase: hydrolise lipids, an important function for the survival of these organisms in the sebaceous areas of infection
Teichoic acids: mediate the attachment of bacteria to mucosal surfaces
Toxins
Cytolytic: some lyse red blood cells, therefore killing them – or can also lyse neutrophils – therefore releasing toxic substance into surrounding tissues.
Exfoliative & Enterotoxin: bind to class II MHC on macrophages, leads to proliferation of T cells, release of cytokines results ==> systemic effects of disease arises from this process.
Note that Staph aureus is coagulase positive, as it helps in the conversion of fibrinogen to fibrin which assists in the aggregation process. They are generally whitish in appearance, are DNAase and Phosphatase negative. Such organisms have great affinity to plastic, IV lines, catheters etc. The organisms (i.e.: staph epidermidis) are introduced at the time of valve replacement (for example), with clinical signs developing only after 1 year after the inoculation. Eventually can lead to an abscess formation, separation of the suture line – therefore valve ‘separates” – mechanical heart failure results?
Other organisms of importance are S. saprophyticus, S haemolyticus, S lugdunensis, S schleiferi.
These organisms can cause the following infections/contamination:
Endocarditis: This occurs usually on artificial valves
Catheter and Shunt infections: Have recently become problem due to long usage of lines, catheters and shunts for the management of critically ill patients. Produce a polysaccharide slime that can protect themselves against antibiotics, and inflammatory cells.
Prosthetic Joint infections: Hip joints commonly infected, risk of re-infection is common after being infected again and treated with re-hip-replacement and antimicrobial therapy.
This is mainly seen as UTI’s in young sexually active females. Infected women have pain upon urination (dysuria), pus in urine (pyuria), and bacteria and white blood cells in urine. Patients respond rapidly with antibiotics, such as: amoxicillin – and trimethoprim.
For the following topics use lecture notes as Murray doesn’t offer any notes:
Micrococcus and Stomatococcus
Nosocomial Staphylococcus Infections
Hospital Staphylococci
MRSA
Laboratory Diagnosis (Murray 3rd Ed. Pg 186)
For a proper diagnosis, a swab from the base of the abscess (per say) should be obtained. Blood cultures are unrewarding due to minute number of organisms for high volumes of blood. Once a swab is sent for culture, they should be put onto sheep blood enriched agar plates for growth. If the swab contains other organisms, then inoculate in agar medium that contains 7.5% NaCl which inhibits growth of other organisms, and also mannitol – important because Staph aureus only ferments it. Within 24 hours, you see the growth of Staphylococci: you see golden appearance if aureus present. Almost all times with S. aureus – you see haemolysins – this is due to the cytolytic toxins (described earlier) that destroy red blood cells.
Diagnosis is done by the appearance of grape like growth and can also be tested for catalase positive reactions, clumping factor, coagulase for Staph aureus etc). Other methods include: antibiotic susceptibility patterns, biochemical profiles, phage typing (susceptibility to bacteriophages).
Treatment, Prevention (Murray 3rd Ed Pg 187)
Obviously drug resistance is a major concern in terms of antimicrobial therapy, and this is particularly true for Staphylococci. In Australia, we are at a verge of a major outbreak of resistant organisms – such that antibiotics will become largely useless if used for treatment. The reason for the resistance is because Staphylococci produce penicillinase that break the beta-lactam rings of the antibiotics, which makes them useless and ineffective. The gene that codes for this enzyme is unfortunately transmissible, therefore the spread of resistance is prominent via this pathway. Also, resistance occurs due to the continuous alterations in the binding site for the antibiotic on the bacteria – thus making it quite difficult for drugs to work – unless we constantly develop newer drugs. Synthetic penicillins were developed, but unfortunately this did not contain the spread of resistance.
Treatment for abscesses is to continuously drain them or surgically excise them and have them dressed with sterile products until healing by secondary intention occurs. Prevention is by having good infection control in hospitals, prescribing antibiotics after lab results come – Isolation of patients with these infection to stop spread, screening at admissions, WASH HANDS!
Use of vancomycin is proving to be effective therapy but the organisms are showing signs of resistance to this drug as well. Signs have been widely reported in the US, and signs have also been reported here in Australia.
Caffeine:- is a CNS depressant
- causes cerebral vasodilation
- reduces the acidity of gastric fluid secretion
- reduces plasma glucose level
- is a potent diuretic
Click Here For Answer / Discussion
The rate of tumour growth is altered by cell kinetics and tumour angiogenesis. Tumours need blood supply to enlarge, as oxygen can only diffuse a certain distance from existing blood vessels. Thus, tumours relying on oxygen diffusion soon develop hypoxia and apoptosis occur due to activation of p53 (tumour suppressor gene).
The reason why angiogenesis is important for tumour growth is diverse, including: 1) angiogenesis means: a) supply of O2 and nutrients, b) new endothelial cells induce adjacent tumour cells to grow by secreting growth factors: PDGF, GM-CSF, IL-1. 2) Angiogenesis is prerequisite for metastasis ===> hence one way of determine prognosis and malignancy is tumour angiogenesis.
How does tumour angiogenesis occur? Tumour associated angiogenic factors may be produced by tumour cells or derived from inflammatory cells infiltrating the area. Two such important factors are: 1) VEGF, 2) basic FBG. These growth factors are highly produced by tumour cells ===> inducing tumour angiogenesis.
Is tumour angiogenesis inhibited as well? Yes, and this is done by presence of antiangiogenesis factors. Thus, tumour growth controlled by TAF & antiangiogenesis factors. Antiangiogenesis factors may be produced by tumour cells (e.g.: thrombospondin 1) or their production may be influenced by tumour cells. Angiostatin, endostatin, vasculostatin belong to the latter group. These are derived from cleavage of collagen, plasminogen & transthyretin.
Clinical trials are being done on whether therapy by antiangiogenesis factors will inhibit tumour growth.
Cancer occurs as a result of mutations of genes that control normal cell growth and differentiation (protooncogenes). Such genetic damage may be acquired through environment factors (i.e.: radiation, chemicals, viruses) or genetic factors (family tree). Thus, the acquisition of genetic malproducts causes cancers. Thus, morphological and biochemical changes seen in cells is as a result of these genetic mutations.
The principal targets of genetic mutations/damage are: 1) protooncogenes, 2) cancer-suppresor genes, 3) apoptotic genes, 4) DNA repair genes.
Carcinogenesis is a multi-step process, known as tumour progression. The phenotypic characteristics expressed by tumour cells are acquired as the tumour progresses (i.e.: first you get excessive growth ===> local invasiveness ===> metastases). The genetic lesions also accumulate as the tumour progresses ===> hence giving rise to the phenotypic characteristics mentioned above.
Monoclonal proliferation refers to proliferation of cells – which all derive from the one cell originally. All cancers have monoclonality, that is, they all derive from the same cell. Originally, there is genetic mutations in some genes (i.e.: protooncogenes, antioncogenes, apoptotic genes, genes for DNA repair) – and this mutated has lost cell cycle regulation – therefore undergoes uncontrolled proliferation ===> new clones. Now it is gnomically unstable, so is vulnerable to another mutation. This newly mutated cell has further cell cycle regulation – therefore further proliferates ===> new clones. In the end, you get numerous subpopulations of tumour cells all derived from the same cell.
Tumour progression is a phenomenon whereby preneoplastic lesions ===> become benign ===> become invasive (malignant). The level of malignancy is acquired over a period of time, where the tumours become more aggressive. We mentioned above that all tumour cells have a monoclonal origin. But, by the time they become clinically evident their constituent cells are heterogenous. This is because, over time, several subpopulations appear and the cells that make up these populations differ with respect to each in terms of their phenotypic characteristics.
All of these subpopulations have differing antigenicity. The most antigenic subpopulation is killed by the host’s immune response, whilst those that are least antigenic survive. Thus, the surviving clones are the most aggressive and the most adapted to invasiveness and adaptation.
Tumour growth depends on the
1) imbalance between cell gain and cell loss. This imbalance is determined by the
2) growth fraction, which is the proportion of cells within a tumour that are in the proliferative phase. The growth fraction has a huge impact on treatment options for neoplasia.
Chemotherapy and Radiotherapy are more efficient when the cells are in the proliferative phase. Thus, tumours with high growth fractions are more susceptible to chemotherapy and radiotherapy.
What happens to tumours that have low growth fraction (i.e.: breast cancer, colon cancer etc)?
We need to shift the tumour cells from G0 phase to cell cycle phase. This can be done by excising part of the tumour, thus the remaining cell sense the ‘loss’ and shift into cell proliferation mode. Now we can attack them with chemotherapy etc.
Cellular senescence describes the fact that normal cells continually divide but reach a stage (after fixed number of divisions) where they become arrested in a nondividing state. What determines this termination? Actually, at the ends of chromosomes there are specialised structures known as telomeres. Each time a cell divides, the telomeres shorten – and if they shorten beyond a certain limit – then the cell cannot divide any more. Germ cells can divide continually, so how are they able to do it? The enzyme telomerase prevents the shortening of the telomeres, therefore termination of cell division does not occur. So, when germ cells differentiate into their specialised variety – the telomerase enzymes become deactivated/absent – therefore are susceptible to cellular senescence.
How does all this relate to tumour growth? Well, tumour growth can occur continually and rapidly. So the concept of cellular senescence does not work here.
How come, don’t tumour cells derive from normal host cells? Yes they do – but tumour cells can reactivate telomerase – therefore can prevent telomere shortening.
For tumours to become malignant, they need to metastasise – but out of the millions of cells released into the blood/lymph stream – only a few metastases are formed – therefore metastasis is an inefficient process.
Why? Because only certain subclones possess the right characteristics to complete all the steps to achieve metastasis.
The tumour cells need to:
1) detach themselves from surround tumour cells,
2) breach basement membrane,
3) traverse extracellular matrix,
4) breach basement membrane of endothelial cells.
They need to do this at the site of metastasis as well.
Invasion of extracellular matrix
The tumour cells become increasingly motile. Normal cells are adhered to each other. Adhesion molecules mediate this adhesion (e.g.: cadherin family of transmembrane glycoproteins is one such example). In tumours, there is down regulation in expression of these molecules, so cells have decreased adherence and increase motility. They now need to attach to the basement membrane, and this is mediated by receptors such as laminin and fibronectin. Once attached, they need to actively degrade membrane and gain access to the extracellular matrix. Penetration is also assisted by passive growth pressure. Tumour cells secrete proteolytic enzymes, or induce host cells to do so. There is a regulation of protease activity, but antiproteases – but obviously this regulation is lost here.
Now, the tumour cells need to be propelled into the extracellular matrix, this is done by two things
1) motility factors made by tumour cells,
2) cleavage products of matrix components (i.e.: collagen, laminin etc).
Note that the proteolytic enzymes not only cleave pathway through basement membrane, but also through ECM. That is, “roads” are set up so tumour cells can traverse the ECM.
Vascular Dissemination and Homing of tumour cells They enter the vascular system via the same mechanism described above – the most important being the proteolytic enzymes produced by the tumour cells, and host cells. Once reaching the vascular system, the tumour cells are highly vulnerable to attack from natural killer cells. So, tumour cells clump to other tumour cells (i.e.: homotypic adhesion) or tumour cells clump to blood cells (i.e.: heterotypic adhesion). This enhances tumour cell survival. Then, they adhere to the endothelium (e.g.: adhesion molecules ==> integrins, laminin receptors) and proteolytically cleave the basement membrane to reach the site of implantation. Vascular dissemination does not always correlate to drainage patterns.
Moulds
Yeasts
Yeast-like Fungi
Dimorphic Fungi
Clinically fungal infections are classified according to which layers they infiltrate. These are superficial mycoses (only affects the outer most layer of the skin and hair), cutaneous mycoses (affects keratinised layers of skin ==> epidermis, hair and nails) and subcutaneous (involves the dermis, subcutaneous tissues, fascia and muscles).
Dermatophytes: These are agents causing cutaneous mycoses. That is, they infect the Keratanised layers of the skin and its integuments – and usually invoke a cellular immune response, causing pathological changes to occur in the deeper layers. There are three genres (need to learn):
Clinically, these mycoses manifest as ringworm (note: it is not a worm) or tinea. The lesions are “snake like” or “ringlike” (resembles worm ==> hence name ==> “ringworm”). The source of these infections are from Humans (anthropophilic ==> mild chronic infections ==> difficult to treat), Animals (zoophilic ==> aggressive infection over milder period of time ==> spontaneous healing, respond well to therapy), Soil (geophilic).
Pathogenicity
These infections are usually confined to outer skin layers (keratinised layers). The reason for this is believed to do with keratin being used as a substrate (keratinophilic fungi). Keratinases have been isolated from these fungi, which indicates this. The skin lesion is symmetrical, it has an active edge (spreading edge), and a healing center. The hair in these regions is lost, nails discolour and crumble.
Tinea can be described according to their various anatomical landmarks (i.e.: Tinea capitis: head, Tinea pedis: feet etc). The species is not important to be learnt, but you should realise that some species are exclusively found in only some parts of the world.
Diagnosis
Woods lamp – fluorescent lamp, is used for some species of dermotophyes. In others, scrapings are taken from lesions: hair, nails – treated with an alkali solution (20% KOH) to get rid of the epithelial cells and other debris. Dermatophytes resist this solution, and appear branching. Closer examination reveals spores (round in appearance – Fig 69-12 pp 572 Murrary 3rd Ed) that are within the hair shaft (endothrix) or outside the hair shaft (ectothrix). Microscopic examination of scrapings only confirms the infection as being fungal. To confirm the type of fungal infection, we need to culture the specimen. Skin contains many bacteria and saprobic fungi as part of its normal flora. So Sabournauds media is not routinely used, as these elements overgrow the actual dermotophytes (slow growing). Other media such as DIM have special antibiotics to inhibit bacterial and fungal growth, allowing dermatophytes to growing within hindrance. Intubation at 25º C normally (2-6 weeks) – treat patient while waiting.
Treatment of dermatophyte infections
Griseofulvin ==>orally administered, only used for dermatophyte infections, interacts with tubulin of susceptible fungi, alters tubulin function (affects cell wall). One problem is that griseofulvin is taken in by other cells also exhibiting tubulin, therefore resistance is due to lack of uptake by susceptible fungi.
Others include: allylamines (terbinafine, naftifine) are topical agents, very active against in vitro dermatophytes (also works for dimorphic fungi ==> expensive drug), affect sterols in cell membrane.
An example of yeast is Cryptococcus Neoformans. It causes cryptococcosis (systemic mycosis) and its primary site of infection is the lungs. But it can spread to other parts of the body (leading cause of fungal meningitis in AIDS patients). The organism grows as a budding yeasts (blastospores), contains a polysaccharide coat important for diagnosis.
Diagnosis is by detection of crypto coccal polysaccharide antigens in CSF. A latex compound with antibodies to Cryptococcus organism is present, and the antigenic polysaccharide coat binds to this. Culturing on Sabornauds is useful to detect the specific organism.
Treatment is by Amp B (but poor penetration through CSF) + 5-fluorocytosine (good penetration into CSF but resistance is problem).
Bread mould (Rhizopus, Mucor): this is an opportunistic infection; free living, available freely in environment. Causes systemic mycotic infections. Diagnosis by culture using Sabournauds. Treatment using: Amphotericin B (polyene) ==> basically binds to cytoplasmic membrane, forms ion channels, essential ions lost, cell dies, K Iodide.
Aspergillus: asthma like disease, allergic bronchopulmonary disease, disseminates to other tissues, mycotic keratitis (destroys cornea), aflatoxins are released by these moulds. Diagnosis is by isolation and culture using Sabornauds, Treatment; Amp B Itraconazole (if dessiminated), surgery correcting bronchial tree
Sick building syndrome: agent grows in old and “diseased” buildings.
The most important species of yeast like fungi is Candida. The most important genre out of this species is albicans. Other genre include: tropicalis, krussei etc. Most of the genre is part of the normal human flora and live as commensals. In about 80% of the popn you can isolate at least one genre of the Candida species. Rarely these organisms gain access to the blood stream from the oral cavity, GI tract or even straight into blood by way of contaminated IV instruments. This causes disseminated infections usually involving the heart, spleen, liver, brain, lungs, kidneys etc. Skin lesions may be present in 10-30% of patients and it is an important in diagnosis as post-mortem blood cultures prove negative.
The most susceptible patients are those that are immunocompromised. Reasons may be that they are on such drugs/therapy after receiving an organ transplant, HIV/AIDS patients etc.
Diagnosis is by preparing a gram stain, which identifies the presence of budding (pseudohyphae). For specific diagnosis prepare a germ tube test and incubate under 37ºC. If germ tubes are produced, then we have species Candida.
Treatment: Topical treatments for the immunocompetent patient usually results good outcomes, for the immunocompromised patient a combination of Amp B + 5-fluorocytosine is recommended + drugs from the azole group such as: ketoconazole, flucocanozole etc. These are less toxic than Amp B. Treatment with azole results in fungal infections to recur after drug therapy is ceased. Probitoic therapy: yoghurt contains lactobacilli, a beneficial species of bacteria that prevents/treats infection.
Dimorphic fungi, as the name suggests, can be yeasts of moulds depending on the incubation temperation. Examples include: Cladosporium sp., Sporothrix schenckii Sporotrichosis. Histoplasma capsulatum: causes histoplasmosis, diagnosis: perform biopsy, culture on Sabornauds at above temps to see which determines growth ==> Treatment is Amp B. Blastomyces dermatitidis – North American blastomycosis is another example, Coccidioides immitis – cause of Coccidiodomycosis.
Diagnosis of dimorphic fungi is by performing a biopsy – if yeasts, but this of little value. Culture at 22ºC & 37ºC to see what category it falls into, allows specific identification, treatment is most often by Amp B.
The following categories are present for mycotic drugs:
Note: Function of these drugs must be known. Not individual function, but rather collective function of individual groupings must be known. Don’t waste time learning all the individual drug function, not examinable at this stage!
General Points about the respiratory system
The respiratory system is divided into upper and lower zones. Above the larynx, the respiratory system contains normal flora. Part of the normal flora may be disease-causing organisms, but they are often carried as normal flora (i.e.: if some organisms from here are taken and put somewhere else in the body, then they might cause disease).
The respiratory system is exposed to air; hence it has many defence mechanisms against infective organisms. The lower respiratory tract has macrophages which can be mobilised in case of infection. The upper respiratory tract has functional cilia, which act to remove mucus from the tract. If there is any impairment in these defences, then there is incidence of infections (i.e.: smoking impairs ciliary function – therefore mucus is stagnant and provides a favourable environment to infection).
Nomenclature (Microbiology & Infectious disease, 3rd Ed, pp 419)
Pneumonia: infections involving the lung parenchyma and air spaces, often showing consolidation. Cause: typically bacterial ==> Strep Pneumoniae.
Bronchitis: infections of the bronchial mucosa WITHOUT involvement of lung parenchyma (if involved, then we called it Bronchopneumonia)
Pneumonitis: interstitial inflammation caused by viral infections or toxic compounds.
Lobar pneumonia: infection of lung parenchyma within anatomic boundaries of a lobe. Cause: Strep Pneumoniae, Klebsiella Pneumonia (not common).
Broadly speaking pneumonia can be caused by: bacteria, virus, fungi, parasites. Some organisms can cause disease in healthy individuals (i.e.: Mycoplasma pneumoniae, Strep. Pneumoniae), some organisms cause disease in immunocompromised individuals (i.e.: Pneumocystis carinii), other organisms cause disease in young children where immune system is imcompletely developed (i.e.: respiratory syncytial virus).
Bacteria
Streptococcus Pneumoniae (i.e.: pneumococcal pneumonia) is the most common. More than 80 serotypes identified but 14 capsular types are most common to cause disease. Accounts for 80% of all pneumonia cases.
Predisposing factors: impaired secretory clearance of URT.
Pathogenesis: a) aspiration of URT secretions causes infection b) pneumococcal multiplication in alveolar spaces causes outpouring of oedema fluid, leukocytes, and RBCs c) bacterial + complement products stimulate chemotaxis of neutrophils but S. pneumoniae has capsular antiphagocytic properties + prevents complement lysis (i.e.: protective mechanism) d) consolidation occurs due to coagulation of exudates e) antibodies to capsular polysaccharide produced, bind to wall, activate complement opsonisation increases efficiency of phagocytosis by macrophages and neutrophils e) healing occurs after macrophages removed debris.
Clinical features: rapid onset of fever, pleuritic chest pain, chills, cough, sputum (rust colour).
Diagnosis: a) large numbers of lancet shaped gram +ve cocci arranged in pairs in conjunction with macrophages + neutrophils in sputum smears b) positive blood cultures confirmatory, but only 30% of pneumonia patients become bacteremic c) pleural fluid obtained by thoracocentesis, gram stain + culture for bacteria.
Treatment: penicillin G but resistance is spreading so use 3rd generation cephalosporin. Vancomycin if resistance spreads.
Prophylaxis: polyvalent vaccin containing capsular polysaccharides from 14 most virulent strains.
Pyogenic cocci: Staph aureus, Strep pyogenes etc. Usually these are 2nd to infections that depress immune system or introduction of infectious agents directly into blood stream by IVDU.
Diagnosis: sputum, blood, pleural fluid culture + identification
Treatment: antimicrobial therapy is targeted at cause of pneumonia gained from culture + identification.
Gram negative bacilli: Haemophilus influenzae (except type B), Klebsiella Penumoniae, Pseudomonas aeuroginosa (main pathogen in CF patients), E. coli, Leigionella Pneumophila. Gram –ve bacillary pneumonia accounts for about 10% of all cases of pneumonia.
Predisposing factors: alcoholics, IVDU
Diagnosis: culture + identification. If you want to differentiate between organisms that colonise the URT and organisms that have caused the pneumonia then do a aseptic: transtracheal or transthoracic aspirates & transbronchoscopic lung biopsy specimens.
Treatment: Selection of antimicrobial agents are based on the results of susceptibility tests of isolated organisms. Cephalosporins + aminoglycosides used initially. Quinolones used to treat P. aeuroginosa + Proteus species.
Mycoplasma pneumoniae, Leigionella sp, Chl pneumoniae + psittaci + tracomatis, Coxiella Burnetti (Q fever), , Influenza: in order of incidence all cause atypical pneumonia syndrome. These organisms are hard to grow in laboratory agar media (unlike Strep, Haemophilus, Staph – which are easy to grow in such media). Diagnosis: antigen detection methods. Treatment: not susceptible to beta lactams (penicillin, cephalosporins) so use macrolides (erythromycin + roxithromycin) + tetracyclines.
Viruses
Most often viruses cause interstitial pneumonitis. Common aetiologic agents include:
RSV (most common in children: < 1yr ="=""> bronchiolitis, 4-5 yrs ==> bronchopneumonia), adenovirus (1, 2, 3, 5 - children), parainfluenza virus (types 1, 2, 3 - children) , influenza A (most common in adults) & B
Less common aetiological agents include:
Herpes virus, rhinoviruses, rubeola virus, echoviruses, corona viruses, coxsackie viruses.
Predisposing factors: age (elderly, very young) + immunological status (underlying disease affecting CMI, hospitalised patients)
Transmission: droplet inhalation (coughing + sneezing). Most prominent in winter + spring due to “population closeness”.
Pathogenesis: a) URT cells are infected by viruses b) spreads to other lung areas via infected secretions by URT, or by haematogenous + lymphatic spread.
Diagnosis:
Influenza A virus: WBC count > 10, 000m3
RSV: WBC are not specific, but CXR shows bilateral bronchopneumonia
Adenovirus: WBC count > 30, 000m3
Rubeola pneumonia (measles): CXR shows interstitial pneumonia
Treatment: most cases --> supportive only. But sometimes: RSV ribavirin
Fungi
Pneumocystis carinii: major cause in immunocompromised patients (esp. AIDS). Approximately half of AIDS patients develop Pneumonocystis carinii pneumonia.
Diagnosis: Demonstration of P. carinii in lung. Bronchoalveolar lavage samples preferred but if –ve then use transbronchial biopsy specimens. Silver stains reveal multinucleated cysts.
Treatment: trimethoprim-sulfamethoxazole is preferred, if intolerable then use pentamidine. Prophylaxis with medication is recommended in immunocompromised patients.
The Correct option is E
Discussion