Practice MCQ: Human Fungal Pathogens PDF

Human fungal pathogens Superficial mycoses ○ Malassezia furfur Cutaneous mycoses ○ Tinea capitis ○ Tinea cruris ○ Tinea pedis Subcutaneous mycoses ○ Sporotrichosis ○ Mycotic mycetoma Systemic mycoses ○ Candida ○ Cryp...

Human fungal pathogens Superficial mycoses ○ Malassezia furfur Cutaneous mycoses ○ Tinea capitis ○ Tinea cruris ○ Tinea pedis Subcutaneous mycoses ○ Sporotrichosis ○ Mycotic mycetoma Systemic mycoses ○ Candida ○ Cryptococcus ○ Histoplasmosis ○ Aspergillus Fluconazole Fungistatic Dose dependent fungicidal Excreted largely unchanged in urine so good in candiduria Terbinafine = use half normal dose if eGFR less than 50mL/minute/1.73m2 Polyenes Nystatin = local oral, oropharyngeal and perioral infections Amphotericin B = IV for systemic Highly protein bound Penetrates poorly into tissues Less toxic ampho B = ampho B liposomal formulations 5-FC + ampho B Amph B = increases cell permeability 5-FC = forms false nucleotide Disrupting nucleic acid and protein synthesis 5-FC = hepatotoxicity + blood disorders Echinocandins = fungicidal against candida but fungistatic against aspergillus Griseofulvin Dermatophytosis Causes disruption of mitotic spindle, inhibiting mitosis Induces hepatic CYP450 Causes dyspepsia + fatigue  Drug class MoA Pharmacokinetics Tri-azoles Block CYP450 and sterol 14 alpha Fluconazole = good penetration into demethylase in cell wall CSF, oral, urine excretion Itraconazole = capsules need acidic environment (stomach), hepatotoxic, drug interactions Voriconazole = drug interactions Posaconazole = for invasive infections unresponsive Terbinafine Inhibits squalene epoxidase that accumulates toxic sterols in cell wall Polyenes Inhibit form pores in fungal membrane Ampho B = IV infusion Nystatin = locally oral Not absorbed when given by mouth Flucytosine Inhibit protein synthesis (5-FC) Echinocand Inhibit 1,3-beta-glucan in cell wall IV only ins polysaccharide Griseofulvin Inhibit fungal mitosis Treatment for invasive candidiasis Echinocandin Fluconazole - clinically stable Ampho B - for CNS candidiasis or alt Voriconazole - fluconazole resistant candida, oral therapy, or intolerant to ampho B + echinocandin Histoplasmosis = parenteral itraconazole or ampho B Aspergillosis treatment ABPA = steroids + itraconazole Aspergilloma = surgery + itraconazole/voriconazole Invasive aspergillosis = voriconazole or liposomal ampho Classifying viruses = baltimore classification system - based on mechanisms of mRNA production HIV, adenosine, tenofovir HSV, aciclovir, guanine  HIV Contains reverse transcriptase = RNA dependent DNA polymerase, making a DNA copy of viral RNA DRUG TYPE TARGET MOA EXAMPLE/FIRST LINE Env gp120 and Effects cell entry env gp41 NRTIs Reverse Compete with reverse transcription, preventing viral Tenofovir - transcriptase, pro-DNA synthesis adenosine RNA → DNA NNRTIs Reverse Bind directly to RT causing conformational change Efavirenz transcriptase, which stops enzyme working RNA → DNA Integrase inhibitors Integrase Integration of provirus DNA into host chromosomal Dolutegravir DNA Protease inhibitors Protease Cleaves initially translated polypeptides into Darunavir, with PK functional viral proteins enhancer Antiretroviral therapy in HIV = 2 NRTIs and 1 from NNRTI, PI, or integrase inhibitor Undetectable + non transmissible Chronic HBV Immunomodulatory - pegylated IFNalpha Nucleotide therapies - active against RT step ○ Tenofovir Influenza = neuraminidase inhibitors Oseltamivir - oral Zanamivir - inhalation Competitively binds NA bindings site, preventing viral release Aims of therapy Viral eradication = HepC + influenza Long term suppression = HIV + HepB Management of flares = HSV Asthma = narrowing, reversible, hyper-responsiveness, inflammation 90% of inhaler swallowed, 10% deposited in lung Drug type MoA Examples Step Beta 2 agonists - Stimulate bronchial smooth muscle SABA = salbutamol 1 = intermittent receptors, relax+dilute = reduce LABA = salmeterol reliever breathlessness 3 = Initial add on - Inhibits mediator release from mast cells + TNFalpha release from monocytes - Increases ciliary action of airway epithelial cells - airway clearance Glucocorticoids - Bind to receptor, modify immune Beclomethasone + 2 = regular response budesonide preventer - Inhibits cytokine formation - Inhibits activation + recruitment of inflammatory cells - Inhibits inflammatory prostaglandins + leukotrienes = less mucosal edema - Decreased mucosal inflammation, widens airways, reduces mucus secretion LTRA - Block bronchoconstriction CysLT1 effects Montelukast 4 = Additional in airways = bronchodilation controller therapy - Reduce eosinophil recruitment, less inflammation, epithelial damage, and airway hyper-reactivity Methylxanthines - PDE inhibitors Theophylline + 5 = specialist - PDE involved in inflammatory cells - aminophylline therapies inhibition reduces inflammation - Increases intracellular cAMP in bronchial smooth muscle = bronchodilation - Blocks adenosine receptors = bronchodilation - Activates histone deacetylase = immunomodulatory SAMAs + LAMAs - Bronchodilation SAMA = ipratropium 5 = specialist - Decreased mucus secretion LAMA = tiotropium - therapies - Increased mucociliary clearance M3 Monoclonal Severe persistent allergic asthma Omalizumab 5 = specialist antibodies - Steroid sparing therapies - Anti IgE treatment Acute moderate asthma = 50-75% PEF Acute severe asthma = 33-50% PEF + resp 25/min + HR 110 bpm + no sentences Life threatening asthma = under 33% PEF Near fatal = raised PaCO2 / ventilation Acute severe asthma Oxygen SABA via neb IV/oral steroids = hydrocortisone or prednisolone Abx? SAMA via neb? No improvement ○ IV magnesium sulphate ○ Neb → IV SABA or IV aminophylline COPD LAMA or LABA LAMA + LABA LABA + LAMA + ICS Others ○ Methylxanthines ○ PDE4 inhibitor - roflumilast - for severe repeated exacerbations ○ Long term O2 High risk COPD pt 2+ exacerbations in one year FEV1 less than 50% Acute severe COPD exacerbations SABA or SAMA via neb Oral prednisolone Abx? 24-28% O2 Extreme = NIV, intubation Resistance mechanisms Enzymatic inactivation - beta lactamases Enzymatic addition - aminoglycosides Impermeability - beta-lactams Efflux - tetracyclines Alternative pathway - MRSA mecA Altered target - rifampicin Resistance transmission Transformation - penicillin in s.pneumoniae Conjugation - beta lactamases Transposons - erythromycin in s.pyogenes ○ Allow genome plasticity Superbug - gained resistance to critical or multiple abx, e.g., MRSA, VRE, GISA, ESBLs CF = autosomal recessive, defect in gene coding for CFTR on chromosome 7, coding for energy dependent chloride channel Diagnosis = sweat test or newborn screening ○ Pilocarpine iontophoresis, chloride conc = more than 60 mmol/L Exacerbation characterised by 2 or more ○ Change in sputum volume or colour ○ Increased cough ○ Increased malaise ○ Anorexia ○ Peak flow more than 10% drop ○ X ray changes ○ Increased dyspnoea Mutation classes ○ Premature stop codon ○ folding/trafficking defect ○ Narrow channel ○ Gating defect ○ Decreased stability ○ Splicing defect Novel therapies ○ Suppressors of premature stop codons Treats nonsense mutations Aim to read thru these stop codons and allow ribosome to continue translating a full length, functional CFTR protein ○ CFTR correctors Helps misfolded CFTR protein reach cell surface ○ CFTR potentiators Enhance function of CFTR proteins already present at cell surface Spirometry measures FVC = total volume forcibly exhaled after full inspiration ○ Indicates lung size ○ Reduces in restrictive lung disease FEV1 = volume forcibly exhaled during first second of a forceful exhalation ○ Indicates degree of obstruction ○ Reduced in obstructive lung disease FEV1/FVC ratio Reduced in obstructive lung disease = less than 0.7 Normal in restrictive lung disease = more than 0.7 Important asthma mediators IL4,5,13 Leukotriene B4 and Cysteinyl-leukotrienes Tissue damaging eosinophil proteins COPD = persistent airflow limitation, progressive, enhanced chronic inflammatory response in airways to noxious particles or gases COPD pathophysiology Inflammation + fibrosis of bronchial wall Hypertrophy of submucosal glands + hypersecretion of mucus Loss of elastic, parenchymal lung fibres - emphysema Alpha1 antitrypsin deficiency COPD at 45 years Lower zone dominant emphysema Liver enzyme counteracting proteinases = tissue damage Autosomal co-dominance Decreased gas transfer in restrive lung disease If disproportionate to decreased lung volumes, consider co existent emphysema or pulmonary hypertension Prognostic indicators for restrictive lung disease 6 minute walk test Changed FVC over 6 months Composite physiological scores GAP score in IPF IPF most common + most feared + most progressive Almost always diagnosed on CT scan Broad spectrum penicillins Ampicillin + amoxicillin Extended spectrum penicillins Carbenicillin Good for pseudomonas aeruginosa Beta-lactam resistant penicillins Methicillin Carbapenems Binds PBPs permanently, acylating them Cephalosporins Oral = cephalexin Overuse = C.diff emergence Glycopeptide Active against cell membrane, targeting C terminal D-ala-D-ala, preventing transglycosylation + transpeptidation Vancomycin - interferes with peptidoglycan elongation, good for MRSA Cyclic peptide Targets C55-isopropyl pyrophosphate Bacitracin - ointment for skin + eye strep and staph infections Phosphonic acids Targets MurA protein Fosfomycin Lipoproteins Targets cell wall stress stimulon, calcium dependent membrane depolarisation Daptomycin Bacterial folate antagonists Inhibits folate pathway Sulfonamides + trimethoprim = cotrimoxazole = toxoplasmosis treatment Sulphonamides + pyrimethamine = drug resistant malaria + toxoplasmosis Macrolides inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit Erythromycin Clarithromycin - QT prolongation Clindamycin - pseudomembranous colitis (c.diff) Aminoglycosides Diffuses into cytoplasm to bind to bacterial ribosomes Streptomycin Good for serious and rare conditions - so reserved Do not give in severe sepsis as can cause acute renal failure Tetracyclines Prevents tRNA attachment to acceptor site on mRNA-ribosomal complex Good for chronic acne Tigecycline Chloramphenicol Inhibits peptide bond formation Aplastic anaemia risk Meningitis good for Topoisomerase IV Catalyses ATP dependent relation of … DNA gyrase Breaks DNA and repairs them Fluoroquinolones Ciprofloxacin Best in enterobacteriaceae Polymyxins Branches chain decapeptides with cationic detergent properties Topical for cutaneous pseudomonas infections Nitrofurans Nitrofurantoin Metronidazole Anaerobic - generates toxic radicals damaging bacterial DNA Effective in therapy of pseudomonas colitis Treat H.pylori infection, with omeprazole, amoxicillin Common cold = rhinovirus Acute pharyngitis + tonsillitis Virus = EBV, CMV Bacteria = strep pyogenes Always IgM serology for resp tract infection test Glandular fever (EBV) complications Burkitt's lymphoma Nasopharyngeal carcinoma Guillain barre syndrome Parotitis = mumps virus Complications ○ CNS ○ Epididymo-orchitis Acute epiglottitis = H.influenzae - life threatening, no throat swab + give IV ceftriaxone or chloramphenicol Diphtheria - bull neck, give penicillin or erythromycin Whooping cough = catarrhal (contagious, 1 week, erythromycin) and paroxysmal stage (whoop cough, 1-4 weeks) Bordetella pertussis Acute bronchitis = rhinovirus Chronic bronchitis = anatomical disturbance of resp system Immune deficiency = SCID Ciliary deficit = kartagener syndrome, smoking Excessively thick mucus = CF Bronchiolitis = RSV Measles = koplik's spots Can cause giant cell pneumonia in immunocompromised, fatal Give ribavirin if severe Antigenic drift in influenza Small point mutations in H and N antigens occurring constantly Allows virus to multiply in individuals with immunity to preceding strains New subtype can reinfect community Antigenic shift in influenza Sudden major change based on recombination between 2 different strains when they infect same cell Produce virus with novel surface glycoproteins New strain can spread thru previously immune populations - new pandemic Cor pulmonale Right sided heart hypertrophy Severe emphysema Congestive heart failure Hypersensitivity pneumonitis - extrinsic allergic alveolitis Type III + IV Young people Sarcoidosis Granulomas Bilateral hilar lymphadenopathy Increased ACE Benign lung cancer = mesenchymoma, papilloma, inflammatory myoblastic tumour Malignant lung cancer  Malignant primary epithelial = metaplasia and dysplasia - commonest ○ Squamous, adenocarcinoma, small cell undifferentiated, carcinoid, large cell undifferentiated, molecular Malignant secondary = sarcoma, renal carcinoma, lymphoma NSCLC - squamous = 40% NSCLC - adenocarcinoma = 40%, more amenable to immune checkpoint treatment NSCLC - adenocarcinoma, bronchoalveolar = intrapulmonary dissemination SCLC - undifferentiated = neuroendocrine, paraneoplastic effects Paraneoplastic effects In undifferentiated SCLC Bioactive amines or peptides produced - ADH, PTN like peptides, ACTH Signs + symptoms not directly caused by the cancer Immunological Acanthosis nigricans - EGF Finger clubbing Increased epo Immune complex GTN Molecular treatment EGFR amplification ALK rearrangements Assessment of PDL1 ○ Immune checkpoints ○ Checkpoint inhibition = so treatment would be to block these signals Mesothelioma Asbestos - crocidolite 20-40 year lag Male 5:1 (same as squamous carcinomas) Fibrous pleural plaques Carcinoid Malignant spectrum Typical = less aggressive Atypical = more aggressive Resp acidosis causes Resp depression Emphysema Chronic bronchitis Lung collapse Drugs reducing resp drive - morphine  Hypoventilation Ventilation perfusion mismatch Resp alkalosis causes Hyperventilation as blowing off more CO2 ○ Brain stem damage ○ Infection driving fever High altitude - reduced O2 stimulates ventilation via peripheral chemoreceptor response Hypoxic drive in pneumonia Metabolic acidosis causes Bicarb loss - diarrhea Aspirin overdose Ketogenesis - DKA Failure to secrete hydrogen, e.g., renal failure Metabolic alkalosis Vomiting - loss of hydrogen chloride from stomach Ingestion of alkali substance Potassium depleting - diuretics Base excess From pH and pCO2 Amount of acid required to restore 1 litre of blood to its normal pH at pCO2 of 5.3kPa Bicarb predominant Normal range +/-2mmol/l Significant negative = metabolic acidosis Significant positive = metabolic alkalosis Anion gap Sum of routinely measured cations in venous blood minus routinely measured anions Always a gap Increased gap = presence of metabolic acidosis Normal anion gap = 12-16 Normal anion gap, without potassium = 8-12 (sodium + potassium)-(chloride + bicarb) Minute volume = tidal volume x resp rate SARS-COV2 ssRNA virus, no.7 Cell entry - via ACE2 Covid signs on CXR = bilateral sings, fine creps  Prognostic biomarkers in covid Lymphopenia Ferritin LDH D-dimer Acute management of covid STRAPP ○ Steroids - dexamethasone ○ Tocilizumab ○ Research ○ Antivirals - remdesivir ○ Proning ○ Positive pressures Treatment pathways - for high risk list Line Name Administration Setting given 1st Paxlovid Oral Outpatients, early infection, community hospital 2nd Sotrovimab IV Hospital, day case, need to manage anaphylaxis 3rd Remdesivir IV, 3 day course Hospital, day case, need to manage anaphylaxis 4th Molnipiravir Oral Acute severe COVID - drugs for patients with covid + requiring oxygen to maintain sats Dexamethasone ○ 6mg OD for 10 days Tocilizumab ○ Added when hypoxia/hyperinflammation/critical illness Remdesivir + baricitinib ○ 5 day course Type What is it? Use Examples Live Organism capable of normal infection + replication Not used against MMR + polio - pathogen that can currently given in cause severe Gaza 2024 disease Attenuated Organism live, but ability to replicate + cause MMR + polio - disease reduced by chemical treatment or growth currently given in adaption in non human cell lines Gaza 2024 Recombinant Genetically engineered to alter critical genes - often HepB vaccine can infect + replicate but does not induce associated disease Killed Organism killed by physical or chemical treatment B.pertussis + so incapable of infection/replication but still cause typhoid strong immune response DNA/mRNA Naked DNA or mRNA injected - host cells pick up Pfizer for covid19 DNA + express pathogen proteins stimulating immune response Extract Materials derived from disrupted or lysed organism When risk of Flu + pneumococcal organism surviving + diphtheria + inactivation steps tetanus Dendritic cells in vaccination - causes activation of T cells and initiation of adaptive immune responses Also express pattern recognition receptors, members of TLR TLR4 = detects lipopolysaccharide, heat shock protein TLR9 = detects CpG - cytosine phosphate guanosine, bacterial DNA CpG in HepB + Flu vaccines = increased antibody or IFN gamma secretion HAI is not present on admission but occurs over 48 hours after admission 1.1% of NHS scotland budget Average length of stay = 7.8 days Contact precautions C.diff, MRSA, S.pyogenes Droplet precautions More than 0.5 microns N.meningitidis, mumps, rubella, covid, flu, RSV, all resp Airborne precautions Less than 0.5 microns FFP3 mask for all aerosol generating procedures TB, chicken pox, measles Invasive medical devices - long or short term, all break skin or mucous membrane barrier Indwelling prosthetic devices long term devices which are buried into tissue under skin E.coli = most common cause of bloodstream infections S.aureus in VADs is a concern Acidosis Rise in PCO2 Fall in bicarb Alkalosis Fall in PCO2 Rise in bicarb Alveolar ventilation = rate at which new air reaches areas, major factor determining O2 + CO2 conc in alveoli Pleural pressure less at apex than the base, and with inspiration, it decreases further Underinflated Smaller alveoli at base more compliant So receive more tidal volume Over Inflated Expanded alveoli at top have lower compliance Receive less tidal volume Pulmonary capillary pressure = low = 7mmHg Interstitial fluid pressure = -8mmHg Colloid osmotic pressures of pulmonary interstitial fluid = 14mmHg Zone 3 receives a continuous blood flow during the entire cardiac output Zone 1 receives no blood flow during all portions of cardiac cycle Ventilation-perfusion matching = relationship between air reaching the alveoli (ventilation) and blood flow through the pulmonary capillaries (perfusion) Ventilation exceeding perfusion = over 1 Perfusion exceeding ventilation = under 1 Normal = 0.85 Causes of hypoxaemia Anatomical shunt - cyanotic congenital heart diseases most common Physiological shunt - atelectasis most common V/Q mismatching - chronic bronchitis, asthma Hypoventilation - muscular dystrophy or diaphragmatic paralysis Absolute polycythaemia Primary ○ Haematocrit levels rise due to overproduction of RBCs in bone marrow ○ Mutation in 2nd messenger system - JAK-STAT ○ Most common type = PV Secondary ○ Increase of epo in response to hypoxia ○ Low O2 levels = mRNA for epo increased + epo produced ○ Causes Hypoxia due to high altitude = 3000m plus Local renal hypoxia or renal artery stenosis Congenital high affinity haemoglobin Tumours producing epo, e.g., renal, uterine Drug, e.g., androgens + abuse of therapeutic epo Smoking, partly due to CO exposure Altered O2 sensing ○ Mutations in genes that bring about increased epo production, e.g., chuvash polycythaemia Treatment for chronic excess epo = removal of 500ml bags of blood to reduce haematocrit to less than 52%-55% JAMA 1944 - must always consider complete bed rest as highly non physiologic and definitely hazardous form of therapy, to be ordered only for specific indications and discontinued as early as possible Experience of a patient Hospital environment Entering the role of a pt Loss of control - therapeutically and organisationally desirable ○ Behavioural control ○ Cognitive control  ○ Decision control ○ Informational control Depersonalisation Institutionalisation Children's tendency to show separation distress peaks at 15 months Issues relating to children as inpatients - separation distress, illness misconceptions, faulty representations Stages of separation ○ Protest, despair, detachment Impact of hospitalization on child behaviour ○ Regression, nightmares, irritable Centre Location Role Importance VRG Nucleus ambiguus Forced respiration Provides powerful and nucleus Mixed inspiratory + expiratory signals to retroambiguus expiratory abdominal muscles during heavy In increased expiration  ventilatory drive, contributes to extra resp drive DRG Nucleus tractus Controls basic rhythm solitarius of breathing Emit repetitive inspiratory neuronal AP bursts Receives sensory input from thorax + abdo organs Pneumotaxic Dorsally in nucleus Modulates rhythm by Weak signal = parabrachialis inhibiting DRG, inspiration over 5 medialis of upper promoting expiration seconds pons Strong signal = inspiration under 0.5 sections Apneustic Stimulates DRG to prolong inspiration Hypercapnia and acidosis detected by central resp centres Hypoxia detected by peripheral chemoreceptors in carotid and aortic bodies, also detects hypercapnia and acidosis Carotid bodies have multiple highly characteristics glandular like cells - glomus cells - that synapse directly or indirectly with nerve endings Hering breuer reflex Helps prevent over inflation of lungs Stretch receptors in muscle of walls of bronchi + bronchioles Sends signals thru vagus to DRG neurons when lungs overstretched Feedback response initiated = turn off inspiratory ramp Reflex not activated until TV increases to 3x normal = 1.5L/breath Type of slowly adapting pulmonary stretch receptors C fibre receptors In alveoli + conducting airways, close to capillaries Respond to chemical + mechanical stimuli Become stimulated by ○ Pulmonary oedema ○ Pneumonia ○ Congestion ○ Endogenous chemicals, e.g., histamine  ○ Glottis closed by vagal efferent activity ○ Forced expiration against closed glottis ○ Pressure increases Rapidly adapting pulmonary stretch - irritant - receptors Cough flex Preparatory inspiration Compression phase ○ Glottis closed by vagal efferent activity ○ Forced expiration against closed glottis ○ Pressure increases Expulsion phase ○ Glottis opened suddenly ○ Trapped air forced out by contraction of internal intercostal muscles + abdo muscles O2 transport Combined with Hb - 98% Physically dissolved in plasma - 2% HbS causes sickle cell anaemia = glutamate at position 6 in the beta-globin replaced with valine O2 capacity = amount of O2/L of blood attached to Hb, at full saturation, depending on the Hb concentration in blood May take 2 years to convert all HbF into HbA Bohr effect - resp acidosis - rightward shift Carbon monoxide increases O2 affinity of Hb - leftward shift Metabolism generates 200ml CO2/min at rest Solubility of CO2 in plasma is 20 times that of O2 CO2 transport Bicarb in RBCs - 70% CO2 dissolved in plasma - 10% Carbaminohaemoglobin - 20% Haldane effect in CO2 dissociation curve As blood enters pulmonary capillaries and binds O2, CO2 carrying capacity falls and blood dumps CO2 O2 consumption in adults 250ml/min, rising to 4L/min in heavy exercise High PO2 in lungs facilitates O2 binding to Hb Leftward shift Decreased PCO2 Decreased temp Increased pH Low PO2 in lungs encourages O2 release Rightward shift Bohr effect Increased PCO2 Increased temp Decreased pH Anatomical dead space - 150mls, up to generation 17 Dalton's law of partial pressures = total pressure of a mixture of gases is the sum of their individual partial pressures Henry's law = concentration of O2 dissolved in water is proportional to the partial pressure in gas phase Alveolar gas composition O2 in lungs is lower (104mmHg) CO2 is higher (40mmHg) Water vapour is higher - so N2 lower PO2 alveolar air = 100mmHg PO2 of venous blood = 40mmHg, so diffusion rapid as conc gradient large At rest, 0.75-1 second for blood to pass thru pulmonary capillaries O2 equilibrium takes 0.25s In exercise, capillary transit time can be reduced to 0.3s PCO2 alveolar air = 40mmHg PCO2 venous blood = 45mmHg, so smaller conc gradient, opposite direction, greater solubility Diffusion limitations on gas exchange Odema = thickness barrier increased Emphysema = breakdown of tissue and alveolar sacs Pulmonary fibrosis = deposition of fibrotic tissues Mucus, inflammation airway, tumours = reduced gas entry