Final year revision Microbiology and ID Shivam Patel

Final year revision Microbiology and ID Shivam Patel [email protected] Contents Introduction and classification Principles of antimicrobial drugs Antibiotics Antivirals Infections by system Respiratory (+TB) Wound, bone, joints/surgical GI and viral hepatitis Special infections

Herpes and opportunistic viral infections Malaria Sepsis Tropical infections There will be lots of basic science in the first 2 sections Probably not too relevant for your exam More detailed slides at the end will be distributed If we run out of time then well skip the tropical infections section There are some practice questions in the lecture Quiz (using smartphones) at the end Bacteria Can be classified into gram negative and positive TB (mycobacteria) are

separate! As are the unculturables Mycoplasma Chlamydia Legionella Outside cell Mycolic Acid Peptidoglycan Plasmamembrane Inside cell Mycobacteria Viruses Fungi Nucleic acid in a protein coat Classification: Eukaryotic organisms

Classification: DNA vs RNA Single vs double stranded Positive vs negative sense Yeasts vs moulds Spore-forming Very important in opportunistic infections Important for skin infections and in immunosuppressed patients Outside cell Chitin cell wall Plasmamembrane rich in ergosterol Inside cell Diagnostic Tools Culture Grow the microbe in cells (viruses) or medium (bacteria)

Takes ages to come back, some are unculturables But can get sensitivities phenotypically Serology Looks for antibody to pathogen Can be false positive in past infection and cross-reactivity Quick and easy PCR Looks for pathogenic genes Accurate and lets us see genotypic resistance and subtyping (TB, HepC) Question A 64 year old man comes in to hospital with a cough productive of red/brown sputum, fever and reduced consciousness. A sputum culture grows gram positive diplococci in pairs. These have a small amount of haemolysis on blood agar medium. What is the causative organism? A. Staphylococcus aureus B. Neisseria gonorrhoea C. Streptococcus pyogenes D. Streptococcus pneumoniae

E. Salmonella typhi Contents Introduction and classification Principles of antimicrobial drugs Antibiotics Antivirals Infections by system Respiratory (+TB) Wound, bone, joints/surgical GI and viral hepatitis Special infections Herpes and opportunistic viral infections Malaria Sepsis

Tropical infections Basic Antibiotic Mechanisms Acting on Nucleic Acids Transcription and Translation Sulphonamides and Trimethoprim Rifamycins (such as rifampicin) will inhibit bacteria RNA polymerase Interfere with folic acid synthesis in bacteria Fluoroquinolones (-floxacin) Inhibit DNA gyrase: involved in DNA replication Metronidazole Breaks up DNA in anaerobic conditions

4 classes of antibiotic act on ribosomes Macrolides such as erythro/clarithromycin Chloramphenicol Aminoglycosides like gentamicin and amikacin Tetracyclines such as doxycycline Cell Wall Inhibitors Bacterial cell walls are made up of peptidoglycan (formed by transpeptidase) Beta lactams inhibit transpeptidase Vancomycin blocks peptidoglycan binding Beta lactams are a broad group Penicillins: mostly gram positive cover Cephalosporins: broader cover

Carbapenems: broadest cover Some bacteria produce beta lactamase enzymes Flucloxacillin has intrinsic resistance However MRSA produces a different transpeptidase Question Which of the following antibiotics will be best suited to treating an uncomplicated episode of cystitis in a 22 year old woman? Assume that she is not pregnant. A. Co-amoxiclav (amoxicillin/clavulanic acid) B. Trimethoprim C. Meropenem D. Gentamicin E. Vancomycin Contents Introduction and classification Principles of antimicrobial drugs Antibiotics

Antivirals Infections by system Respiratory (+TB) Wound, bone, joints/surgical GI and viral hepatitis Special infections Herpes and opportunistic viral infections Malaria Sepsis Tropical infections Antivirals Herpesvirus drugs Viral hepatitis drugs

Aciclovir (good for HSV) Ganciclovir (good for CMV) Hep B Both work by blocking DNA replication If resistant Cidofovir and foscarnet IFN alpha, tenofovir and lamivudine Hep C Everyone gets IFN alpha and ribavirin New expensive drugs Protease, NS5/6a inhibitors can clear the infection fully Both block DNA replication in a different way Nephrotoxic so give with lots of iv saline

All current influenza drugs act on neuraminidase: these include zanamivir and oseltamivir Question Which of the following drugs is NOT suitable for the treatment of herpesvirus encephalitis? A. Cidofovir B. Aciclovir C. Lamivudine D. Foscarnet E. Valaciclovir Contents Introduction and classification Principles of antimicrobial drugs Antibiotics Antivirals Infections by system Respiratory (+TB) Wound, bone, joints/surgical

GI and viral hepatitis Special infections Herpes and opportunistic viral infections Malaria Sepsis Tropical infections Pneumonia Typical Atypical Streptococcus pneumoniae Leigonella pneumophilia

Most common, rusty-brown sputum Gram + diplococci Haemophilus influenzae Gram ve coccobacilli Staphylococcus aureus Post influenza Gram + coccus (clusters>chains) Klebsiella pneumoniae Gram ve rod Rx with amoxicillin Low sodium, urine antigen Mycoplasma pneumonia Cold agglutinins, erythema multiforme Chlamydia (psittaci and pneumoniae) Rx with clarithromycin

In HIV: Aspergillus Pneumocystis jiroveci (classic staining pattern) In CF: Pseudomonas Burkholderia Tuberculosis Primary infection Ghon focus in lower lobes Usually asymptomatic Post-primary Upper lobe cavitating lesion Haemoptysis, SOB etc Risk TB meningitis or military/bone spread Investigations:

Sputum microscopy ZN/auramine staining Sputum culture Lowenstein-Jensen medium Skin tests Heaf/mantoux IGRA PCR (allows genetic resistance profile) TB Treatment 6 months of rifamipicin and isoniazid 2 months of ethambutamol and pyrazinamide MDR vs XDR TB Side effects

I: LFTs, B6 deficiency/neuropathy R: orange secretions, P450 inducer E: colour blindness/optic atrophy P: LFTs Vaccination: BCG (live attenuated) Do not give in HIV Causes positive Mantoux test! Does not cause positive IGRA test VSAs (Very Short Answer) Questions 1. A 55 year old man returns from a conference in Italy with a fever and cough. He has a sodium of 123 (135-144) and a mildly raised ALT. Which is the most

likely causative organism? 2. A 30 year old HIV positive man with a low CD4 count presents to A&E with a shortness of breath on exertion, dry cough, mild fever and reduced saturations. Chest auscultation is largely normal. What stain would be most appropriate to use on his BAL sample? Contents Introduction and classification Principles of antimicrobial drugs Antibiotics Antivirals Infections by system Respiratory (+TB) Wound, bone, joints/surgical GI and viral hepatitis Special infections

Herpes and opportunistic viral infections Malaria Sepsis Tropical infections Wound, bone and joints Surgical Site Infections and cellulitis Usually staphylococcus aureus Treat with flucloxacillin Septic Arthritis Mostly staph/strep, can be Neisseria Drain joint and give fluclox or ceph Osteomyelitis MRI for diagnosis, usually staphylococcus aureus Salmonella in sickle cell patients Contents

Introduction and classification Principles of antimicrobial drugs Antibiotics Antivirals Infections by system Respiratory (+TB) Wound, bone, joints/surgical GI and viral hepatitis Special infections Herpes and opportunistic viral infections Malaria Sepsis Tropical infections Anaerobes

Aerobes Clostridium difficile E.coli 4 x Cs of C diff Metronidazole and Vancomycin PO Clostridium botulinum Canned foods Descending paralysis (cf GBS) Giardia lamblia Protozoa Pear-shaped, linked to foul smelling farts 4 types EHEC linked to HUS

Salmonella Typhi causes typhoid (not GI) Septic, rose spots, relative bradycardia and splenomegaly Enteritidies cause diarrhoea Vibrio cholera Rice-water stools Osmotic chloride-channel toxin Viral hepatitis Virus Timeframe Consequences Diagnosis Treatment

A (RNA) Acute Usually just self-limiting jaundice and abdominal pain. Faeco-oral transmission (shellfish) IgM (acute) Supportive Vaccine B (DNA) Mostly acute, some chronic Most will have initial jaundice then clear virus 15% become carriers and can get cirrhosis 2% can get acute liver failure. Transmitted by blood products and sexually

Various antibodies (look them up) PCR for viral load LFTs Peg IFNa Tenofovir Lamivudine Vaccine C (RNA) Mostly chronic Most become chronic carriers and get cirrhosis years later. Transmitted by blood produces and sexually ALT Anti-HCV assay

Peg IFNa Ribavirin New drugs D (RNA) Acute-onchronic Acute Superinfects HBV, rise in LFTs when stable. Not a pathogen on its own Similar to Hep A Serology Peg IFNa E (RNA) IgM?

Question Which patient description matches the following HBV serology results: A. B. C. D. E. HBs Ag: negative HBs Ab: positive IgG, negative IgM HBc Ab: positive HBe Ag: undetectable New infection with HBV, patient infectious Past vaccination with HBV vaccine Past infection with HBV, patient remains infectious Past infection with HBV, virus now cleared

Patient has received HBV IVIG prophylaxis recently Contents Introduction and classification Principles of antimicrobial drugs Antibiotics Antivirals Infections by system Respiratory (+TB) Wound, bone, joints/surgical GI and viral hepatitis Special infections Herpes and opportunistic viral infections Malaria Sepsis

Tropical infections Herpesvirus infections (all dsDNA) Virus Consequences Buzzwords Treatment HHV 1/2 (aka HSV) Oral/genital ulcers Encephalitis (usu HSV 1) Neonatal herpes infection Painful ulcers, coalesce Aciclovir,

foscarnet/cidofovir HHV 3 VZV Chickenpox/shingles (dermatomal reactivation) Congenital varicella syndrome Ramsay Hunt syndrome Dermatomal Vesicles>ulcers Aciclovir VZIG in foetal exposure Vaccine available HHV4 EBV Glandular fever Burkitts lymphoma PTLD, oral hairy leukoplakia

African child big jaw Penicillin rash Splenomegaly Ganciclovir, Cidofovir/foscarnet HHV5 CMV RCHEP in immunosuppressed Retinitis, colitis, hepatitis, encephalitis, pneumonitis Congenital (microcephaly/death) Roseola Infantum Owls eye inclusions BMT/HIV patients Ganciclovir, Cidofovir/foscarnet

Fever followed by rash 3d later HIV, purple lesions LNopathy Supportive HHV6 Roseola HHV8 Kaposi Sarcoma Multicentric Castlemans disease Tocilizumab (anti IL-6) Aciclovir Other opportunistic viral infections JC virus John Cunningham Progressive multifocal

leukoencephalopathy BK virus Haemorrhagic cystitis Interstitial nephritis Measles virus Rapidly progressing pneumonitis or encephalitis Investigation of choice is PCR Serology is pretty useless (Not viruses) Toxoplasmosis Cryptococcus neoformans Pneumocystis jiroveci Question

A patient with long term poorly controlled HIV presents with new fleshy purple/ brown painless lesions on his skin. What is the most likely causative pathogen A. Toxoplasma gondii B. HSV1 C. CMV D. HHV8 E. EBV Contents Introduction and classification Principles of antimicrobial drugs Antibiotics Antivirals Infections by system Respiratory (+TB) Wound, bone, joints/surgical GI and viral hepatitis Special infections

Herpes and opportunistic viral infections Malaria Sepsis Tropical infections Malaria Classification Clinical/investigations Falciparum Fever, splenomegaly, shock/coma/low GCS Rigors, headache, ARDS, haemolytic Most common/severe Maurers clefts Most unwell patients

Vivax/ovale Liver stage (hypnozooites) Schuffners dots Malariae Indolent Additionally P knowlesi Ovale now 2 forms (curtesi, walkeresi) Thick and thin blood films RDT (antigen test) Check FBC, platelets and LFTs! Treatment of malaria Falciparum Others Severe (>2% parasites) Chloroquine

Ovale/vivax get primaquine to eradicate liver hyponooites IV artesunate Fluids and ITU support Otherwise Quinine and doxycycline Most falciparum strains are resistant to chloroquine Contents Introduction and classification Principles of antimicrobial drugs Antibiotics Antivirals Infections by system Respiratory (+TB) Wound, bone, joints/surgical GI and viral hepatitis

Special infections Herpes and opportunistic viral infections Malaria Sepsis Tropical infections Definitions Old New Sepsis should be defined as life-threatening organ dysfunction caused by a dysregulated host response to infection Septic shock should be defined as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater

risk of mortality than with sepsis alone. a new bedside clinical score termed quickSOFA (qSOFA): respiratory rate of 22/min or greater, altered mentation, or systolic blood pressure of 100 mm Hg or less. JAMA. 2016;315(8):801-810. doi:10.1001/jama.2016.0287 Treatment Oscar Caught A FLU Oxygen if needed Blood (and other) cultures Antibiotics within 1 hour Fluids

Lactate measurement Urine output monitoring Plus Clarify source of infection Change antibotics once organism and sensitivity known Consider escalation to intensive care especially if blood pressure not increasing with fluid challenges Different hospitals have different antibiotics suggested when you have a septic patient but no organism known. E.g. Tazocin, Co-amoxiclav+gentamicin Contents Introduction and classification Principles of antimicrobial drugs Antibiotics Antivirals Infections by system

Respiratory (+TB) Wound, bone, joints/surgical GI and viral hepatitis Special infections Herpes and opportunistic viral infections Malaria Sepsis Tropical infections (optional) Thanks for listening Any Questions? [email protected] Tropical Medicine Malaria

Protozoa Trypasnoma Leishmaniasis Tropical Infections Roundworms Helminths Tapeworms/flukes Filarial disease Protozoan infections Trypasnoma Leishmaniasis T cruzi Vector is sandflies (poor fliers) Cutaneous (L major/L tropica)

Chagas disease (S America) Triatomia/reduviid bugs Achalasia, eye swelling, cardiomyopathy T brucei (sleeping sickness) Gambiense in North Africa (common) Indolent sleep, late neuro signs (delirium) Rhodesiense in South Africa (rare) Acute and severe, near fatal Vector is Tsetse flies Skin ulcer, often poorly healing Mucocutaneous (braziliensis) As above but with mouth/anus Visceral (Kala-Azar) Caused by L donovani (mostly) Fever, anaemia, massive splenomegaly Roundworms

Faeco-oral Trough the skin Enterobius vermicularis Hookworms (barefoot infection) Threadworms, itchy, sellotape test Single dose mebendazole Ascaris lumbricoides Bowel obstruction Massively multiply in GIT Toxocara canis Spread by dogs Visceral: nonspecific eosinophilia Ocular: can cause blindness See under skin (cutaneous larva migrans)

Anaemia and reduced growth Strongyloides (similar to hookworm) Risk hyperinfection with HTLV-1 in immunosuppressed patients Tapeworks and flukes Tapeworms Flukes Echinococcus granulosus Schistosomiasis (bilharzia) Hydatid disease Cysts in sheep/dogs spread to liver

Liver cysts can rupture anaphylaxis Common in farmers and homosexuals Spread by water-snails Move to lungs : katyama fever (wheeze/cough) Hepatomegaly and portal HTN Can lead to cirrhosis S haematobium is bladder form Increased risk of bladder ca and cholangiocarcinoma Filarial Disease Onchocerciasis (river blindness) Black flies Itching and scratching leads to blindness

Loasis (Loa Loa) Chrysops flies Calabar swellings (can be seen in the eye) Elephantiasis (Wucheria bancrofti) Lyphoedema Dance sign on ultrasound Dracunculiasis (guinea worm) Water flea ingested, adults grow up to 1m long Long extraction Question Which of the following pathogens is the most common cause of African sleeping sickness? A. Leishmania donovani B. Trypasnoma cruzi C. Trypasnoma brucei rhodesiense D. Ascaris lumbrocoides E. Trypasnoma brucei gambiense Thanks for

listening Any Questions? [email protected] Drugs acting at nucleic acids DHF reductase Bacteria only DHOP DHF THF Purines Methionine DHOP synthase PABA

Sulphonamides inhibit DHOP synthase Trimethoprim inhibits DHF reductase but cannot penetrate eukaryotic cell membranes Used in uncomplicated UTIs Normally, DNA gyrase eases the tension on DNA during replication to stop it snapping by temporarily opening it up. Quinolones (and fluoro-quinolones) such as ciprofloxacin inhibit DNA gyrase, hence very broad spectrum Metronidazole is an nitroimidazole: under anaerobic conditions the reduced form is able to break up and destroy DNA Commonly used for anaerobic infections Transcription and translation inhibitors RNA polymerase is the enzyme complex that forms RNA from a DNA template, bacteria have a different

form!! Ribosomes allow the formation of protein from an RNA template. Bacterial ribosomes are 70s whereas eukaryotes have 80s versions Rifamycins (such as rifampicin) will inhibit bacteria RNA polymerase 4 classes of antibiotic act on ribosomes Macrolides such as erythro/clarithromycin Chloramphenicol Aminoglycosides like gentamicin and amikacin Tetracyclines such as doxycycline Mnemonic: MCAT Cell wall inhibitors

Bacterial cell walls are made of peptidoglycan (PTG), formed by an enzyme called transpeptidase Glycopeptides such as vancomycin bind pentapeptide units on PTG hence PTG isnt formed Beta lactams such as penicillins, carbapenems and cephalosporins inhibit transpeptidase Penicillins good for streptococcal and staphylococcal infection Cephalosporins have good gram positive and negative cover Carbapenems are very broad spectrum and can overcome ESBL Cephalosporins and penicillins Cephalosporins Penicillins Inhibits transpeptidase Many classes and 5 generations E.g. cephalexin is 1st gen, ceftriaxone is 3rd gen and very broad spectrum Resistance by: Inhibits transpeptidase

Again resistance is by beta lactamases Overcome resistance by: Beta lactamases cleave beta lactam ring ESBL will cleave up cephalosporins Carbapenems are usually ESBL resistant Beta lactamase resistant drugs like flucloxacillin (methylated penicillins) Giving with beta lactamase inhibitors: exampleco-amoxiclav is amoxicillin and clavulanic acid MRSA produces a different kind of transpeptidase, flucloxacillin or coamoxiclav will not work

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