Title: PHRM3101 Week 1: Infection

Q: Describe why microorganisms can be beneficial for health
A: Microorganisms and its association health
- Often microorganisms are abundant and all around us and are not harmful and in many cases, beneficial and essential for health
- These benefits can include digestion of nutrients to make available for absorption, protection against virulent pathogens, and constant stimulation and strengthening of immune function

Q: Describe how microorganisms cause disease
A: Microorganisms and its association with disease
Only in some cases microorganisms are harmful to health. Microorganisms that cause disease are called pathogens. Severity of the disease is termed virulence.
These microbes can exist in low numbers and not cause disease which are termed commensal microbes. The following events can potentiate disease:
- Overgrowth: Increase in number
- Translocation: Move to another site in the body
- Cross-infection: Transferred to another individual

Q: What types of pathogens are there
A: Types of Pathogens
Opportunistic: Cause disease when the host's resistance to the microbe is supressed
(e.g. immunosuppression due to disease, age, or immunosuppressive medication or host's microbiota)
Primary: Microorganisms that can cause disease despite normal host defence

Q: Describe the location of microorganisms in the upper respiratory tract
A: Upper respiratory Tract: Haemophilus influenzae and Streptococcus pneumoniae are present. If these are transferred to the lower respiratory tract (aspiration of vomit), they can be associated with the development of pneumonia

Q: Describe microorganisms on the skin
A: Skin: If the skin is damaged, Staphylococcus on the skin can invade to cause cellulitis

Q: Describe the location of microorganisms in the GIT
A: GIT: Escherichia coli, if transferred to the urinary tract, can cause UTIs.

Q: Describe the location of microorganisms in the vagina
A: Vagina: Candida albicans is normally present in the vagina. Changes in pH or amounts of other vaginal flora may allow overgrowth of candida and lead to vaginal candidiasis (thrush)

Differentiate innate and adaptive immunity

Q: Describe microscopy as a method of identification of microorganisms
A: 1. Microscopy (fast): When a sufficient sample is available, microscopy can immediately be performed to classify bacteria via shape (e.g. cocci, bacillus), and further classified by gram-staining of the bacterial wall (gram-pos/neg/atypical). Combining this information with the infection site and symptoms and usual causative organisms can support initial selection of antibiotic.

Q: Describe Culturing as a method of identification of microorganisms
A: 1. Culturing (24hr): Increasing the amount of bacteria for microbial identification. Includes culturing on selective media to determine of bacteria is aerobic or anaerobic or to perform biochemical or mass spec identification. Taking 24hrs, it affects utility for initial selection of an antibiotic

Q: Describe antimicrobial susceptibility as a method of identification of microorganisms
A: Antimicrobial susceptibility (>24hrs): Information where antimicrobial susceptibility is requested, culturing in the presence of a library of antimicrobials needs to be performed (2-3 days). This guides a prescriber which antibiotics can be used to effectively treat an infection. Useful where antibiotic resistant microorganisms are present.

Q: Describe PCR as a method of identifying microbes
A: Polymerase chain reaction: Amplification and detection of bacterial genes combined with techniques (e.g. sequencing, micro assays) to identify which bacteria is present. Fast bacteria identification with small sample amounts and can be used when microorganisms cannot be cultured.

Q: Describe chest xrays as a method of identifying microbes
A: Chest X-ray: Useful for pneumonia diagnosis. Regions that are filled with air are black while regions that are infected (air sacs filled by pus) appear dense and white

Q: Describe WBC count as a method to identify infection
A: White cell count (WCC): WBCs (leukocytes) are important for fighting infections where the normal range is 4-11 x 109 WCCs/L. Raised levels indicate possibility of infection but can also indicate other conditions (cancers, inflammatory conditions). This test provides guidance on what type of microbe is causing the infection (raised neutrophils indicate bacterial infection)

Q: Describe ESR and CRP as a method to identify infection
A: Inflammatory markers: Erythrocyte Sedimentation Rate (ESR) and C-Reactive Protein (CRP) are raised in response to infection. CRP is produced by the liver and released in response to inflammation and infection. ESR measures the rate at which RBCs clump together and sediment which is increased in response to inflammation. These markers are not specific to infection but is useful to determine if a confirmed infection is improving.

Q: Describe disk diffusion tests to determine antimicrobial susceptibility
A: Disk diffusion test: Disks impregnated with specific concentrations of microbial agents

Q: Describe Etest as a method to determine antimicrobial susceptibility
A: Etest: Test strips containing a range of antibiotic concentrations onto bacterial agar cultures

Q: Describe broth (micro)dilution assays to determine antimicrobial susceptibility
A: Broth (micro)dilution assays: Asses the capacity for a two-fold dilution series of an antimicrobial to inhibit growth of a microorganism. Provides minimal inhibitory concentration data (MIC) which is the lowest concentration of the assessed antimicrobial that inhibits the overnight growth of a microorganism.

Q: Define bactericidal and bacteriostatic and its relevance to the MIC
A: - Antibiotics that are able to kill bacteria are bactericidal
- Antibiotics that inhibit bacterial replication are termed bacteriostatic
- At the MIC, some antibiotics will be bacteriostatic while at higher concentrations will display bactericidal activity
The lowest concentration in an MIC assay, which kills bacteria is called the minimal bactericidal concentration (MBC)

Q: What are breakpoints?
A: Breakpoints
Breakpoints are considered to determine if a microbe is susceptible to an antibiotic

Q: What is the reliability of antimicrobial susceptibility tests
A: Reliability of antimicrobial susceptibility tests
For some microorganisms, the data from antimicrobial susceptibility tests is not reliable. The ESCHAPPM pathogens are reported to be susceptible to beta-lactam antibiotics in these tests, however, they develop resistance rapidly in clinical practice due to overexpression of an inducible chromosomally encoded AmpC cephalosporinase. Therefore, many laboratories will report these microbes as being resistant to cephalosporins. Unlike other beta-lactamase type enzymes, this enzyme is not inhibited by clavulanic acid.

Q: What pathogens are major causes of life-threatening hospital aquired infections associated with increasing rates of resistance to many antibiotics?
A: ESKAPE Pathogens

Q: Describe the timeline of infection
A: Timeline of infection
Timeframes over which the host will progress from being infected, to being able to infect others, displaying symptoms and resolution of symptoms.
Latent period: The period between an individual being infected with a pathogen and the infection being detectable
Incubation period: The period between the pathogen invading tissues and the appearance of clinical features of an infection - longer than the latent period
Period of infectivity (communicability): The time over which the infected individual is infectious to others. This period may commence before symptoms of infection are observed, increasing the risk that the host can infect others.

Q: How does the spread of infection occur?
A: Spread of infection
Spread of pathogens occur:
Directly: Person to person or animal to person
Indirectly: Person comes into contact with an environment contaminated by infected person/animal

Q: What are methods of preventing infection
A: Preventing the spread of infection
- Handwashing
- Immunisation
- Exclusion of sick individuals (staying away from others - associated with workplaces and facilities and childcare)

Signs of infection in the acute phase

Signs of infection in the chronic phase

Describe the different methods of taking body temperature

What are the temperatures that are considered a fever, mild fever, or high fever

Signs and symptoms of sepsis for adults

Signs and symptoms of sepsis in children

Signs and symptoms of meningitis

Q: Describe what the glass test is
A: The glass test
Is often described to investigate for a non-blanching rash (not becoming white). A clear transparent glass is pressed against the rash. If the rash does not disappear, this is suggestive of meningitis or septicaemia.
People who show other signs of meningitis or sepsis but not a non-blanching rash should not wait to seek medical attention. Shit is time sensitive cuh.

Q: Describe the QUM of antimicrobials for the patient and the healthcare system
A: QUM of antimicrobials
For the patient, agents need to be:
- Effective
- Safe
For society and the healthcare system:
- Avoid antimicrobial resistance
- Cost-effective

What are the principles for prescribing antimicrobials

Q: What are host-drug interactions
A: Host-drug interaction: Patient factors affect pharmacokinetics that cause toxicity or subtherapeutic outcomes

Q: What are host-bug interactions?
A: Host-bug interaction: Infection will have different outcomes on people where immune response will vary and thus symptoms will present in varying magnitude

Q: What are bug-drug interactions?
A: Bug-drug interaction: The drug is trying to inhibit the replication of the bug while the bus is trying to build resistance to the drug

Q: Describe the prophylactic approach in prescribing antibacterials
A: Prophylactic
This is where an antimicrobial is used to prevent an infection from occurring
This method of antibiotic therapy is restricted to situations where there is a high clinical risk of infection or infection would be severe.
Surgical prophylaxis is administered to prevent post-operative infections and involves a single dose of an antibiotic to achieve high tissue concentrations during surgery.
Non-surgical prophylaxis is administered when:
1. Treating contacts of people who have bacterial meningitis or active tuberculosis
2. Prevention of rheumatic fever
3. Prevention of UTI
4. Needlestick injuries
5. Prevention of opportunistic infections in HIV infection

Q: Describe the empirical approach to prescribing antibacterials
A: Empirical
This is when an antimicrobial is selected to treat an infection based on the most likely and/or important potential pathogen as well as their antimicrobial susceptibilities. The pathogen has not been identified.
The clinician will diagnose an infectious medical condition and consult with appropriate evidence-based guidelines to decide which antimicrobial to prescribe. Empirical treatment of infections is the most commonly commenced.

Q: What is directed therapy when prescribing antibacterials?
A: Directed therapy
This is where a patient has an infection and the causative pathogen has been identified. This allows selection of an antimicrobial that is active against the pathogen to be selected. This however takes time and empirical prescribing may be initially performed.
Directed therapy is important for life-threatening infections but is not often used where conditions are normally successfully treated with empirical antimicrobials.

Q: In what cases should combination of antibiotics be prescribed?
A: Prescribing Combination of Antibiotics
Although antibiotic monotherapy should be used in most situations. There are some cases where combinations can be used.
This is when a patient has an infection that is caused by a mix of pathogens that can't be addressed with a single antibiotic. Synergistic combinations are recommended and in some cases to help prevent development of antibiotic resistance.

Q: What is the synergistic combination of beta-lactams with aminoglycosides?
A: Beta-lactams with aminoglycosides: Beta-lactam damages the bacterial wall that allows the aminoglycoside into the bacteria to inhibit protein synthesis, effectively killing bacteria.

Q: What is the synergistic effect of trimethoprim with sulfamethoxazole?
A: Trimethoprim with sulfamethoxazole: Both agents inhibit sequential steps in the bacterial folate metabolism pathway

Q: What is the significance of beta-lactamase inhibitors?
A: Beta-lactamase inhibitors (e.g. clavulanic acid, tazobactam or avibactam) may also be administered with beta-lactam antibiotics (e.g. penicillins or cephalosporins) to reduce their degradation by beta-lactamase enzymes. They don't have antibacterial activity at clinically used concentrations but demonstrate synergy when used with beta-lactam antibiotics - increases antibacterial coverage.

Direct adverse effects of antibiotics

Q: Indirect adverse effects of antibiotics
A: Indirect adverse effects:
- Candida overgrowth (thrush): Candida overgrowth of the throat and/or vagina can occur
- Clostridioides difficle infection: Overgrowth of C. difficle in the large intestine can result in severe diarrhoea
- Increased colonisation with antibiotic resistant bacteria

Q: Which kinds of antibiotics have more adverse effects?
A: Adverse effects are more common with broad-spectrum antibiotics and have greater effects of the host bacterial microbiome compared to narrow-spectrum antibiotics.

Q: If monitoring a patient taking aminoglycoside antibiotics, what parameters need to be taken into account?
A: Monitoring of antibiotic levels
When monitoring a patient taking aminoglycoside antibiotics:
- Serum creatinine (for eGFR estimation) as aminoglycosides are nephrotoxic
- Concentration monitoring if using for longer than 48 h to maximise antimicrobial effectiveness to reduce toxicity
- Audiometry testing for ototoxicity (hearing and balance). Can cause permanent hearing loss
Concentration monitoring should not be needed for patients with normal renal function where aminoglycosides are used for less than 48hrs

Q: What are some causes of antibiotic resistance?
A: Causes:
- Using antibiotics when they are not indicated (e.g. viral infections)
- Failing to complete antibiotic courses
- Doses that are too low
There is clear correlation between antimicrobial use and increased antibiotic resistance

Q: What is intrinsic resistance?
A: 1. Intrinsic Resistance: Bacteria have properties that make them inherently resistant to an antibiotic (e.g. impermeable, extrude, or enzymatically degrade antibiotics)

Q: What is aquired resistance?
A: Acquired resistance: Where a spontaneous mutation or horizontal transfer of resistance genes occurs (more common)

Q: What is transduction in terms of antimicrobial resistance?
A: Transduction - Bacteriophages (viruses that infect bacteria) mediate transfer of DNA between bacteria via transduction. DNA from a donor bacterium is packaged into a virus particle and transferred into a recipient bacterium during infection.

Q: What is conjugation in terms of antimicrobial resistance?
A: Conjugation - The mechanism of gene transfer most common concerning antimicrobial resistance. A sex pilus (small ube) forms between two bacterial cells through which a plasmid is transferred from one to another containing resistant genes.

Q: What is transformation in terms of antimicrobial resistance?
A: Transformation - Some bacteria are able to take up free DNA from the environment and incorporate it into their chromosome

Q: How can you prevent antimicrobial resistance?
A: Prevention of antibiotic resistance
- Promotion of wise use of antibiotics
- Improving surveillance of the levels of antibiotic resistance
- Increasing hygiene and infection control
- Investing in development of new antimicrobials
- Raising awareness of issues stemming from the development of antimicrobial resistance

Q: What is the bystander effect when it comes to antimicrobial resistance?
A: Bystander effect
Unnecessary use of antibiotics can cause the bystander effect. This is where the use of an antibiotic both kills the pathogen as well as harmless bacteria. This can encourage the growth of resistance bystanders that can transfer those resistant genes to different pathogenic bacteria.

Q: Which antibiotic needs CAL2 prior to dispensing and why?
A: There is an exception that the consumption of alcohol should be avoided in patients who are taking Metronidazole during use and for up to 24-48 hours after finishing
CAL 2 is applied to these products when dispensing
These interactions have been described as disulfiram-like interactions, named after the drug disulfiram used to treat alcoholism. This interaction causes patients to experience nausea, vomiting, flushing, headaches, and heart palpitations. The interaction is however proven controversial and evidence of the interaction lacks.

Q: What is the difference between type A and B ADRs?
A: Hypersensitivity is a broad term used to describe adverse drug reactions (ADRs).
ADRs are classed into Type A and Type B:
Type A: Are pharmacologically predicable reactions
Type B: Include immediate IgE-mediated and delayed T-cell mediated reactions. Only Type B ADRs caused by immune-mediated mechanisms should be labelled as 'Allergies'

Q: What are some issues with antimicrobial allergies?
A: Issues with antimicrobial allergies
If antimicrobials are dispensed to a truly allergic patient, a severe reaction or even death can occur. However, many patients who state they are allergic to an antimicrobial will tolerate the drug if it is taken again.
Penicillins are 1st line options for the treatment of many infections due to good tolerability and efficacy. Broad spectrum agents such as quinolones and carbapenems are used when penicillins cannot be used - as a result, these agents are developing antimicrobial resistance that can cause no options to treat some patients with infections
- Over 90% of reported penicillin allergies are demonstrated to be not current when patients undergo skin testing or rechallenge with penicillin
- Incorrectly labelling a penicillin allergy costs the healthcare system by forcing clinicians to use more expensive antibiotics

How do you do history taking for someone suspected for antimicrobial allergy

Q: How is a diagnosis of antimicrobial allergy done?
A: - Clinical history
  - Details of reaction
  - Timing
  - Severity
  - Signs such as swelling, SOB, rash
- Physical examination
- Skin testing: small amount of the antimicrobial agent on skin
- In vitro testing to measure IgE antibodies in response to agent

Q: What is a drug challenge?
A: Drug challenge, graded challenge or drug test dosing describes careful administration of a drug in order to see whether a patient is truly hypersensitive. Often used to confirm tolerance to an antimicrobial when skin-prick or intradermal tests are negative.
The decision to rechallenge should be based on severity of previous reaction, the availability of alternative agents and urgency of infection. To be performed under medical supervision usually in hospital after consultation with a specialist.
For people whom a true immune-mediated allergy is not suspected and require treatment with penicillin but advised the patient has a vague penicillin allergy label (clinician suspects is not real). A 1/100th or 1/10th dose is administered and monitored to confirm no allergy. If the challenge is successful, the label is removed. This challenge is for patients with low to no risk of true immune mediated reactions. Patients with clear history of immune medicated reaction or severe cutaneous adverse drug reactions (SCARs) are not suitable for the drug challenge.
- Appropriate in patients with a history of mild rash in childhood or other delayed non-severe skin reaction
- Prolonged administration for 5-7 days following supervised single-dose provocation is often used to ensure true delayed hypersensitivity is not missed

Q: Describe penicillin and cephalosporin cross reactivity
A: Immune-mediated reactions from penicillins and cephalosporins are thought to be due to the R1 side-chain that causes an immune response (previously thought to be beta-lactam ring)
Because penicillins and cephalosporins have varying R1 side-chains, cross-reactivity can also vary depending on which agents are prescribed. Penicillins and cephalosporins with similar R1 chains are likely to have cross-reactivity.
- Amoxicillin has similar R1 chains to cephalexin and cefaclor - likely to have cross-reactivity
- There is common misconception that cephalosporin allergy occurs in approximately 10% of patients who are allergic to penicillin (true figure is 0.2%-2%)
- Cefazolin (used commonly for surgical antimicrobial prophylaxis) has no common side-chains with other beta-lactams and is often tolerated in patients with penicillin or cephalosporin allergies
- Carbapenems are also beta-lactam antibiotics. In patients with penicillin allergy, the rate of cross reactivity is approx. 1%
- Patients with severe penicillin hypersensitivity such as anaphylaxis or angioedema - all penicillins and all cephalosporins are to be avoided

Q: What are the commerically available sulfonamide antibiotics in Australia?
A: Sulfonamide antibiotics
commercially available in Australia include:
Sulfamethoxazole: Contains Bactrim, Septrin, or Resprim. Also contains a second antibiotic called trimethoprim
Sulfadiazine: Not commonly used but is listed as a treatment option for Toxoplasma gondii (passed from animals to humans)
Sulfacetamide: Antibiotic eye drop
Sulfasalazine: Not used as an antibiotic but used for IBD such as UC and RA. It is a combination of sulfapyridine (sulfonamide antibiotic) and a salicylate.

Q: Discuss allergies relating to sulfonamides, namely sulfamethoaxozole and trimethoprim
A: Allergies relating to sulfonamides
Up to 8% of hospitalised patients and 1-2% of those in the community are reported to suffer an ADR with the combination of sulfamethoxazole and trimethoprim, although 3% of these are thought to represent hypersensitivity.
Most hypersensitivity reactions are relatively mild, however, sulfonamides account for a disproportionate number of cases of life-threatening Stevens-Johnsons Syndrome and the most severe form of Toxic Epidermal Necrolysis.
In the case a patient has an allergic reaction to sulfamethoxazole-trimethoprim, there is no way to determine which API caused it. It is generally assumed to be the sulfamethoxazole. However both agents should be both avoided if the reaction was severe.
Labelling someone allergic to sulfur from a reaction taking a sulfonamide antibiotic is inappropriate. Sulfur is an element that occurs throughout the human body as a building block of life and in many foods as sulfates and sulfites. Thus, it is not possible to be allergic to sulfur itself.
Allergic reactions to sulfonamide antibiotics do not increase the likelihood of allergy to sulfur in other forms, including drugs containing the sulfonamide moiety such as frusemide and celecoxib.

Q: Describe the appropriateness of prescribing a drug (in a different class) with a sulfonamide moiety to a patient known to have an allergy to sulfonamide antibiotics?
A: Patients who are allergic to one antibiotic generally have an increased risk of allergy to any other antibiotic. Patients with a 'sulfur' allergy can be prescribed another drug with a sulfonamide moiety from a different class is generally considered appropriate.
In cases with severe allergy or ADR (DRESS syndrome, SJS, TENS), drugs with structural similarity should be avoided (frusemide, bumetanide) - seek specialist advice. Sulfasalazine breaks down in vivo to release sulfapyridine which is a structurally a sulphonamide antibiotic, it should not be used in patients who have severe ADRs related to sulfamethoxazole.

Q: What is desensitisation?
A: Performed for people where a true immune allergy is suspected but require treatment with penicillin. The medication is given in a controlled manner with a small dose (1:10 000) dilution and gradually increasing the dose to tolerate the medicine without an allergic reaction. Done when clinical indication for the drug is strong and no other reasonable options are available.
Not all types of reactions are safe to undergo desensitisation. Not effective for all types of reactions. Only recommended for Type-1 (IgE mediated) reactions and not indicated for severe ADRs
Desensitisation is temporary. A person is unlikely to have an allergic reaction once desensitised and continue taking penicillin. Ceasing the antibiotic for more than 24hrs predisposes the patient makes them at risk for sudden allergic reaction. Do not remove antibiotic allergy label and write 'desensitised to amox - /dd/mm/yyyy)'.