Theme 3- part 1 Flashcards
1
Q
What are antimicrobials for?
A
- To increase the likelihood that a person with an infection will make a clinical recovery
- Inhibit critical process in bacterial/fungal cells – antimicrobial targets-
Enzymes, molecules or physical structures
cell wall
protein synthesis
DNA synthesis
RNA synthesis
-With minimal harm to the patient – selective toxicity
2
Q
What is an antibiotic?
A
Chemical products of microbes that inhibit or kill other organisms
3
Q
Whar are types of antibmicrobial agents?
A
Antimicrobial agents (antibacterial, antifungal, antiviral)
4
Q
What are antimicrobial agents?
A
- Antibiotics
- Synthetic compounds with similar effect
- Semi-synthetic i.e. modified from antibiotics -Different antimicrobial activity/spectrum, pharmacological properties or toxicity
5
Q
What does a bacteriostatic/fungistatic do?
A
Inhibit growth- Mainly protein synthesis inhibitors
6
Q
What does a bacteriocidal/ fungicidal do?
A
Cause cell death-Mainly cell wall-active agents
7
Q
What is minimum inhibitory concentration?
A
Minimum concentration of antimicrobial agent at which visible growth is inhibited
8
Q
What is minimum bacteriacidal/fungicidal concentration?
A
Minimum concentration of antimicrobial agent at which most organisms are killed
9
Q
Antimicrobial interactions- what is synergy?
A
A combination is considered to be synergistic when the effect observed with a combination is greater than the sum of the effects observed with the two drugs independently
10
Q
Antimicrobial interactions- what is antagonism?
A
Activity of two antimicrobials given together is less than the activity of either if given separately
11
Q
What is the antimicrobial spectrum?
A
Range of bacterial/fungal species likely to be sensitive to a particular antibacterial/antifungal agent
12
Q
What are broad spectrum antibiotics?
A
Broad spectrum – kills most types of bacteria/fungi encountered
13
Q
What are narrow spectrum antibiotics?
A
Narrow spectrum – kills only a narrow range of organisms
The narrowest-spectrum antibiotic that is appropriate should be used at all times
14
Q
What is the cell wall of bacteria made up of?
A
Peptidoglycan (murein)
- Major structural component of bacterial cell wall
- Polymer of glucose-derivatives, N-acetyl muramic acid (NAM) and N-acetyl glucosamine (NAG)
- Oligopeptide crosslinks formed by transpeptidases known as “penicillin binding proteins” (PBPs).
15
Q
Why are cell wall synthesis inhibitors allow selective toxicity?
A
No cell wall in animal cells
16
Q
Examples of cell wall synthesis inhibitors?
A
- β-lactams (beta-lactams, penicillins)
- Glycopeptides
17
Q
What do β-lactam antibiotics contain?
A
- All contain β-lactam ring
- Four-membered ring structure (C-C-C-N)
18
Q
Mechanism of action for β-lactam antibiotics?
A
Mechanism of action: Inhibition of PBPs (penicillin binding proteins)
19
Q
What are types of B-lactam antibiotics?
A
Penicillins, Cephalosporins and Cephalosporins, monolactams
20
Q
What are examples of penicillins for B-lactam antibiotics?
A
Benzylpenicillin, amoxicillin, flucloxacillin
Relatively narrow spectrum
21
Q
What are examples of cephalosporins
A
Cephalosporins- better for gram negative
Cefuroxime, ceftazidime etc.
- Broad spectrum
- Arranged into ‘generations’- age into clinical use
Cephalosporins Meropenem, imipenem
Extremely broad spectrum
22
Q
What are examples of monobactams?
A
MonobactamsAztreonam
- Gram-negative activity only
- And has slightly different ring structure
23
Q
What are examples of glycopeptides?
A
Vancomycin, teicoplanin
24
Q
What do glycopeptides do? Are they able to penetrate gram-negative of postive?
A
Large molecules, bind to terminal amino acids on NAM pentapeptides- Inhibit binding of transpeptidases and thus peptideoglycan cross-linking
Gram-positive activity- Unable to penetrate Gram-negative outer membrane
25
What is the mechanism for bacterial protein synthesis inhibitors?
Protein synthesis takes place on the bacterial ribosome- inhibit this stop the growth
26
What are examples of bacterial protein synthesis inhibitos?
* Aminoglycosides (e.g. gentamicin, amikacin)
* Macrolides (e.g. erythromycin, clarithromycin) and lincosamides (clindamycin)
* Tetracycline, doxycycline
* Linezolid – Gram-positive infections
* Mupirocin – topical agent for staphylococcal/streptococcal infection
* Fusidic acid (not used very much)
27
What are examples of DNA synthesis inhibitors?
trimethoprim and sulfonamides
28
What do trimethoprim and sulfonamides inhibit?
Both agents inhibit folate synthesis
29
What does trimethoprim treat?
Commonly used to treat urinary tract infections
30
What is co-trimoxazole?
Co-trimoxazole (trimethoprim-sulfamethoxazole)
Treats Antibacterial, antifungal (Pneumocystis jirowecii) and antiparasitic (Toxoplasma gondii)
31
What is a DNA synthesis inhibitor?
fluoroquinolones
32
What does fluoroquinolones inhibit?
Inhibit one or more of two related bacterial enzymes
* DNA gyrase and topoisomerase IV
* Involved in remodelling of DNA during DNA replication
33
fluoroquinolones examples?
Ciprofloxacin, levofloxacin
34
What is an RNA synthesis inhibitor?
Rifampicin
35
What is the mechanism for rifampicin?
* RNA polymerase inhibitor
* Prevents synthesis of mRNA
36
What are examples of gram-negative cell membrane agents?
Colistin/polymyxin E (Gram-negatives)
37
What are examples of gram positive cell membrane agents?
Daptomycin (Gram-positives)1
38
Mechanism of cell membrane agents?
Destruction of outer membrane or cytoplasmic membrane
39
Summary of antibacterial mechanisms
40
Pathogenic fungi divided into what?
filamentous fungi and yeasts
41
What is the structure of a fungal cell?
* Fungal cell has cell membrane, cell wall and protein synthesis apparatus within it.
* Fungal cell membrane ergosterol which has the same function as cholesterol in cell membranes.
42
What is the fungal cell wall made of?
β-1,3-glucan
No cell wall in animal cells- Ideal potential for selective toxicity
43
What are antifungal cell wall inhibitors?
Echinocandins (antifungal)
44
What is the mechanism of antifungal cell wall inhibitors?
Inhibit β-1,3-glucan synthase
45
Examples of Antifungal cell wall inhibitors?
* Anidulafungin
* Caspofungin
* Micafungin
46
Antifungal cell membrane agents examples?
* Azoles
* Terbinafine
* Amphotericin B (and nystatin)
47
What are examples of azoles?
Azoles (eg clotrimazole, fluconazole, voriconazole)
48
What is the mechanism for terbinafine?
Inhibit synthesis of ergosterol
49
What is the mechanism for Amphotericin B (and nystatin)?
Bind to ergosterol causing physical damage to the membrane
50
Antifungal RNA/DNA synthesis inhibition- what agent is used?
5-fluorocytosine
51
What is the mechanism for Antifungal RNA/DNA synthesis inhibition?
Transported into fungal cells by a fungal enzyme-Cytosine permease
Metabolised into inhibitory molecules- Mainly 5-fluorouracil
52
Summary of antifungal mechanisms
53
What are the steps for use of antimicrobial agents?
Empiric therapy- based on predicted susceptibility of likely pathogens and local antimicrobial policies
Targeted therapy- predicted susceptibility of infecting organisms
Susceptibility-guided therapy- based on susceptibility testing results
54
What is empiric therapy?
Empiric therapy – initial selection of antimicrobial agent(s) of broad enough spectrum to cover the range of organisms likely to be causing the patient’s infection
55
What is targeted therapy?
Targeted therapy – use of narrowest-possible spectrum agent(s) based on the ID and sensitivities of the causative organism(s)
56
Choice of empiric therapy stages?
* Know the likely organisms – based on site of infection, patient’s immunological status and microbiological history
* Identify what antimicrobial/combination is likely to have a spectrum that covers the organisms identified in (1)
* Select an antimicrobial/combination from (2) that is appropriate for the patient and the site of the infection – taking into account any history of antibiotic allergy, availability at different body sites, drug interactions and adverse effects
57
What does a virus consist of?
Consist of:
* Nucleic acid (DNA or RNA)
* Protein (coat - structural, enzymes-non-structural)
* +/- Lipid envelope
Obligate intracellular parasites
58
Virus infections that are acute are caused by what?
Acute (RNA viruses)
59
What are examples of acute viruses?
Influenza, measles, mumps, hepatitis A virus
60
What are chronic viruses caused by?
Chronic (generally DNA viruses)
61
What are examples of latent chronic viruses?
Latent with (or without) recurrences
Herpes simplex, Cytomegalovirus
62
What are examples of persistent chronic viruses?
HIV, HTLV, Hepatitis B virus, Hepatitis C virus
63
What are non-vesicular rashes from?
* Measles
* Rubella
* Parvovirus
* Adenovirus
* HHV6
64
What are vesicular rashes?
red raised rashes but then become fluid filled
65
What do you get vesicular rashes from?
* Chickenpox (HHV3)
* Herpes simples (HHV1/2)
* Enterovirus
66
Respiratory infection examples?
* Influenza A/B
* Respiratory Syncytial Virus
* Parainfluenza virus
* Human Metapneumovirus
* Rhinovirus
* Coronavirus (including SARS)
67
Gastroenteritis examples?
* Rotavirus
* Norovirus
* Astrovirus
* Sapovirus
* Adenovirus (group F)
68
Neurological Disease examples?
Encephalitis/Meningitis
* HSV
* Enteroviruses
* Rabies
* Japanese encephalitis virus
* Nipah Virus
69
Blood-borne viruses examples?
* Hepatitis viruses
* Retroviruses
70
Example of Hepatitis viruses?
* HBV
* HCV
71
Retroviruses examples?
HIV
72
When to use antivirals?
* Acute infections in general population
* Chronic infections
* Infections in immunocompromised
73
What are infections in immunocompromised?
* Post-transplant
* Individuals receiving immunosuppressive therapies
* Patients with primary immunodeficiencies
74
What is the treatment of HSV?
Aciclovir
75
What does aciclovir treat?
Treat invasive disease
* encephalitis
* disseminated HSV (immunocompromised and neonates)
76
What is treatment of primary oral-labial or genital herpes?
Primary oral-labial or genital herpes- don’t require treatment but are given prophylaxis (treatment that prevents disease)
Prophylaxis if frequent reactivations- to prevent
77
What is the treatment of chickenpox and shingles (VZV)?
Treat with aciclovir
Treat all adults with chickenpox
Treat shingles
* \>60 (reduce incidence of post-herpetic neuralgia- affects nerve fibres and skin causing burning pain)
* involves eye
* immunocompromised
78
Treatment of influenza?
Neuraminidase inhibitors oseltamivir (oral) and zanamavir (inhaled)
79
Who is the treatment of infleunza?
Treat high risk patients
* Chronic neurological, hepatic, renal, pulmonary and chronic cardiac disease
* Diabetes mellitus
* Severe immunosuppression
* Age over 65 years
* Pregnancy (including up to two weeks post-partum)
* Children under six months of age
* Morbid obesity (BMI ≥40)
80
Treatment of chronic virus infections- how long do you give treatment for?
Usually has to be given lifelong – for DNA and retroviruses
81
What virus is not treated with lifelong medications that is a chronic virus?
Exception is HCV which is caused by an RNA virus but can get a chronic infection so is treated with antivirals
82
What are the steps for virus replication?
1. Virus attachment to cell (via receptor)
2. Cell Entry
3. Virus Uncoating
4. Early proteins produced – viral enzymes
5. Replication
6. Late transcription/translation – viral structural proteins
7. Virus assembly
8. Virus release and maturation- some released by killing the cell, others are released by reverse endocytosis out of the cells
If antivirals affect any steps in this process will inhibit viral replication. Cytotoxic T cells kill viral cells. Immunocompromised don’t make good cytotoxic T cells.
83
Eukaryotes and DNA viruses use polyemerases to produce DNA to what?
* DNA to DNA
* DNA to RNA (mRNA)
84
RNA viruses can produce what using polymerases?
RNA to RNA - RNA viruses can produce RNA from RNA so require RNA polymerase
85
RNA use polymerases to DNA in what diseases?
RNA to DNA - take RNA to make DNA to insert into host genome
Retroviruses (HIV)
Hepatitis B virus
86
Nucleoside Reverse Transcriptase Inhibitors (NRTI) inhibit what?
inhibit reverse transcriptase
87
What are examples of NRTIs?
* AZT (azidothymidine)
* HIV NRTIs
* HBV NRTIs
88
What are examples of HIV NRTIs?
Pyrimidine analogues
* Thymidine analogues-Zidovudine
* Cytosine analogues-Lamivudine
Purine analogues (Adenosine and Guanosine)
* Abacavir
* Tenofovir
89
What do Nucleoside Reverse Transcriptase Inhibitors (NRTI) treat?
* HIV NRTIs
* HBV
90
What are Herpesvirus polymerase inhibitors?
* Guanosine
* Acyclovir- HSV and VZV
* Ganciclovir- CMv, HHV6 (as well as HSV and VZV)
91
HCV RNA polymerase nucleotide inhibitor example?
Sofosbuvir- prodrug
92
Non-Nucleotide Reverse Transcriptase inhibitors (NNRTIs)- what do they do?
inhibit different parts of the enzyme
93
Non-Nucleotide Reverse Transcriptase inhibitors examples?
* Efavirenz
* Nevirapine
94
Protease Inhibitors (PIs) mechanisms?
All cells have proteases- they clip the proteins to make shorter lengths which then fold to bind to the protein- virus do this by make their own proteins and then make their own enzymes
95
What do protease inhibitors treat?
HIV and HCV
96
What are the types of PIs that treat HIV?
Atazanavir
Darunavir
Ritonavir- boost levels of other PIs
97
What are the types of PIs that treat HCV?
* Paritaprevir
* Grazoprevir
98
HIV drugs- Entry inhibitor?
* Enfuviritide
* Maraviroc
99
HIV integrase inhibitors?
Integrase Inhibitors (retroviruses)
* Raltegravir
* Dolutegravir
100
What is highly active antiretroviral therapy (HAART)?
* 2 NRTIs + NNRTI
* 2 NRTIs + boosted PI or integrase inhibitor
* Often use fixed drug combinations (more than one drug in pill)- this is because there are high levels of replication, single agent won’t treat it as much. Also, viruses can adapt quickly so having more than one drug stopping viral resistance
* Aim to switch off virus replication
* Require lifelong treatment
* For treating some chronic virus infections multiple antivirals are used to drive down viral loads and avoid development of antiviral resistance (eg HIV and HCV).
101
RNA viruses can become chronic in immunocompromised individuals due to lack of what?
RNA viruses can become chronic in immunocompromised individuals due to lack of an adequate cytotoxic T-cell response.
102
In acute viral infection antivirals only improve recovery if what?
* In acute viral infection antivirals only improve recovery if started early during the illness (typically \<48hrs of onset).
* Therefore, antivirals are only generally used to treat acute infections where individuals are at higher risk of significant morbidity or mortality.
103
Mutations occur quicker in RNA or DNA?
This may happen quickly for RNA viruses but can be slower for DNA viruses such as herpesviruses. Inadequate dosing of antivirals can promote antiviral resistance.
104
What are tests done for infection?
* Full blood count, Inflammatory markers (CRP, ESR, procalcitonin) Lactate, Blood gases
* LFTs (biliary sepsis) U&Es (severe sepsis, urinary tract infection)
* Serology
* PCR
* Microscopy, culture, sensitivity testing
* Chest and bone x-rays, CT scans and FDG-PET/CT scans
105
Symptoms suggestive of infection can be “system specific” or “non-specific”. What is the difference?
System specific e.g.
* Cough (\*respiratory)
* Neck stiffness (\*CNS)
* Bony pain (\*orthopaedic)
* Skin pain/redness (\*SST)
* Dysuria (\*urinary)
SST = skin and soft tissue; CNS = central nervous system
Nonspecific e.g.
* Fever “burning up”
* Shaking episodes/chills
* Sweating/night sweats
* Feeling muddled/confused
106
Examination findings can also be “system specific” or “non-specific” what is the difference?
System specific e.g.
* Lung crackles (\*respiratory)
* Meningism (\*CNS)
* Bony tenderness (\*orthopaedic)
* Skin erythema (\*SST)
* Loin tenderness (\*urinary)
Non specific e.g.
* Pyrexia
* Witnessed rigor/chills
* Sweating
* Confusion
SST = skin and soft tissue; CNS = central nervous system; \*clinical infection lecture
107
What does Hb tell us about infection?
Haemoglobin (Hb) Not much help diagnosing infection – but anaemia of chronic disease (normocytic, normochromic) can be caused by infection
108
What happens to WBC in infection?
White blood cell count (WCC) can be raised in infection, but other conditions too (poor specificity). Severe sepsis can lower WCC
109
What are inflammatory markers?
* C-reactive protein
* Procalcitonin
110
When do C-reactive protein and procalcitionin increase?
* C-reactive protein \<5mg/L- will go up in bacterial infections, not as much in viral
* Procalcitonin \<0.5µg/L (different centres use different cut-offs)- increases in bacterial infections and less so in viral infections
111
Blood lactate and blood gases are tests for what?
Blood lactate and blood gases are tests that can help to identify severe sepsis and respiratory failure
112
What is the tool to test for pneumonia?
CURB-65 (risk prediction tool for pneumonia)
113
Methods of microbiological diagnosis?
* Culture
* Direct detection
* Immunological tests
114
What do blood cultures show us?
Identification-Immediate or by further testing
Typing-To establish organism relatedness
Sensitivity testing-To direct antimicrobial therapy
115
What are false positives and negatives from in blood cultures?
False positives- from contamination
False negatives- not inoculating enough blood
116
What is a gram stain?
Chemical process that distinguishes between bacterial cell walls that retain crystal violet, and those that do not, when stained and washed with acetone.
117
Gram positive and gram negative stains after dye?
Gram positive- purple
Gram negative- pink
118
What do Gram positive and negative cocci look like?
Gram positive cocci- long chains or clusters
Gram negative cocci- very small
119
What do gram positive and negative bacilli look like?
Gram positive bacilli- chunky
Gram negative bacilli- very small
120
What is sensitivity testing?
* Culture of micro-organism in the presence of antimicrobial agent
* Work out if the concentration of antimicrobial that will be available in the body is high enough to kill the micro-organism
* Solid or liquid media
121
What does sensitivity testing require?
Requires viable micro-organisms
Usually bacteria or fungi
122
What is empirical therapy?
Initial treatment is with “empiric” therapy- based on experience from clinician
123
What is targeted therapy?
Subsequent treatment is “targeted”
Requires
1. Isolation of micro-organism
2. Antimicrobial susceptibility testing- determines which antibiotics a bacteria or fungi is sensitive to
124
Uses and limitations of cultures?
* Establishes the presence of a micro-organism at a particular site
* Cultivable organisms only
* Allows the use of empiric and targeted antimicrobial therapy
* Provides epidemiological and typing information
* Is usually slower than direct detection
125
What is direct detection?
Detection of whole organism- Microscopy
Detection of component of organism
- Antigen
- Nucleic acid (DNA or RNA)
126
Direct detection - uses and limitations?
Establishes the presence of a micro-organism at a particular site
* Cultivable and non-cultivable organisms
Allows the use of appropriate empiric antimicrobial therapy
Does not give any information on:
* Antimicrobial susceptibility
* Typing
Is usually the fastest diagnostic method
127
Immunological tests function?
Detection of immune response to infectionAntibody detection
* IgM detection
* Seroconversion- Change from negative to positive result from one test to a subsequent test
* Fourfold rise in titre- Rise in concentration of antibody from one test to a subsequent test
Other immunological tests- IFN-γ release assays in tuberculosis
128
Antibody testing uses and limitations?
* Confirms exposure to a specific micro-organism-Cultivable and nun-cultivable organisms
* Is restricted to patients with a detectable antibody response
* Is retrospective- Often too late to inform antimicrobial therapy decisions
129
Should culture tests be taken before or after antibiotics are given?
Culture tests should be taken before antibiotics are given
