Antimicrobial Chemotherapy COPY Flashcards
What are the principles of antivirals?
- All are virustatic, none are virucidal
- Toxicity to host cell not uncommon: side effects
- Only used in a minority of viral infections
- Several stages of the virus life cycle are targets
- Most targets are intracellular
- Greater effect on viral replication than on the host cell function
What are most antivirals?
Nucleoside analogues that inhibit nuclei acid synthesis
Why are there limited potential targets for antiviral drugs?
- Viruses are obligate intracellular parasites
- They utilise host cell enzymes in order to replicate, hence limited targets for drug
When may virus infection be treated?
- Prophylaxis (to prevent infection)
- Pre-emptive therapy (when evidence of infection detected, but before symptoms apparent)
- Overt disease
- Suppressive therapy (to keep viral replication below the rate that causes tissue damage in asymptomatic infected patient)
Why may suppressive treatment be required following successful treatment of overt infection?
Antivirals do NOT eradicate virus from latently infected cells
When are antivirals used in herpes simplex infection
- Mucocutaneous: oral, genital, eye, skin
- Encephalitis
- Immunocompromised: any site
When are antivirals used in chickenpox?
Those at increased risk of complications
- Neonate
- Immunocompromised
- Pregnant
Immunocompetent adult if begun within 24 hours of onset of rash
When are antivirals used in shingles?
Only decreases post-herpetic neuralgia in the immunocompetent host if begun within 72 hours of onset of symptoms
What antivirals are used in HSV and VZV?
- Aciclovir: Oral, IV, eye ointment, cream
- Valaciclovir: Oral
- Famiciclovir: Oral
- Foscarnet: IV
What is the activity of acyclovir in herpes infection?
Only active in herpes infected cells, it has low toxicity for uninfected cells
What is the mode of action for acyclovir?
- Aciclovir converted by viral thymidine kinase to ACVMP
- ACVMP converted by host cell kinases t ACV-TP
- ACV-TP competitively inhibits and inactivates HSV-specific DNA polymerase
- Preventing further viral DNA synthesis without affecting the normal cellular processes
When is CMV treated with antivirals?
- Only in life or sight threatening infection as all available drugs have significant toxicity
- HIV patients with CM retinitis or colitis
- Transplant patients with pneumonitis
- May used to treat neonates with symptomatic congenital CMV infection
What antivirals are used in CMV infection?
- Ganciclovir: IV, ocular implant
- Valganciclovir: Oral
- Cidofovir: IV
- Foscarnet: IV
How have antivrials transformed HIV care?
- Restoration of immune function in AIDS
- Decrease in opportunistic infections
What is cART?
Combination anti-retroviral therapy
What antivirals are used in chronic hepatitis B?
Pegylated interferon alpha (subcut.)
Nucleoside/tide analogues
- Tenofovir
- Adefovir
- Entecavir
- Lamivudine
- Emtricitabine
- Telbivudine
What are the current therapies for chronic hepatitis C?
- Pegylated interferon alpha (subcut.) & ribavirin (oral)
- Plus protease inhibitor (telaprevir or boceprevir)
What new-directly acting antivirals are there for chronic hepatitis C infection?
- Daclatasvir
- Sofosbuvir
- Simeprevir
How long is the therapy regime for chronic hepatitis C?
12-48 weeks
How should antivirals be used in influenza A or B?
- Role in both treatment and prophylaxis
- Not always indicated, but if used, should usually start within 48 hours of onset of symptoms/contact.
What antiviral is used in respiratory syncytial virus?
Ribavirin (rarely indicated though)
How can resistance to antivirals be tested?
- Phenotypic: can virus grow in presence of compound, e.g. HSV
- Genotypic: sequence genome and identify resistance-associated mutations, e.g. HIV
When should resistance be suspected in herpes virus?
In immunocompromised if there is no response to appropriate antiviral doses within 7 days
What is usually effect in acyclovir resistant HSV and CMV?
Foscarnet
When is HIV resistance testing performed?
- Baseline diagnosis
- Failing therapy
- New treatment approach required for other reasons
When do trough and peak levels need to be monitored in acyclovir use?
In patients with renal impairment
What are the principles of prescribing antibiotics?
- Indications for antimicrobials
- Making a clinical diagnosis
- Patient characteristics
- Antimicrobial selection
- Regimen selection
- Liaison with laboratory
- Antimicrobial Stewardship
What is empiric antimicrobial therapy?
Therapy without microbiology results
What is directed antimicrobial therapy?
Therapy based on microbiology results
Give examples of primary antimicrobial prophylaxis.
- Anti-malarial; immunosupressed patients
- Pre-operative surgical
- Post-exposure e.g. HIV, meningitis
Give an example of secondary antimicrobial prophylaxis.
To prevent a second episode of PJP
What is involved in diagnosis when prescribing antimicrobials?
Diagnosis of infection
- Clinical
- Laboratory
- None (no treatment)
Severity assessment
- ?Sepsis (qSOFA; systolic BP <100, altered mental state, RR>20)
- ?Septic shock
What patient characteristics contribute to the prescribing of antimicrobials?
- Age
- Renal function
- Liver function
- Immunocompromised
- Pregnancy
- Known allergies
What antimicrobial selection/ choice must be made when prescribing?
- Guideline or “individualised” therapy
- ? likely organism(s)
- Empirical therapy or result-based therapy
- Bactericidal vs. bacteriostatic drug
- Single agent or combination
- Potential adverse effects
What should antibiotic selection be based on?
Known (or likely) organism
What bacteria are implicated in soft tissue infections?
- Streptococcus pyogenes
- Staphylococcus aureus
- Streptococcus group C or G
- E. coli
- Pseudomonas aeruginosa
- Clostridium species
What bacteria are implicated in pneumonia?
- Streptococcus pneumonia
- Haemophilus influenzae
- Staphylococcus aureus
- Klebsiella pneumonia
- Moraxella catarrhalis
- Mycoplasma pneumonia
- Legionella pneumonia
- Chlamydia pneumonia
What are the features of bactericidal antibiotics?
- Example: B-lactams
- Act on cell wall
- Kill organisms
- Indications include neutropenia, meningitis and endocarditis
What are the features of bacteriostatic antibiotics?
- Example: macrolides
- Inhibit protein synthesis
- Prevent colony growth
- Require host immune system to ‘mop up’ residual infection
- Useful in toxin-mediated illness
What are the advantages of single therapy?
- Simpler
- Fewer side effects
- Fewer drug interactions
When is combination therapy used?
- HIV and TB therapy
- Sever sepsis (febrile neutropenia)
- Mixed organism (faecal peritonitis)
What must be considered when selecting a regime for antimicrobials?
- Route of administration
- Dose
- Adverse effects (side effects/toxicity)
- Duration
- Intravenous to oral SWITCH therapy
- Inpatient or Outpatient therapy (outpatient parenteral antimicrobial therapy OPAT)
- Therapeutic drug monitoring
What is oral bioavailability?
- Ratio of drug level when given orally compared with level when given iv
- Varies widely: flucloxacillin 50-70%, linezolid 100%
When is the oral routed used to administer antimicrobials?
If not vomiting, normal GI function, no shock or organ dysfunction
When is the IV route used to administer antimicrobials?
For severe or deep-seated infection and when oral route is not reliable
What types of allergic reactions can occur with antimicrobials?
Immediate hypersensitivity
-Anaphylaxis
Delayed hypersensitivity
-Rash, drug fever, serum sickness, erythema nodosum, Steven’s Johnson syndrome
Most occur with penicillin’s and cephalosporins
What gastrointestinal adverse effects can occur with antimicrobials?
- Nausea, vomiting, diarrhoea
- C. diff infection
What neurological adverse effects can occur with antimicrobials?
- Ototoxicity - gentamicin, vancomycin
- Optic neuropathy - ethambutol (TB)
- Convulsions, encephalopathy - penicillins, cephalosporin
- Peripheral neuropathy - isoniazid (TB), metronidazole
What haematological adverse effects can occur with antimicrobials?
- Marrow toxicity
- Megaloblastic anaemia (folate metabolism) co-trimoxazole
What types of antibiotics are most likely to cause candida (thrush)?
- Broad spectrum penicillins
- Cephalosporins
What drugs can have an adverse effect on the liver?
- All drugs, particularly tetracyclines, TB drugs
- More likely if pre-existing liver disease
What drugs can have an adverse effect on the renal system?
- Gentamicin, vancomycin
- More like if pre-existing renal disease or on nephrotoxic meds
When does liaison with the laboratory take place?
Sending appropriate specimens
-Culture / direct detection/ serology
Receiving results
- Preliminary culture results
- Sensitivity results
- Final results
Monitoring
- Disease activity
- Therapeutic drug monitoring
What is antimicrobial stewardship?
-Making the best use of our current antimicrobials
Who is involved in antimicrobial stewardship?
Antimicrobial management team
- Antibiotic pharmacists
- Infectious diseases
- Acute medicine
- Medical microbiology
- Infection prevention and control
- General practice
- Public partner
What is the role of the antimicrobial management team?
- Produce antimicrobial guidelines and policies
- Audit of quality of antimicrobial prescribing
- Education
What are the 4C antibiotics implicated in CDI?
- Co-amoxiclav
- Ciprofloxacin
- Ceftriaxone
- Clindamycin
Give examples of antimicrobial classes.
- Penicillins (β-lactams)
- Cephalosporins (β-lactams)
- Aminoglycosides
- Macrolides
- Quinolones
- Glycopeptides
- Others
- Antifungals
- Antivirals
What are the 3 main mechanisms of action of antibiotics?
- Inhibition of cell wall synthesis
- Inhibition of protein synthesis
- Inhibition of nucleic acid synthesis
Give examples of antibiotics which inhibit cell wall synthesis.
B-lactams
-Penicillins and cephalosporins
Glycopeptides
-Vancomycin and teicoplanin
Give examples of antibiotics that inhibit protein synthesis.
- Aminoglycosides: gentamicin
- Macrolides: clarithromycin
- Tetracyclines: doxycycline
- Oxazolidinones: linezolid
Give examples of antibiotics that inhibit nucleic acid synthesis.
- Trimethoprim
- Sulfonamides: sulfamethoxazole
- Quinolones: ciprofloxacin
Give examples of classes of antifungals.
- Azoles
- Polyenes
- Echinocandins
- Terbinafine
Give example of azole antifungals.
- -Fluconazole: Candida, some resistance
- Itraconazole: Candida & Aspergillus
- Voriconazole: Candida & Aspergillus
Give examples of polyene antifungals.
- Amphotericin: candida and aspergillus
- Nystatin: candida
Give examples of echinocandin antifungals.
Caspofungin, anidulafungin, micafungin : candida, aspergillus
What is terbinafine used for?
Tinea and fungal nails
What emerging resistance to pathogens is of global interest?
- MRSA
- MDR
- VRE
- Acinetobacter baumannii
- Clostridium difficile
What contributes to the propagation of MRSA in the UK?
- Re-admission of MRSA carriers from community
- Bed/staff shortage
- Lack of isolation facilities
- Poor hygiene, cleaning and disinfection
- Antibiotic mis-use
- Standard precautions
Give examples of causes of increased pathogenicity of MRSA when exposed to antibiotics.
- Biofilm formation
- Small colony variants
- Efflux
- Hypermutation
- Skin/RT colonization leads to transmissibility
- Fibrinonectin-binding protein
- Toxin production eg x, TSST-1
- SOS response leads to horizontal gene transfer
- Phage induction
- Quorum sensing
- agr expression
- Autolysis
- Intracellular persistence
What factors contribute to MRSA colonisation?
- Poor infection control
- MRSA colonization pressure
- MRSA in the environment
- Length of stay, medical devices
- Antimicrobial consumption
What factors contribute to MRSA infection?
- Exposure to fluoroquinolones,
- ß-lactams - selection,
- Increased adhesion
- Increased virulence
- Patient risk factors, etc.
What is the problem with antimicrobial resistance?
Patients with infections caused by drug-resistant bacteria are generally at increased risk of worse clinical outcomes and death, and consume more healthcare resources than patients infected with the same bacteria that are not resistant
What accelerates the emergence of drug-resistance?
The use and misuse of antimicrobials
What is the UK 5 years antimicrobial resistance strategy?
- Improve knowledge & understanding of AMR
- Conserve and steward the effectiveness of existing treatments
- Stimulate the development of new antibiotics, diagnostics and novel therapies
What do the Scottish antimicrobial prescribing group (SAPG) do?
Co-ordinates & delivers a national framework for antimicrobial stewardship to enhance the quality of antimicrobial prescribing & management in Scotland
What are the current HEAT targets for hospital prescribing?
- Indication for antibiotic is documented and compliant with local policy
- Duration of oral antibiotics is documented and compliant with local policy
What are NHS Grampian’s strategies for reducing AMR?
- Policies and guidelines
- Audits and feedbacks
- Surveillance date
- Education
What acute policies and guidelines do NHS Grampian have to prevent AMR?
- Empirical guidelines
- Documentation & review/stop date
- IVOST policy
- Penicillin allergy
- Alert Antimicrobials
- Gentamicin
- Vancomycin
When should you consider switching a patient from IV to oral antibiotics?
After 48 hours provided that:
- The patient is improving clinically
- Is able to tolerate an oral formualtion
What criteria should be met before switching a patient from IV to oral antibiotics?
- Able to swallow and tolerate fluids
- Temp. 36-38°C for at least 48 hours
- Heart rate < 100bpm for previous 12 hours
- WCC between 4 and 12x109L
What are alert antimicrobials?
- For restricted use only under the authorisation of a microbiologist, or infectious diseases (or other relevant) specialist eg meropenem
- Administered according to approved indications within local guidelines/policies e.g. ceftriaxone allowed for meningitis
What measures are in place in primary care to help prevent AMR?
- Empirical Guidelines
- Delayed prescriptions
- ‘Non-Prescription’ Pad
- Patient information leaflets on management of self-limiting upper respiratory tract infections and cystitis
How can healthcare workers tackle AMR?
- Practicing effective infection prevention & control
- Prescribing and dispensing antibiotics only when truly needed
- Prescribing & dispensing the right antibiotic(s) for the right duration to treat the illness
How can the public tackle AMR?
- Use antibiotics only when prescribed
- Complete the full course
- Never share antibiotics or use leftover prescriptions
