Week 5: Drugs for Treating Infections Flashcards
Briefly describe the main steps involved in viral replication for the Influenza virus.
(1) Virus binds to a sialic acid-containing receptor on cell surface.
(2) Receptor mediated endocytosis as virus is engulfed by the cell plasma membrane to form an endocytic vesicle.
(3) Delivery of the virus to the endosomal cell compartment.
(4) Fusion of the viral membrane with the membrane of the endosome, induced by the mildly acidic pH in the endosomal lumen.
(5) Viral RNA delivered to the nucleus, synthesis of messenger RNA (mRNA) and viral RNA replication.
(6) Synthesis of viral protein components in the cell cytosol (internal proteins) and endoplasmic reticulum (ER) (membrane proteins).
(7) Assembly and budding of progeny viruses
How do the three main classes of Influenza virus differ in terms of their severity?
Influenza A: most virulent, multiple host species, antigenic drift and shift (evades immune system)
Influenza B: No animal reservoir (humans only except seals and ferrets), slower mutation rate leads to less antigenic variability and higher immunity, Lower mortality
Influenza C “Common Cold Like”: Less common, limited animal reservoir, usually common cold like symptoms
Outline the key steps involved when an influenza virion gains entry to a host cell.
Steps following uptake of the virus into a host cell by endocytosis:
i. ATP driven proton entry into the endosome to allow fusion of the viral membrane with the internal endosomal membrane.
ii. entry of protons into the virus itself via a viral ion channel known as M2.
iii. The low pH inside the virus results in breakdown the viral coat of the nucleocapsid. “viral uncoating”
iv. The RNA can then escape out into the host cell cytoplasm
Oseltamivir is a prodrug, administered by oral ingestion, what is a prodrug?
Prodrug: pharmacologically inactive/less active compound which gets metabolised to the active compound
The volume of distribution Vd of the active metabolite of Oseltamivir is in the range 23-26 L, from this value estimate the fluid/tissue compartment distribution of the drug.
This value is larger than the plasma compartment, so the drug is certainly in the extracellular cellular fluid and probably also distributed in the intracellular fluid too, but not bound to tissue protein or fatty tissue.
Describe the antiviral action of Oseltamivir.
Oseltamivir is a neuraminidase inhibitor.
Neuraminidase is one of three transmembrane viral proteins which enables newly formed virions escape from their host cell.
Many newly formed viruses re-attach to the sialic acid membrane glycoprotein residues on the cell membrane. To get released and infect other host cells they need to break this bond which is carried out by the viral neuraminidase.
Oseltamivir is a sialic acid analogue with a very high binding affinity for neuraminidase. Therefore it binds more strongly with the neuraminidase than the competing endogenous sialic acid.
The results from clinical trials with Oseltamivir have provided information for optimal treatment strategies.
When is the optimal time to begin treatment with Oseltamivir following infection and when will it no longer have any significant effect in reduction of symptom duration?
The earlier treatment is started after symptom onset the shorter the duration of symptoms. The time window for significant reduction goes up to 48 hours. Little benefit accrues past this time
Is there any evidence that Oseltamivir reduces mortality as a result of Influenza?
One study suggests a potential decrease risk of mortality by 70%
A 62-year-old man presented to A/E with acute shortness of breath. He gave a 7-day history of cough with yellow-green sputum and increasing wheeze. He had a history of smoking unfiltered cigarettes since the age of 13 years. His usual exercise tolerance of 400 yards, limited by breathlessness, was now only a few yards. He had not sought the advice of his GP prior to admission and as a consequence takes no medication. He had an anaphylactic reaction to penicillin 50 years ago. Full blood count reveals a high neutrophil count of 20. His admission chest X-ray revealed hyper-inflated lung fields with right basal collapse.
What are the probable diagnoses?
Chronic Obstructive Pulmonary Disease (COPD)
Right lower love pneumonia with right basal colapse
Would not class as infective exacerbation of COPD as he has purulent sputum as well as radiographic changes (would use diagnosis of IECOPD rather than pneumonia when there are no radiographic changes but chest infection is suspected).
A 62-year-old man presented to A/E with acute shortness of breath. He gave a 7-day history of cough with yellow-green sputum and increasing wheeze. He had a history of smoking unfiltered cigarettes since the age of 13 years. His usual exercise tolerance of 400 yards, limited by breathlessness, was now only a few yards. He had not sought the advice of his GP prior to admission and as a consequence takes no medication. He had an anaphylactic reaction to penicillin 50 years ago. Full blood count reveals a high neutrophil count of 20. His admission chest X-ray revealed hyper-inflated lung fields with right basal collapse.
What percentage oxygen therapy should be administered?
Controlled O2 in first instance.
Venturi mask 4L/min at 24 or 28% are both appropriate to start with and then titrate.
Aim to maintain saturations 88-92%
Should do arterial blood gas to determine if retain CO2 and O2 levels
A 62-year-old man presented to A/E with acute shortness of breath. He gave a 7-day history of cough with yellow-green sputum and increasing wheeze. He had a history of smoking unfiltered cigarettes since the age of 13 years. His usual exercise tolerance of 400 yards, limited by breathlessness, was now only a few yards. He had not sought the advice of his GP prior to admission and as a consequence takes no medication. He had an anaphylactic reaction to penicillin 50 years ago. Full blood count reveals a high neutrophil count of 20. His admission chest X-ray revealed hyper-inflated lung fields with right basal collapse.
Would this patient benefit from corticosteroid therapy? What route of administration is appropriate?
Yes, short course 30mg prednisolone for 7-14 days, provided no contraindications. In this case offer for COPD – wheeze, ex-smoker and hyper inflated lungs. Otherwise do not offer to people with pneumonia routinely.
Route of administration: NICE recommends in the absence of significant contraindications oral corticosteroids should be used, in conjunction with other therapies, in all patients admitted to hospital with an exacerbation of COPD.
A 62-year-old man presented to A&E with acute shortness of breath. He gave a 7-day history of cough with yellow-green sputum and increasing wheeze. He had a history of smoking unfiltered cigarettes since the age of 13 years. His usual exercise tolerance of 400 yards, limited by breathlessness, was now only a few yards. He had not sought the advice of his GP prior to admission and as a consequence takes no medication. He had an anaphylactic reaction to penicillin 50 years ago. Full blood count reveals a high neutrophil count of 20. His admission chest X-ray revealed hyper-inflated lung fields with right basal collapse.
Are antibiotics indicated?
Use CURB65 score to assess severity
CURB65 severity score: 1 point for each feature present: Confusion Urea > 7mmol/l Respiratory rate ≥ 30/min Blood pressure (SBP < 90 or DBP ≤ 60mmHg) Age ≥ 65 years
If low (score 0-1)– first line normally amoxicillin but as penicillin allergic can use a macrolide e.g. Erythromycin, clarithromycin Or a tetracycline e.g. Doxycycline
If mod-high severity - a 7 – 10 day course is indicated. Consider dual antibiotic therapy with amoxicillin and a macrolide for patients with moderate-severity community-acquired pneumonia.
Or if high severity, a beta-lactamase stable beta-lactam (e.g. co-amoxiclav, cefotaxime, ceftriaxone, cefuroxime and piperacillin with tazobactam (tazocin)) and a macrolide.
In penacillin allergic – 2nd or 3rd generation cephalosporin, but there is some cross reactivity, discuss with Consultant Microbiologist
A 62-year-old man presented to A&E with acute shortness of breath. He gave a 7-day history of cough with yellow-green sputum and increasing wheeze. He had a history of smoking unfiltered cigarettes since the age of 13 years. His usual exercise tolerance of 400 yards, limited by breathlessness, was now only a few yards. He had not sought the advice of his GP prior to admission and as a consequence takes no medication. He had an anaphylactic reaction to penicillin 50 years ago. Full blood count reveals a high neutrophil count of 20. His admission chest X-ray revealed hyper-inflated lung fields with right basal collapse.
What is the relevance of his allergic reaction?
Important in antibiotic choice as first line are penicillins. He is definitely classed as allergic and not intolerant given the past anaphylaxis to penicillin.
The frequently cited figure of 10% cross reactivity between penicillin and cephalosporins is an overestimate. Cross reactivity between penicillins and second and third generation cephalosporins is low and may be lower than the cross reactivity between penicillins and unrelated antibiotics. Anaphylaxis with cephalosporins is rare (0.1-0.0001%)
A 30-year-old lady presented with a six-week history of worsening cough, fever, and weight loss, which had not responded to two successive courses of antibiotics. A sputum smear is positive for Acid-fast bacilli (AFB).
What is her diagnosis?
Tuberculosis – active (currently infectious pulmonary TB) as sputum positive
A 30-year-old lady presented with a six-week history of worsening cough, fever, and weight loss, which had not responded to two successive courses of antibiotics. A sputum smear is positive for Acid-fast bacilli (AFB).
Which drugs would you use and for how long?
Quadruple therapy
NICE: For people with active TB without central nervous system involvement, offer:
isoniazid (with pyridoxine), rifampicin, pyrazinamide and ethambutol for 2 months then
isoniazid (with pyridoxine) and rifampicin for a further 4 months.
Modify the treatment regimen according to drug susceptibility testing.
A 30-year-old lady presented with a six-week history of worsening cough, fever, and weight loss, which had not responded to two successive courses of antibiotics. A sputum smear is positive for Acid-fast bacilli (AFB). She is prescribe quadruple therapy for currently active pulmonary TB.
What baseline tests would you do prior to starting drug therapy?
CXR, CT, HIV test, U and E (check renal function and adjust doses accordingly, avoid ethambutol)
LFTs (hepatic impairment with 3/4 drugs mentioned above)
Visual acuity (before ethambutol)
A 30-year-old lady presented with a six-week history of worsening cough, fever, and weight loss, which had not responded to two successive courses of antibiotics. A sputum smear is positive for Acid-fast bacilli (AFB). You wish to prescribe quadruple therapy for her TB.
The patient is taking the combined oral contraceptive pill (COCP), but wishes to start a family soon.
What should she be advised? Does the COCP affect her treatment?
Not effective whilst taking rifampicin to use alternative method whilst being treated. Rifampicin is a CYP450 inducer causing the COCP to be metabolised before it has effect.
A 30-year-old lady presented with a six-week history of worsening cough, fever, and weight loss, which had not responded to two successive courses of antibiotics. A sputum smear is positive for Acid-fast bacilli (AFB). The patient is taking the combined oral contraceptive pill (COCP), but wishes to start a family soon. You prescribe quadruple therapy for her currently infectious pulmonary TB.
After 3 weeks on treatment the patient notices that she has become jaundiced. What should be done?
Discontinue treatment and seek immediate medical attention, as Isoniazid, rifampicin and pyrazinamide are all hepatotoxic.
Infectious endocarditis
An 18-year-old man has a congenital mitral valve prolapse (with ausculatory pansystolic murmur), but is otherwise well.
What advice would you give him regarding dental treatment?
Antibiotic prophylaxis against infective endocarditis is not recommended anymore.
for people undergoing dental procedures
for people undergoing non‑dental procedures at the following sites:
o upper and lower gastrointestinal tract
o genitourinary tract; this includes urological, gynaecological and obstetric procedures, and childbirth
o upper and lower respiratory tract; this includes ear, nose and throat procedures and bronchoscopy.
1.1.4 Chlorhexidine mouthwash should not be offered as prophylaxis against infective endocarditis to people at risk of infective endocarditis undergoing dental procedures. [2015]
An 18-year-old man has a congenital mitral valve prolapse (with ausculatory pansystolic murmur), but is otherwise well.
He develops bacterial endocarditis and Streptococcus viridans is isolated from blood cultures. How would you treat this condition and for how long?
The viridans group streptococci have remained the primary cause of native valve endocarditis. These are either penicillin-sensitive or relatively penicillin-resistant. Antibiotic regimens include a beta-lactam e.g. Benzylpenicillin (with or without gentamicin, if large vegetation, intracardial abscess – for 2 weeks) or I.v. vancomycin if penicillin allergic (4 weeks) . Patients with native valves are generally treated for 4 to 6 weeks.
An 18-year-old man has a congenital mitral valve prolapse (with ausculatory pansystolic murmur), but is otherwise well.
He develops bacterial endocarditis and Streptococcus viridans is isolated from blood cultures. He eventually requires a mechanical valve replacement. What long-term drug treatment will he need?
Warfarin/novel anticoagulant therapy due to high risk of thrombosis from metallic valve. As he is 18 years old he wouldn’t be considered for a tissue valve (which do not necessarily require anticoagulants) as they have a shorter life span
What type of virus is HIV-1?
A retrovirus. The virus has single stranded RNA genome and targets a host cell, where it transcribes a DNA copy of its genome which is integrated into the host cells genome. The host cell then transcribes and translates the viral proteins
What does the acronym HAART stand for in for the treatment of HIV-1 infection? How did it revolutionise treatment of HIV?
highly active antiretroviral therapy
It dramatically reduced the morbidity and mortality associated with HIV-1 infection and AIDS by suppressing the replication of the virus replication and therefore viral load, allowing recovery of the immune system.
Considering the mechanism by which a virus can gain drug resistance, why does a cocktail of 3 (or more) antivirals give a more durable treatment?
Viruses gain resistance by mutations. Using a cocktail of 3 drugs requires a virus to pick up 3 separate mutations to allow its survival and replication in the host cell.
List the 6 classes of retroviral drugs for treatment of HIV-1 infection.
(1) nucleoside-analogue (or nucleoside/nucleotide) reverse transcriptase inhibitors (NRTIs)
(2) non–nucleoside reverse transcriptase inhibitors (NNRTIs)
(3) integrase inhibitors
(4) protease inhibitors (PIs)
(5) fusion inhibitors
(6) coreceptor antagonists
Zidovudine was the first drug successfully used to treat HIV infection, which class of drugs does it fall into and which stage of viral replication do they inhibit? Is this unique to the virus or does the human host also utilise this type of reaction?
Zidovudine is a nucleoside-analogue reverse transcriptase inhibitors (NRTIs) targeting the reverse transcription of the viral RNA genome into a DNA molecule. This is unique to retroviruses not their human hosts
How do NRTIs and NNRTIs differ in their mechanism of action?
NRTIs are competitive inhibitors entering the active site of the viral reverse transcriptase enzyme and being transferred onto the newly synthesised DNA molecule where they terminate the synthesis. NNRTIs act as non or uncompetitive inhibitors by binding adjacent to the enzyme active site.
Which class of influenza is the most virulent, with multiple host species, antigenic drift and shift (evades immune system)
Influenza A = ANTIGENIC drift and shift
Which class of influenza has no animal reservoir (humans only except seals and ferrets), and its slower mutation rate leads to less antigenic variability and higher immunity, and lower mortality
Influenza B = Better off than A (lower mortality), BE only in humans (no animal reservoirs)
Which class of influenza is less common, has limited animal reservoirs, and usually common cold like symptoms
Influenza C = “Common Cold” Like
How do Amantadine and Rimantadine act to block entry of influenza into cells?
Which one of these agents is generally preferred in use and why?
Amantadine and Rimantadine are examples of two M2 Ion channel blockers that inhibit viral uncoating.
Amantadine has more marked ADR risk than Rimantidine of about 5-10%. ADRs include dizziness, GI disturbance and hypotension. More serious are confusion and insomnia and hallucination which can be problematic in the elderly in whom these symptoms may be present and further exacerbated.
For this reason, Rimantidine is usually preferred over Amantadine. However widespread M2 mutations mean that neither Amantadine nor Rimantadine are recommended by NICE for treatment or prophylaxis of influenza.
Oseltamivir is a prodrug, administered by oral ingestion. How is oseltamivir metabolised?
Oseltamivir or oseltamivir phosphate is metabolised by removal of the phosphate and ester hydrolysis to yield the oseltamivir carboxylate active compound.
True or false?
Neuraminidase is one of three transmembrane viral proteins which enables newly formed virions escape from their host cell.
True.
What are the common side effects of Oseltamivir?
Occur in over 1% of patients, generally not serious, GI disturbance inc. nausea & vomiting, headache, nose bleed. Rarely respiratory depression, bronchospasm. A Cochrane review reported dose dependent psychiatric effects.
A 62-year-old man presented to A/E with acute shortness of breath. He gave a 7-day history of cough with yellow-green sputum and increasing wheeze. He had a history of smoking unfiltered cigarettes since the age of 13 years. His usual exercise tolerance of 400 yards, limited by breathlessness, was now only a few yards. He had not sought the advice of his GP prior to admission and as a consequence takes no medication. He had an anaphylactic reaction to penicillin 50 years ago. Full blood count reveals a high neutrophil count of 20. His admission chest X-ray revealed hyper-inflated lung fields with right basal collapse.
The consultant prescribes a short course 30mg prednisolone for 7-14 days,
What would be the mechanism of action?
The mechanisms for improving lung function in patients treated with steroids during exacerbations may include a reduction in airway inflammation or a decrease in airway oedema, especially as in some studies the changes have occurred relatively early after the start of treatment
Mechanism of action of Amoxicillin
Amoxicillin is an inhibitor of bacterial cell wall synthesis. It is a β-lactam antibiotic, a 3rd generation derivative of penicillin. It has a higher oral bioavailability (95%) than most other antibiotics of this class. It contains a chemically reactive β-lactam ring which forms a covalent bond with the side chain –OH of a serine amino acid in the active site of the bacterial transpeptidase enzyme. The bacterial transpeptidase is responsible for the cross-linkage between the linear peptidoglycan polymer chains that make up a major component of the cell wall of Gram-positive and a minor component of Gram-negative bacteria. Amoxicillin irreversibly inhibits this cross-linkage preventing further cell wall synthesis and leading to cell lysis therefore it is a bactericidal agent
What is the mechanism of action of macrolides?
Macrolides inhibit RNA-dependent protein synthesis by reversibly binding to the 50S ribosomal subunits of susceptible microorganisms. The macrolides inhibit the peptidyltransferase enzyme and weaken tRNA-ribosome interactions. This interferes with the addition of new amino acids onto the growing polypeptide chain in the ribosome and so blocks the synthesis of new protein. This has a mainly bacteriostatic effect.
What is the mechanism of action of tetracycline antibiotics?
Tetracycline antibiotics are also protein synthesis inhibitors. Whereas macrolides bind to the large subunit of the bacterial ribosome tetracyclines bind to the small 30S ribosomal subunit. Their binding prevents incoming amino acid ‘charged tRNA’ binding to the RNA-ribosome complex and so stops the supply of amino acid building blocks for protein synthesis.
A 30-year-old lady presented with a six-week history of worsening cough, fever, and weight loss, which had not responded to two successive courses of antibiotics. A sputum smear is positive for Acid-fast bacilli (AFB). She is prescribed quadruple therapy for currently in factious pulmonary TB.
What monitoring of the drugs is required?
Routine ophthalmological monitoring for ethambutol
Since isoniazid, rifampicin and pyrazinamide are associated with liver toxicity – if preexisting liver disease or alcohol dependency frequent checks, particularly in first 2 months when hepatic toxicity is more likely.
If no evidence of liver disease check if fever, malaise, jaundice, vomiting or unexplained deterioration
If used renal dose of ethambutol in patient with renal impairment should monitor drug plasma concentration levels
A 30-year-old lady presented with a six-week history of worsening cough, fever, and weight loss, which had not responded to two successive courses of antibiotics. A sputum smear is positive for Acid-fast bacilli (AFB). She is prescribed quadruple therapy for currently in factious pulmonary TB.
What advice would you give to the patient after starting treatment?
To report if symptoms of liver disease occur or any changes in vision. If using COCP to use alternative means whilst taking rifampicin a CYP450 inducer Inform of side effects – urine orange-red discolouration with rifampicin
GI side effects common
A 30-year-old lady presented with a six-week history of worsening cough, fever, and weight loss, which had not responded to two successive courses of antibiotics. A sputum smear is positive for Acid-fast bacilli (AFB). You wish to prescribe quadruple therapy for her TB.
The patient is taking the combined oral contraceptive pill (COCP), but wishes to start a family soon.
What should she be advised? Does the COCP affect her treatment?
What will happen to the immediate family contacts?
Screening offered to close contacts of patient
If symptomatic will be assessed for active TB and managed accordingly
If asymptomatic contact less than 65 test for latent TB using Mantoux testing.
If inconclusive refer to TB specialist.
If positive (induration 5mm or larger) assess for active TB. Once rule out active TB, consider interferon gamma release assay (IGRA) if need more evidence to decide on treatment. If positive, offer treatment for latent TB infection, offer either of the following drug treatments:
o 3 months of isoniazid (with pyridoxine) and rifampicin or
o 6 months of isoniazid (with pyridoxine).
If negative Mantoux offer BCG vaccination if:
o Previously unvaccinated
o 35 years and younger
o Over 35 but healthcare of laboratory worker
If asymptomatic and over 65 consider a chest X-ray, possibly leading to further investigation for active TB
Patients with the following cardiac conditions are at risk of developing infective endocarditis:
acquired valvular heart disease with stenosis or regurgitation
hypertrophic cardiomyopathy
previous infective endocarditis
structural congenital heart disease, including surgically corrected or palliated structural conditions, but excluding isolated atrial septal defect, fully repaired ventricular septal defect or fully repaired patent ductus arteriosus, and closure devices that are judged to be endothelialised valve replacement.
Infectious endocarditis
An 18-year-old man has a congenital mitral valve prolapse (with ausculatory pansystolic murmur), but is otherwise well.
He develops bacterial endocarditis and Streptococcus viridans is isolated from blood cultures.
How would you monitor his drug treatment? What are the common ADRs relating to this treatment?
Plasma gentamicin measurement – dose calculated (loading and maintenance) based on patient weight and renal function e.g. Using nomogram. Adjustments made based on plasma concentrations. When possible do not exceed 7 days of treatment.
Require plasma vancomycin measurement after 3 or 4 doses if renal function normal or earlier if renal impairment
Blood counts – should see inflammatory markers decreasing if on correct treatment
Blood cultures – will need 3 sets of cultures from 3 different sites, each taken 1 hr apart- these guide antibiotic treatment
Urinalysis
Renal function test
Monitor auditory function if elderly or renal impairment
Common ADRs:
Vestibular and auditory damage (tinnitus)
Nephrotoxicity
Blood disorders e.g. neutropenia with vancomycin
What are the 5 components of the CURB65 severity score?
Confusion Urea > 7mmol/l Respiratory rate ≥ 30/min Blood pressure (SBP < 90 or DBP ≤ 60mmHg) Age ≥ 65 years
To gain entry into a host cell, the invading virion first attaches to what on the cell surface?
A neuraminic or sialic acid residue on a membrane glycoprotein. The complex then allows the virus to gain entry by endocytosis.
To gain entry into a host cell, the invading virion first attaches to a neuraminic or sialic acid residue on a membrane glycoprotein. The complex then allows the virus to gain entry by endocytosis. Following uptake of the virion into a host cell by endocytosis, there are two steps that must precede uncoating and successful transcription of viral RNA.
What are these two steps?
The first step involves ATP driven proton entry into the endosome to allow fusion of the viral membrane with the internal endosomal membrane.
The second step involves entry of protons into the virus itself via a viral Ion channel known as M2. The low pH inside the virus then results in breakdown the viral coat of the nucleocapsid. “viral uncoating” The RNA can then escape out into the host cell cytoplasm.
