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This Gasta posits a strategic approach to integrating AI into HEIs to prepare staff, students and the curriculum for an evolving world and workplace. We will highlight the advantages of working with these technologies beyond the realm of teaching, learning and assessment by considering prompt engineering skills, industry impact, curriculum changes, and the need for staff upskilling. In contrast, not engaging strategically with Generative AI poses risks, including falling behind peers, missed opportunities and failing to ensure our graduates remain employable. The rapid evolution of AI technologies necessitates a proactive and strategic approach if we are to remain relevant.
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http://sandymillin.wordpress.com/iateflwebinar2024
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The US House of Representatives is deeply concerned by ongoing and pervasive acts of antisemitic
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• The Committee on Education and the Workforce has been investigating your institution since December 7, 2023. The Committee has broad jurisdiction over postsecondary education, including its compliance with Title VI of the Civil Rights Act, campus safety concerns over disruptions to the learning environment, and the awarding of federal student aid under the Higher Education Act.
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This Gasta posits a strategic approach to integrating AI into HEIs to prepare staff, students and the curriculum for an evolving world and workplace. We will highlight the advantages of working with these technologies beyond the realm of teaching, learning and assessment by considering prompt engineering skills, industry impact, curriculum changes, and the need for staff upskilling. In contrast, not engaging strategically with Generative AI poses risks, including falling behind peers, missed opportunities and failing to ensure our graduates remain employable. The rapid evolution of AI technologies necessitates a proactive and strategic approach if we are to remain relevant.
2. Antitubercular Agents
Presented by –
Dr.Praveen kumar singh
Pulmonary medicine,JR1
Moderator-
Dr AK Gupta
HOD
Department of Pulmonary medicine
Balrampur Hospital, Lucknow.
5. M. tuberculosis: peculiar features
Rapid growers: Extracellular, in the wall of cavitary
lesion.
Slow growers: Intracellular, within the macrophages
at inflamed sites.
Spurters: intermittent growth spurts.
Dormant: Do not grow for long time, become active
at times of low host resistance.
Bacilli continuously shift from one to other subpopulation.
6. Chemotherapy in tuberculosis
Goals of anti-tubercular chemotherapy
Kill dividing bacilli: Patient is non-contagious :
transmission of TB is interrupted.
Kill persisting bacilli: To effect cure and prevent relapse.
Prevent emergence of resistance: so that the bacilli
remain susceptible to the drugs.
7. History of Antitubercular Agents
First successful drug for treating TB was
PAS (Para- aminosalicylic acid) developed by Lehman in 1943.
Dramatic success came when Waksman & Schutz discovered
Streptomycin which has made remarkable progress.
Followed by Thiacetazone by Domagk in 1946.
In 1952 Isoniazid came.
Pyrazinamide by Kushner & colleagues in 1952.
8. History of Antitubercular Agents
Later on Rifampicin in 1957 by S. Margalith has totally changed
the strategy in the chemotherapy.
Ethambutol came in 1961 by Lederle-laboratories.
Fluoroquinolones, newer macrolides, congener of Rifampicin
→Rifabutin, Clofazimine, Linezolid, Bedaquiline, Delamanid are
recent addition in antimycobacterial drugs.
9. Antitubercular Agents for DS-TB
First line drugs:
Isonized ( H)
Rifampicin (R)
Ethambutol (E)
Pyrazinamide ( Z)
Streptomycin ( S) now reserved drug in
first line
10. Antitubercular Agents
Second line drugs:
Thiacetazone
Para aminosalicylic acid (PAS)
Ethionamide (Eto)
Kanamycin (Km)
Cycloserine (Cs)
Amikacin (Am)
Capreomycin (Cm)
14. Isoniazid (H)
Isoniazid (Isonicotinic acid hydrazide,H):
-Essential component of all anti TB regimen
(except intolerance to H or resistance).
-It is tuberculocidal, kills fast multiplying organism & inhibit slow
acting organism.
-Acts both on intracellular( present in macrophages ) & extracellular
bacilli.
-Atypical mycobacteria are not inhibited by INH.
-Not active against any other micro-orgs.
15. Isoniazid
Mechanism of Action :
-Inhibit synthesis of mycolic acid ( unique fatty acid component of
mycobacterial cell wall).
-INH enters the bacilli by passive diffusion. It is prodrug, must be activated to
become toxic to bacilli.
It became toxic by Kat G (multifunctional Catalase - peroxidase, a
bacterial enzyme ) which catalyzes the product from INH an Isonicotinoyl
radical that subsequently inter-acts with mycobacterial NAD & NADP to
produce dozen of adducts.
-one of these a nicotinoyl NAD isomer which ↓ the activity of enoyl acyl carrier
protein reductase (Inh A) & β- ketoacyl carrier protein synthase ( Kas A),
inhibition of these enzymes ↓ the synthesis of mycolic acid an essential
component of the mycobacterial cell wall & causes cell death.
16. Isoniazid
Mechanism of action:
-Another adduct, a nicotinoyl–NADP isomer potentially mycobacterial
dihydrofolate reductase → interfere with nucleic acid synthesis .
-These adducts also produce H2O2, NO radical & other free radicals which
are toxic to bacilli.
-If INH is given alone, inherent resistant bacilli proliferate selectively &
after 2-3 months an apparently resistant infection emerges .(Mutation
of the catalase –peroxidase gene in bacilli do not generate the
active metabolite of INH )
- Combination therapy with INH has good resistance preventing action .
17. ISONIAZID
Pharmacokinetics :
- Completely absorbed orally, diffuses readily into body fluid e.g. pleural
fluid, ascetic fluid, CSF. penetrate all body tissues tubercular cavities,
placenta & meninges .
- Metabolized in liver by acetylation & metabolites are excreted in
urine .
- Rate of acetylation shows genetic variation
( fast acetylators > 30% Indians - t½ -1 hr
Slow acetylators >60% Indians -t ½- 3 hrs)
Dose – 4-6 mg/kg, for >50 kg – 300mg daily
19. ISONIAZID
ADRs -
Well tolerated drug
1.Peripheral neuritis & other neurological manifestations, parasthesia,
numbness, mental disorientation & rarely convulsion(due to
interference with utilization of pyridoxine & ↑ excretion in urine). Due to
this Pyridoxine given prophylactically 10 mg/day which prevents
neurotoxicities
- (INH neurotoxicity treated with Pyridoxine-100 mg/ day )
2. Hepatitis – more common in older patients & alcohlics ( reversible)
3. Rashes, fever, acne & arthralgia.
4- ingestion of toxic amount of INH(1.5g) causes recurrent seizure.
20. ISONIAZID
Drug interactions-
- INH inhibits the metabolism of phenytoin, carbamazepine, diazepam &
warfarin.
- Aluminum hydroxide inhibits INH absorption.
Contraindications-
- INH should be avoided in hypersensitivity & active liver disease.
- INH is safer in pregnancy.
21. RIFAMPICIN (R)
Rifampin ( Rifampicin ):
-Semisynthetic derivative of Rifamycin-B from Streptomyces mediterranei
-Bactericidal to M. Tuberculosis & others –S. aureus Klebsiella, N.
meningitides, Pseudomonas, H. influenzae Proteus, E. coli &
Legionella.
- Best action on slowly or intermittently dividing bacilli on
extracellular as well as intracellular organisms
-Also act on many atypical mycobacteria.
-Have good resistance preventing action
22. RIFAMPICIN
Mechanism of action:
- Inhibit DNA dependant RNA Synthesis
(by ↓ bact RNA polymerase, selective because does not
↓ mammalian RNA polymerase).
- TB patient usually do not get primary Rifampicin resistance – If
occurs is due to mutation in the repo -B gene (β subunit of RNA
polymerase ).
-
23. RIFAMPICIN
Pharmacokinetics:
Well absorbed orally widely distributed in the body, penetrate cavities,
caseous mass, placenta & meninges.
- Metabolized in liver, Excreted mainly in bile & some in urine.
- t½- 2-5 hrs.
- Dose- 10 mg ( 8-12 mg/kg), for > 50 kg = 600 mg OD
24. RIFAMPICIN
ADR’s
1. Hepatitis – mainly in pts having preexisting liver disease & is dose
related- Jaundice req. stoppage of drug.
2. Respiratory syndrome –breathlessness, shock & collapse .
3. Purpura, hemolysis, renal failure.
4 Cutaneous syndrome – flushing, pruritis & rashes ( face & scalp ), redness
& watering of eyes.
5. Nausea, vomiting, abdominal cramps.
Drug imparts an orange-red color urine, feces, saliva, sputum, tears &
sweat. which are harmless & Pt should be told about this effect)
25. RIFAMPICIN
Drug interactions:
Rifampicin is microsomal enzyme inducer
-↑ several CYP-450 isoezymes
-↑ its own metabolism as well as of others
e.g.-Oral contraceptive Digoxin
Warfarin Theophylline
Steroids Metoprolol
Sulphonyl urea Fluconazole
Ketoconazole
- contraceptive failure can occur if given simultaneously in child bearing
age women taking oral contraceptive.
26. RIFAMPICIN
Other uses Rifampicin –
1. Atypical myc. Inf. (M. kansasii, marinum, avium & intracellulare)
2. Leprosy
3. Prophylaxis of meningococcal & H. infl.
meningitis
4. MRSA, Diphtheroids & legionella inf.
5. Along with Doxycycline –first line therapy
in Brucellosis.
27. PYRAZINAMIDE (Z)
. Pyrazinamide ( Z)
Chemically≡ INH
- Weak tuberculocidal more active in acidic medium.
- More lethal to intracellular bacilli & to those at sites showing an
inflammatory response.
- (Therefore effective in first two months of therapy where inflammatory
changes are present).
- Good sterilizing activity.
- It’s use enabled total duration of therapy to be shortened & risk of relapse
to be reduced.
28. PYRAZINAMIDE
Mechanism of action:
Z ≡ INH - ↓ fatty acid synthesis but by interacting with a different fatty
acid synthesis encoding gene.
- Z is thought to enter in Mycobacterium by passive diffusion and
converted to pyrazinoic acid (its active metabolite) by bacterial
enzyme pyrazinamidase. This metabolite inhibits mycobact. Fatty
acid synthase-I enz. and disrupts mycolic acid synthesis needed for
cell wall synthesis.
- Mutation in the gene (pcn A) that encodes pyrazinamidase
enzyme is responsible for drug resistance (minimized by
using drug combination therapy)
30. PYRAZINAMIDE
ADRs :
- Hepatotoxic -dose related.
- Arthralgia, hyperuricemia, flushing, rashes, fever, GI upset & anaemia.
- Loss of diabetic control.
Contraindications:
- Z is C/I in hypersensitivity & hepatic dysfunction.
31. ETHAMBUTOL (E)
Ethambutol (E) :
- E is a congener of 1,2-ethanediamine.
- Tuberculostatic, Fast multiplying bact. are more sensitive.
- Also act against atypical mycobacteria.
- If added in triple regimen (HRZ) it is found to hasten the rate of sputum
conversion & to prevent development of resist.
32. ETHAMBUTOL
Mechanism of action:
- Not well understood. Found to ↓arabinosyl transferase-III involved in
arabinogalactone synthesis & also interfere with mycolic acid
incorporation in mycobacterial cell wall (this is encoded by emb AB
genes).
- Resistance develops in vivo via single amino acid change in emb A genes
when given in absence of another effective drugs.
33. ETHAMBUTOL
Pharmacokinetics:
- 3/4th of an oral dose of E is absorbed.
- Distributed widely but penetrates in meninges incompletely.
- Excreted in urine, caution is required in pts of renal disease.
Dose – 15-20 mg/kg, For >50kg -1000mg Daily.
34. ETHAMBUTOL
ADRs:
- Loss of visual acquity/color vision due to Retrobulbar optic neuritis,
which is most imp. dose & duration dependent toxicity.
(children can not report this complaint easily therefore not given below 6
yrs of age)
- Early recognition –reversible
- Hyper uricaemia is due to interference with urate excretion.
- Others- Nausea, rashes & fever, Neurological changes.
35. STREPTOMYCIN (S)
Streptomycin (S):
-It was 1st clinically useful antibiotic drug
-It is protein synthesis inhibitor by combining with 30S ribosome.
-It is tuberculocidal , but less effective than INH / Rifampicin.
-Acts on extracellular bacilli only ( poor penetration in the cells )
It penetrates tubercular cavities but does not cross BBB.
36. STREPTOMYCIN
- Atypical mycobact.s are ineffective.
- Popularity ↓ due to need of IM inj. & lower margin of safety
( because of ototoxicity(vestibular) & nephrotoxicity.).
- Dose- 15 ( 12-18 ) mg/kg, >50 Kg- 1000mg.
37. MOA of 1st line drugs
Mycolic Acid
Arabinogalactan
Peptidoglycan
Cell membrane
R
I
B
O
S
O
M
e
Protein
Isoniazid
-
Pyrazinamide
- Mitochondria
(ATP)
- Rifampin
-
Ethambutol
-
Streptomycin
- Cytoplasm
38. Relative activity of first line Drugs
INH: potent bactericidal
Rifampin: potent bactericidal
Pyrazinamide: Weak bactericidal, active against intracellular bacilli.
Ethamutol: bacterisostatic, prevents resistance development.
Streptomycin: bactericidal, active against extracellular rapid
growers.
Never use a single drug for
chemotherapy in
tuberculosis, a combination
of three or more drugs
must be used.
Combination is synergistic
39. The Basis for Multi-Drug Therapy
Antibacterial attack
against all
subpopulations
of bacilli.
D
Dormant
(No cure)
B
Acid
inhibition
C
Spurts of
metabolism
А
Continuous
growth
RIF
PZ
A
INH
(RIF, SM)
High
Speed of
bacteria
growth
Low
Mitchison, Tubercle 66: 219-226, 1985
Rapid
growers
Slow
growers
INH
Rifampin
Streptomycin
INH, Rifampin
Ethambutol, PZ
No drug
is effective
Rifampin
Spurters
2
40. THIACETAZONE (TZN)
Thiacetazone (TZN) :
-First AT drug tested but low efficacy drug.
-Discarded due to hepatotoxicity.
-Tuberculostatic , does not add to the therapeutic effect of H,S, R, E.
-Should not be used in HIV patients.
-ADRs -
Hepatotoxic
Exfoliative dermatitis, Stevenson Johnson’s syndrome
Cerebral edema
Others- Nausea , anorexia , abd. Discomfort
41. PARAAMINOSALICYLIC ACID (PAS)
PAS – Paraaminosalicylic acid:
- Related to sulfonamides chemically as well as in mech. of action.
- PAS disrupt folic acid metabolism through competitive binding with
dihydrofolate reductase.
- Tuberculostatic, not add to therapeutic value, only delay resistance
-Interfere with absorption of Rifampicin
Dose- 10- 12 gm (150 mg/ kg) / day
ADRs - - Acceptability is poor due to frequent anorexia, nausea,
malabsorption synd & epigastric pain.
- Hypothyroidism.
42. ETHIONAMIDE (Eto)
Ethionamide / Prothionamide:
-Tuberculostatic, acts both on extra as well as intracellular bacterias.
(Mycobacterial EthaA,containing mono- oxygenases, converts
Ethionamide to a sulfoxide, it ↓mycobacterial growth by ↓ the activity
of the inh A gene product, the enoyl acyl reductase of fatty acid
synthase II ,the same enzyme which is ↓ by INH ).
-Absorbed orally ,distributed all over body including CSF.
Dose- 15-20 mg/kg/day, .
ADRs -
- GI -Anorexia, Nausea, vomiting, diarrhea, wt loss.
Allergic reactions, Rashes, pellagra like synd,
Hepatitis, Peripheral/ Optic neuritis.
Psychotic disturbances, Neurotoxicity.
43. CYCLOSERINE
Cycloserine (Cycs):
- Chemical analogue of D- alanine.
-↓ Bacterial cell wall synthesis.
-Tuberculostatic & ↓ other G -ve organisms( E. coli, Chlamydia)
-Resistance develop slowly , no cross resist.
Dose – 10-15mg/kg
ADRs -
- Common CNS toxicity is high, sleepiness, headache, tremor, psychosis &
convulsions.
44. FLUOROQUINOLONES
Levofloxacin (Lfx), Moxifloxacin(Mxf)-:
- Fluoroquinolone, bactericidal acts by inhibiting A subunit of DNA gyrase
(topoisomerase).
- Completely absorbed after oral administration, orally should not be
administered within 4hrs of other medicines containing divalent cations(
iron, zinc, vitamins, magnesium, sucralfate), no intraction with milk &
calcium.
- ADRs -
- GI intolerance, allergic rxn, headach, dizziness, insomnia.
D/I – should not be given to pt receiving class Ia antiarrhythmic
(quinidine,procainamide), class III antiarrhythmic (amiodaron, sotalol).
- -Decrease absorption by aluminum ions containing sucralfate & antacids.
- -Dose adjustment in renal & hepatic diseases needed in Lfx, but not in Mfx.
45. CLOFAZIMINE (Cfz)
Clofazimine-:
Bacteriostatic , bind to myco DNA & inhibit myco
replication & growth.
ADRs -
-: Ichthyosis & dry skin, pink to brownish discoloration of skin, abdominal
pain.
D/I-: Cfz may dec absorption rate of R, INH inc Cfz serum & urine
concentration & dec skin concentration.
ingestion of Cfz with orange juice resulted in modest reduction in Cfz
bioavailability.
46. LINEZOLID (Lzd)
Linezolid -:
- Inhibits protein synthesis by binding to the P site of the 50S ribosomal
subunit & preventing formation of the larger ribosomal fMet- rRNA
complex that initiates protein synthesis.
- Linezolid has nearly 100% oral bioavailability, with good penetration into
tissues and fluids, including CSF.
ADRs -
- Lzd causes frequent GI upset and rash. Rare case peripheral & optic
neuropathy.
47. IMIPENEM/CILASTATIN(Ipm/Cln)
Imipenem belongs to the carbapenem group of drugs which is beta-lactam
antibiotics.
- Beta lactam antibiotics inhibits transpeptidase, so that crosslinking of the
adjacent peptide chains does not take place, which interfere with the
synthesis of bacterial cell wall.
- Ipm not absorbed orally, rapidly hydrolysed by the enzyme
dehydropeptidase-I , hence Ipm is combined with cilastatin which is
reversible inhibitor of dehydropeptidase and thus Ipm is protected from
hydrolysis.
ADRs – frequent GI upset, hypersensitivity rxn, palpitation & tachycardia.
- Occassional Hypotension, thrombophlebitis, seizures, anemia.
48. BIDAQUILINE (Bdq)
Bidaquiline-:
- Bdq is bactericidal diarylquinoline antimyco drug that inhibits the proton
pump of myco ATP synthase.
- Bacteria that have smaller ATP store (usually in dorment, nonreplicating
bacilli) are more susceptible to Bdq.
- -food inc the oral bioavailability.
- ADRs –
- m/c nausea, arthralgia & headache.
49. DELAMANID(Dlm)
Delamanid is a prodrug that confers mycobactericidal activity by inhibiting
the synthesis of mycolic acid through myco F420 system.
Both INH & Dlm act by preventing the synthesis of mycolic acid, inhA is a
specific factor for the function of INH, while Dlm needs myco F420 system
for its activation.
Dlm shows dose dependent bactericidal activity..
ADRs –
GI upset , tremor, hypokalemia, QTc prolongation.
53. Peripheral
neuropathy
- Suspected agent(s): Lzd, Cs H, Am, FQ, rarely Eto, E
Suggested management strategies:
- To prevent occurrence of such adverse reaction, all patients on an NTEP
regimen should receive daily pyridoxine.
- The commonest offending agent is Lzd, almost 60–70% of the patients on
Lzd 600 mg/ day may develop neuropathy and pyridoxine does not help in
preventing Lzd induced neuropathy.
- Early recognition of neuropathy symptoms and early dose reduction of Lzd
helps to prevent the progression. If there is no improvement or symptoms
worsen, amitriptyline 25mg will be added (to be avoided with Bdq) and if
there is still no improvement, the patient should be referred to a
neurologist.
- correct any vitamin or nutritional deficiencies and maximum daily dose (100
mg/day).
- initiate medical treatment: non-steroidal anti-inflammatory drugs or
acetaminophen may help alleviate symptoms.