Antimicrobial Pharmacology Flashcards
How are bacterial cell wall inhibitors classified?
Penicillins
Cephalosporins
Carbapenems
Others
What is the process of cell wall synthesis in bacteria?
- starts with 2 major proteins - NAM and NAG ( N - acetylmuramic acid and N-acetylglucosamine).
- Very long chains of these proteins are bound together to make a train.
- In order to make a wall, 2 trains need to be bound together by 2 chains of amino acids.
- Penicillin-binding protein cleaves off 2 end units, binds the amino acid chains together tightly, and keeps doing that over and over again until two very long trains are hooked together to make a strong cell wall for the bacteria.
What is the mechanism of action of the cell wall synthesis inhibitors?
- They stop the production of the cell wall - hence cell wall synthesis inhibitors.
- Beta-lactam antibiotics are given.
- Beta-lactam ring binds to the penicillin-binding protein and prevents the cross-linking of NAM and NAG chains to each other.
- This does not affect the pre-existing bacteria but when the bacteria try to divide, the new cell cannot build a new wall.
- Spheroplast = bacteria without a cell wall. It cannot infect the body, it autocatalyzes and dies.
What are the mechanisms of antibiotic resistance?
- B-lactamase-mediated resistance
- Penicillin-binding protein-mediated resistance
- Porin-mediated resistance
What is B-lactamase mediated resistance?
- Beta-lactamases are enzymes within the bacteria that break down the beta-lactam ring.
- They break down the antibiotic that is killing them.
- This affects many antibiotics with beta-lactam rings in their structure - penicillins, cephalosporins, some cephamycins, and other carbapenems.
- produced mainly by gram + bacteria ( can also be from gram -).
- secreted in presence of antibiotics.
What can be done to counteract the beta-lactamase activity?
- With penicillin-based beta-lactamases, we can counter it with certain types of inhibitors of these enzymes.
- Clavulanic acid is an example of a beta-lactamase inhibitor.
- Pair clavulanic acid with amoxicillin
- Tazobactam with piperacillin
- Ampicillin with Sulbactam
What is penicillin-binding protein-mediated resistance?
- Penicillin-binding protein that is resistant to the effects of beta-lactam activity.
- Naked DNA from resistant bacteria gets incorporated into the cell.
- The host DNA is now changed. When host DNA produces a new penicillin-binding protein, it’s slightly different - enough to be resistant to the beta-lactam antibiotic but is still able to produce a cell wall.
- Reduced affinity to the new beta-lactam antibiotic.
What is porin-mediated resistance?
- Porins are water-filled channels.
- Tubular structure seen in cell walls.
- Antibiotics travel through the porins to get into the bacteria.
- If bacteria has adapted and makes fewer porins you’ll have less ability for the antibiotic to get in.
- seen in Pseudomonas aeruginosa.
trick = P for porins and P for Pseudomonas.
What are the 5 different types of penicillins?
- Natural Penicillins
- beta-lactamase resistant penicillins
- Aminopenicillins
- Carboxypenicillins
- Ureidopenicillins
What are the types, structures, and indications of natural penicillin?
Types:
- Several different types
- Penicillin G is the most common
- Also K, N, V
Structures:
Indications:
- Penicillin G is used in strp throat and necrotizing enterocollitis.
- These agents are used in syphilis, leptospiralis, and in gonorrhea.
Given IM or IV.
Focus mostly on gram + organisms.
- Penicillin V - used more commonly in strp throat, otitis media in children, cellulitis and in rheumatic fever.
- Is acid stable - can survive the gut and therefore can be given orally.
What is the pharmacology of beta-lactamase-resistant penicillin?
- Methicillin, Oxacillin, Cloxacillin
- Cloxacillin used in skin infections, cellulitis, impetigo, some pneumonias, septic arthritis, otitis.
- Safe in pregnancies
- Staph that produce beta-lactamase can be treated with cloxacillin.
- Long R chain present in cloxacillin - prevents beta lactamase from binding to it,
Methicillin:
- not used as much anymore
- Important = lot of resistance to this drug.
- MRSA - big problem in hospitals.
- Methicillin is liked to interstitial nephritis.
Nafcillin:
- Associated with neutropoenia.
What is the pharmacology of aminopenicillins?
- Ampicillin and amoxicillin
- Wide spectrum antibiotics but can still be susceptible to beta lactamases.
- can be give IM or IV.
- Indications: bacterial meningitis, endocarditis, GI infections like salmonella, genitourinary tract, used in catheter-based infections.
- Also used in bacterial endocarditis prophylaxis.
- Ampicillin can by enhanced with an additional agent (sulbactam) to protect it from the effects of the beta-lactamase.
- In enterococcal infections we use aminoglycosides in combination with ampicillin or amoxicillin - gentamycin + ampicillin (common type of regimen for complicated infections).
What are the pharmacological features of ureidopenicillin?
- Pipercillin is an intensive care unit kind of drug.
- Broad-spectrum agent
- Very good gram-negative coverage but it also has some good gram-positive coverage as well.
- Pair this with a beta-lactamase inhibitor.
- Pipercillin + Tazobactam
- Pseudomonas seen in wet infections
- Intubated patients in ICU - complicated infections involving areas like a wet mucosa = wet infection - pipercillin is used to treat it.
- Lacks strong activity against staph aureus
Indications:
- pipercillin tazobactam used in neutropenic sepsis
How are cephalosporins classified?
- Cephalosporins are divided into generations
- 1st generation (fal,fad,faz)
- 2nd generation (fam,fur,fac)
- 3rd generation
- 4th generation (cefepime)
- 5th generation
- Unclassified
What are the 1st generation cephalosporins?
- Cefazolin, Cefalotin, Cefalexin, Cefadroxil
- Cefazolin - excellent coverage against gram + organisms.
- Used in surgical infections, for skin infections,
- Not effective against gram negative bacteria - not good for urinary tract infection.
What is the mechanism of action of 2nd generation Cephalosporins?
- Cefuroxime, Cefaclor, Cefamandole , Cefotetan, Cefoxitina
- Effective against gram - bacteria
What are the uses of 2nd gen cephalosporins?
- Effective against gram - bacteria.
- Used in respiratory infections.
- Cefuroxime works against gram-bacteria such as Haemophilus Influenzae.
What are the mechanisms of action of 3rd gen cephalosporins?
- Ceftriaxone, Cefoperazone, Cefotaxime, Ceftazidime, Ceftributen, Cefixime, cefpodoxime, cefoperazone + sulbactam
- Effective against gram - bacteria, less effective against gram + bacteria
- some like Cefotaxime will work against organisms that are resistant to penicillins.
- We only use these types in serious infections.
What is the mechanism of action and uses of 4th gen cephalosporins?
- Cefepime
- Zwitterions - 2 different charges on the same molecule.
- More resistant to beta-lactamase producing organisms
What is the pharmacology of Penems?
Penems - can be sulfapenems and carbapenems
- Sulfapenems - e.g., Faropenem
- Orally active unsaturated b-lactam antibiotic.
- Resistant to many different forms of extended-spectrum beta-lactamases.
- better chemical stability than most agents.
- Effective in TB
- Carbapenems = Imipenem, Meropenem
- Imipenem - powerful
- Contains b-lactam ring but has low susceptibility to penicillinase.
- It is susceptible to a kidney enzyme called dehydropeptidase so it must be administered along with an inhibitor called cilastatin.
- wide-ranging agent = used against all kinds of organisms
- gram + cocci, gram - rods, anaerobic infections, used against pseudomonas and Acinetobacter species.
-Pneumosepsis, bleeding gut
What are the structure, uses, and spectrum of activity of imipenem, doripenem, and meropenem?
- Carbapenems = Imipenem, Meropenem
- Imipenem - powerful
- Contains b-lactam ring but has low susceptibility to penicillinase.
- It is susceptible to a kidney enzyme called dehydropeptidase so it must be administered along with an inhibitor called cilastatin.
- wide-ranging agent = used against all kinds of organisms
- gram + cocci, gram - rods, anaerobic infections, used against pseudomonas and Acinetobacter species.
-Pneumosepsis, bleeding gut
What are the pharmacological features and indications of vancomycin?
- Vancomycin = bacterial glycoprotein - binds to peptidoglycan in the cell wall.
- Binds to alanine terminal - stops cell wall synthesis.
- downside = if cell wall has an altered alanine terminal on its NAG, it will not allow vancomycin to bind - decreased affinity to vancomycin = Vancomycin-resistant.
- Vancomycin is limited to serious infections only.
- Powerful agent - has some side effects :
- Large molecule - doesn’t cross BBB.
- Often used intrathecally in serious spinal infection (severe spinal or central meningitis)
- Can use the drug orally in certain conditions - doesn’t pass the gut barrier (stays in the gut) - used in gut infections - Enterococcus mediated infections.
- Vancomycin-Resistant cocci (VRE)
What are the toxicity issues of Vancomycin?
- Red man syndrome
- Severe cutaneous reaction where you have tremendous flushing (bright red) due to histamine release.
- Other side effects include:
phlebitis, ototoxicity, nephrotoxicity.
What is the structure and indications of Teicoplanin?
- Has a complicated structure
- Used in prophylaxis (not really used in a lot of clinical practice)
- used to treat MRSA and methicillin-resistant enterococcus faecalis.
- Also used in the treatment of pseudomembranous colitis and in clostridium difficile diarrhea.
What is Bacitracin?
- Intra-cellular agent
- Used as a prophylactic measurement in wards
- It is a bacterophenol inhibitor ( aka dolichol-11. It is a lipid in the cell wall of the bacteria. By inhibiting the bacterophenol pathway, you can inhibit the growth of the new bacteria)
- Used in the topical treatment of certain types of infections and in decontamination syndromes.
- Used in staph colonization in the skin and used in particularly bad superficial infections.
- When bacitracin is taken Intravenously or parenterally it can cause nephrotoxicity
- Prefer to use it on the surface of the skin
What are the bacterial protein synthesis inhibitors?
Classification:
1. Narrow spectrum agents that act on the 50S subunit - Linezolid, lincosamides
- Broad-spectrum agents that act on the 50S subunit- macrolides, chloramphenicol
- Broad-spectrum agents that act on 30S subunit -tetracyclines, aminoglycosides
What is a post-antibiotic effect?
- an anti-ineffective effect that lasts after the elimination of the antibiotic from the body
- long-lasting effect on the 50 or 30S subunits
What is the difference between a bactericidal and a bacteriostatic agent?
- Bactericidal means that it kills bacteria.
- Bacteriostatic means it slows down the replication but doesn’t kill the bacteria.
What is a 70S ribosomal mRNA agent?
- is composed of the 50S and 30S subunits
What are time-dependent and concentration-dependent agents?
Drugs that have increased killing activity with time = time-dependent agents
Increased killing activity with concentration = concentration-dependent agents
What are the structure of the 70S ribosomal unit and the associated mechanism of action of the bacterial protein synthesis inhibitors?
- 70S subunits are made of 50S and 30S units.
- the 50S on top and 30S at the bottom
- 30S is smaller and flatter
- 50S is bigger and puffier.
- charged tRNA brings the 7th amino acid and sits on top of the mRNA
- the mRNA is the base that determines what the coding is going to be for the protein.
- There’s a specific code that is coded by mRNA - it tells the tRNA which amino acids to bring in.
- as it goes through the 70S subunit, you get a different coding.
- a very specific sequence is formed = protein
- the uncharged tRNA is discarded and eventually becomes charged again and grabs another amino acid.
- The protein synthesis inhibitor drugs act on different points of the 70S ribosomal unit.
- C = Chloramphenicol blocks the transpeptidation - which is the joining of the two amino acids
- M = Macrolides also block the transpeptidation but at another site
- T = Tetracyclines bind to the 30S subunit and prevent binding of incoming transfer-RNA
- L = Linezolid has a unique site that inhibits initiation complex formation
- S = Streptogramins block exit ports for polypeptides so new ones can’t come in and overall translation is inhibited.
What are the uses, mechanisms of action, and toxicity of linezolid?
- Used in drug-resistant gram + cocci infections - MRSA, Penicillin-resistant strep-pneumo, and Vancomycin-resistant enterococcus.
- They bind to the 50S ribosomal subunit - inhibit initiation complex formation
- They are reserved for multi-drug resistant agents
- Toxicity: thrombocytopenia and neutropenia
- Serotonin syndrome - IV drug users tend to be on antidepressants
What is the structure, uses, mechanism of action, and toxicity of chloramphenicol?
- Has a very distinct structure
- No other drugs in its class
- has a wide distribution
- Non-polar molecule - crosses the BBB and the blood-uterine barrier
- Inactivated in the liver and it has minimal renal excretion.
- It is bacteriostatic against Haemophilus, Neisseria, Bacteroides species.
- Also used as a backup drug against Salmonella, pneumococcal disease and meningococcus.
- Can be used topically as well
- Resistance is through a plasmid-mediated formation of an enzyme called acetyl-transferase, that inactivates the drug.
- Toxicity -for topical use is direct irritation, infections like candidiasis (chloramphenicol doesn’t work against candida)
- aplastic anaemia is a potential side effect
- Grey Baby Syndrome - anaemia, cyanosis, cardiovascular collapse - seen in neonates (especially those who are premature) - may be due to deficiency in the hepatic glucuronyl transferase.
What is the mechanism of action of macrolides?
- Important - used all the time
- Used in Respiratory infections
Block the 50S unit from translation
- Rapidly eliminated from the body
What is the pharmacology of erythromycin?
- rapidly eliminated from the body
- Broad-spectrum antibiotics
- Used in respiratory infections
What is the pharmacology of clarithromycin?
- rapidly eliminated from the body
- broad-spectrum antibiotics
- used in respiratory infections
What is the pharmacology of azithromycin?
- Concentrates in the macrophages and other tissue - eliminated quite slowly
- effective in gonorrhea
Explain the mechanism and patterns of resistance to macrolide antibiotics.
- 1)Ejector pump mechanisms - bacteria will pump out the active drug out of the cell
- 2) Changing the binding site of the macrolide (by adding a methyl group)
- 100% cross-resistance between one macrolide and another
- partial cross-resistance with other drugs like streptomycin and streptogramins
- 3) Production of drug esterases - seen in the resistance of Enterobacteriaceae
- 100% cross-resistant pattern
What are the structure, mechanism of action, and uses of important ketolides (telithromycin)?
- structurally similar to the macrolides
- Same mechanism of action as macrolides
- Macrolide resistant strains are susceptible to ketolides
- Increased affinity to the ribosomes with ketolides than with macrolides
- poorly ejected through ejector pores - good choice
What is the mechanism of action and spectrum of activity of tetracycline?
- Broad-spectrum bacteriostatic medications
- commonly used orally
- work for both gram + and - bacteria, may work on some protozoan as well
What is the mechanism of action and spectrum of activity of doxycycline, minocycline, demeclocycline, and tigecycline?
- prototypical drug in tetracycline family - doxycycline or tetracycline
- very long duration of activity
- used in long-term acne treatment
- relatively non-toxic
- also used in bronchitis, bronchitis prevention, and leptospirosis
What are the uses of tetracyclines?
work for both gram + and - bacteria, may work on some protozoan as well
What is the development process of resistance to tetracyclines?
1) Efflux pump - seen in proteus and pseudomonas species
- Both multi-drug pumps
2) Ribosomal protection proteins - prevent binding
- like a shield around the ribosome
What are the 7 adverse effects of tetracyclines?
- GI symptoms - common but minor side effects
- rare episodes of life-threatening enterocolitis
- Bacterial overgrowth syndrome ( elimination of normal gut flora) and candidiasis
- Fetal exposure = dental enamel dysplasia
- hepatotoxicity
- dizziness, vertigo (mainly with doxycycline)
What is the mechanism of action, pharmacokinetics, and indications of aminoglycosides?
- Aminoglycoside antibiotics are incorporated into the bacteria through an oxygen-dependent process
- Don’t work on anaerobic bacteria
- Binds to the 30S subunit of the ribosome - interfere with protein synthesis by preventing the initiation complex from forming.
- Can also cause misread errors on the messenger RNA - mRNA now prone to make mistakes
- Cause some inhibition of translocation
- Aminoglycosides are concentration-dependent antibiotics
- work better when given intermittently
- Very strong post-antibiotic activity
- AMinoglycosides are really polar - given IVor IM, Not given orally
- Excreted through the kidneys - renal function determines the dose
- Do not cross the BBB
- Work better as large single doses than as multi doses
What is the spectrum of activity of aminoglycosides?
- Broad-spectrum agents cover many classes of bacteria
- E.coli, H.infuenzae, Klebsiella, Moraxella species, Proteus species, Serratia species, Shigella species
- They are almost always used in combination with Penicillins
- Pairing: Ampicillin with Gentamicin = broad spectrum
Piperacillin with Tobramycin = gram-negative diseases - Combinations work so well due to antibacterial synergy
- Ampicillin and piperacillin open up the cell wall
- Allows gentamicin and tobramycin to get into the cell
What are 5 commonly used aminoglycosides?
Gentamicin - prototypical drug
Tobramycin - against Pseudomonas, used more in gram-negative diseases
Streptomycin
Describe the ototoxicity and nephrotoxicity caused by aminoglycosides?
Ototoxicity - auditory symptoms = amikacin, vestibular symptoms = gentamycin, and tobramycin
Neuromuscular blockade
What are the other toxicities of aminoglycosides?
- Neuromuscular blockade disorder
- Skin reactions
What are antimetabolites?
- agents that act on DNA and folic acid production within cells
- Sulfonamides
- Trimethoprim
- Fluoroquinolones
What is the structure and mechanism of action of sulfonamides?
- Weak acids
- Structurally similar to a chemical called para-aminobenzoic acid (PABA)
- Bacteriostsatic inhibitors of folic acid synthesis
- Mammals acquire folic acid from diet, whereas bacteria have to manufacture it.
- Most of the drug will be excreted in the urine.
what is the mechanism of action of trimethoprim, sulfamethoxazole-trimethoprim, and their toxicity?
- Trimethoprim is usually added to the sulfonamides - these are selective inhibitors of dihydrofolate acid reductase
- It inhibits the bacterial form and prevents the formation of tetrahydrofolate.
- Bacterial tetrahydrofolate reductase is five times more sensitive to trimethoprim than the human version of the enzyme.
- Sulfamethoxazole and trimethoprim are combined to create an agent called Septra (SMP/TMP)
- Bacterial synergy is obtained - acting on two different levels of the folic acid production pathway
- Sulfonamides work on a particular enzyme at the top of the pathway and trimethoprim works on dihydrofolic acid reductase in the middle of the structural pathway.
- These drugs are concentrated in the bladder = particularly effective in bladder infections
- also use this agent in pneumocystis carnii infections and toxoplasmosis infections in HIV patients
- Toxicity:
- Hypersensitivity reactions
- Cross allergies with other agents - if a patient is allergic to Septra they may also be allergic to ACE inhibitors and even ARBs (but this is rare)
- Nausea, vomiting, diarrhea
- Rare episodes of granulocytopenia and thrombocytopenia
- Hemolysis (in patients with G6PD deficiency)
What are the 1st, 2nd, and 3rd generations of fluoroquinolones?
1st generation: Norfloxacin
2nd generation: Ciprofloxacin, Ofloxacin
3rd generation: Moxifloxacin, levofloxacin
- 1st gen - norfloxacin not clinically used anymore due to high toxicity and lack of efficacy.
- ciprofloxacin is the prototypical drug - best-known fluoroquinolone
- has more gram - activity, especially against gonococcus
- quite effective against atypical bacteria like M.Pneumoniae and C.pneumoniae
- 3rd gen include levofloxacin - much less active against gram - bacteria, much greater activity against gran-positive cocci and MRSA and anaerobes.
- Used in pneumonia
- good oral availability
- Eliminated through the kidney - be aware of renal function
- excretion blocked by probenecid
- Moxifloxacin has hepatic clearance and may be used in renal failure
What is the mechanism of action and 3 mechanisms of resistance to fluoroquinolones?
Mechanism of action of fluoroquinolones:
- They interfere with DNA topoisomerase II.
- DNA isomerase takes the helical twisted 3D structure and untwists it - access the genetic information inside
- By interfering with it, we interfere with the first step of DNA transcription.
- Topoisomerase II is inhibited in the gram - organisms and type IV is inhibited in the gram-positive organisms
- Bactericidal agents
- have a post-antibiotic effect
Bacterial resistance:
- Change their porins - reduce the intracellular accumulation of the drug
- Efflux mechanisms in M.tuberculosis, S.aureus, and S.Pneumoniae.
- Changes in the sensitivity of the target enzymes - sometimes DNA topoisomerase will have a point mutation that prevents the fluoroquinolone from doing its job.
What are the 8 toxic effects of fluoroquinolones and its contraindications?
- gastrointestinal distress
- skin rash
- headache
- insomnia
- phototoxicity
- tendinitis and tendon rupture
- Arthropathy - in growing age
- prolonged QT interval
- drug not given in pregnancy or in children who are growing - arthropathy = damage their cartilage
What are antimycobacterial agents?
Antimycobacterial agents are agents used to treat leprosy, tuberculosis, and atypical mycobacterium.
What are the drugs used to treat Mycobacterium tuberculosis?
- can be bactericidal or bacteriostatic
- 3 to 4 drug regimens required
- use DOT regimen (Directly observed therapy)
What are the three classes of drugs used to treat Mycobacterium tuberculosis?
- First line agents
- Other TB agents
- New agents
What are the 1st line drugs used to treat M.tuberculosis?
RIPE
- Isoniazide
- Rifampicin
- Ethambutol
- Pyrazinamide
What is the chemical structure, and mechanism of action of isoniazid?
- Similar to pyridoxine or vitamin B6
- it is a prodrug - bacteria converts it into the active drug
- Inhibit cell wall production of the Mycobacterium species.
- acts like penicillin - ‘ penicillin of the anti-TB drugs’
- Bactericidal
- Metabolism -
needs to be acetylated into its active form
Resistance:
- can be rapid if not used in combination with other medications
- use multi-drug regimens
What are the 5 toxic effects of isoniazid and their clinical manifestations?
Toxicity is very common with this drug
-neurotoxicity = restless leg, peripheral neuritis, paresthesia -> can be treated with vitamin B6
-hepatotoxicity -> hepatitis, abnormal liver function tests, jaundice, hepatomegaly
- Psychiatric problems -> suicidal risks, depression, poor memory, poor mental function, poor mental concentration
- vitamin B6 related problems and G6PD issues -> vitamin B6 depletion (suicide risk, poor memory), needed for peripheral neurological function
glucose-6-phosphate deficiency (enzymopathy) -> isoniazid can trigger hemolysis in these patients
- patients with non-spherotic hemolytic anemia are more prone to this problem with isoniazid
What is the mechanism of action and development of resistance to rifampin and rifampicin?
- an inhibitor of DNA-dependent RNA
- prototypical Cytochrome inducer
- important to give multi-drug therapy = resistance
- Development of resistance:
- Polymerase doesn’t bind to the drug
- Changing in the drug binding pharmacokinetics of the polymerase and the rifampin
Toxicity:
- associated with light chain proteinuria
- skin rash
- thrombocytopenia
- Nephritis
- Liver dysfunction
What is the mechanism of action of ethambutol and the 3 toxic effects?
- Bacteriostatic drug (stops division and growth of this bacteria)
- cell wall production inhibition
- Excreted in the urine
Toxicity:
- Neurological - visual disturbances (red/green colour blindness)
- Optic neuritis
- retinal damage
- hyperuricemia
- peripheral neuritis
What are the mechanism of action, 5 toxic effects, and development of resistance to pyrazinamide?
- always given in combination with the other drugs
- it is well absorbed
- crosses inflamed tissues well
- excreted in the urine
- removed by hemodialysis
- renally excreted drug - half-life increased in patients with kidney failure
- liver failure can also increase its half-life - hepatitis
Mechanism of action:
- inside the mycobacterium, there is an enzyme that converts pyrazinamide into pyrazinoic acid.
- At low pH (5/6), pyrazinoic acid leaks out and gets protonated.
- crosses the membrane and goes back into the bacterium at this acid pH.
- the more acidic the tissue, the more concentrated the intracellular amount of pyrazinoic acid becomes.
- the agent becomes more effective against bacteria that are existing in an acidic environment
Toxicity:
- Joint complaints - ankle and toe pains -> migratory
- asymptomatic hyperuricemia
- Myalgias
- rashes
- medication not suitable in pregnancies
- interfering with the normal metabolism of a growing fetus
- crosses barriers so well - can cause fetal abnormalities
Resistance:
- if the bacteria has a change in the particular gene, there are changes in the enzymatic activity within the bacterial cell.
- this reduces the conversion of pyrazinamide into pyrazinoic acid - don’t have as much active drug.
What are the guidelines for TB treatment?
- first 2 months patients with adult TB (but don’t have HIV) - isoniazid, rifampin, pyrazinamide, and ethambutol
- following 4 months:
isoniazid and rifampin
Adult with TB and HIV:
- ART (antiretroviral therapy) and isoniazid
- following 4 months - ART, isoniazid, and rifampin
MOthers who are pregnant:
- isoniazid, rifampin, and ethambutol - pyrazinamide in NOT given
- in final 4 months - isoniazid and rifampin
