Lecture 15 - Antibiotics & Antituberculars Flashcards
When are antibiotics needed for sinus infections?
- Thick or green mucus doesn’t indicate a sinus infection
- Needed for some lasting over 7 days or severe infections
When are antibiotics needed for a sore throat?
Most often caused by viruses, but strep throat needs antibiotics
Do colds respond to antibiotics?
No b/c caused by viruses
What normally causes symptoms of upper respiratory tract infections?
Toxins released by pathogens and the inflammatory response to fight the infection
Majority of infections are caused by ____
Viruses
When should antibiotics be recommended for upper respiratory tract infections?
Confirmation of significant bacterial cultures in sputum
Which diseases pose a serious threat due to antibiotic resistance?
- Carbopenem resistant enteritis
- Vancomycin resistant enterococci
- Tuberculosis
- Staph aureus skin infections
- C. difficile food poisoning
- Gonorrhea
Which organism is resistant to almost all antibiotics?
Enterobacter
What is the current recommended treatment for gonorrhea?
Combination therapy of injectable cephalosporin and oral azithromycin
Which antibiotic is critically important for treating salmonella and E. coli infections?
Ampicillin
What are the causes of antibiotic resistance?
- Overuse/abuse in humans
- Overuse/abuse in non-humans
- Developing countries
- World travel
- Critically ill px
- Industry advertising/promoting
What increases the risk of antibiotic resistance infections?
- Patient-related factors (increasing age and severity of underlying disease)
- Hospital-related factors (increased length of stay, ICU, proximity to infected px)
- Treatment-related factors (prolonged use of broad spectrum antibiotics, contaminated devices)
How do bacteria become antibiotic resistant?
- Spontaneous mutation
- Acquisition of new DNA
How can bacteria acquire new DNA?
- DNA comes from environment after being released by another cell
- Virus transfers DNA btwn bacteria
- Contact btwn cells as DNA crosses from donor to recipient
What are the possible mechanisms of acquired antibiotic resistance?
- Alteration in target site
- Decreased uptake
What do beta-lactamases do?
Inactivate beta-lactam drugs through cleavage of their central ring structure (beta-lactam)
What is clavulanic acid?
Inhibitor of beta-lactamases
How can you overcome beta-lactamases?
- Clavulanic acid
- Combine penicillin w/ other antibiotic (ex: penicillin and clavulanic acid)
- Add bulkier side chains to the basic penicillin structure, hindering enzyme access to the beta-lactam ring
What causes tetracycline resistance?
Decreased uptake or increased extrusion
What is the most common tetracycline resistance mechanism? What are some other mechanisms?
- Mg2+-dependent active efflux mediated by the TetA gene
- Other – bacterial enzymes that inactivate tetracyclines; expression of bacterial proteins that inhibit binding of tetracycline to ribosome
How can bacteria become resistant to aminoglycosides?
- Decreased uptake of drug (absence of porin channels or oxygen-dependent transport system)
- Enzymes inactivate aminoglycosides
Which enzyme inactivate aminoglycosides?
- Acetyltransferases
- Nucleotidyltransferases
- Phosphotransferases
How can bacteria become resistant to macrolides?
- Decreased uptake of drug
- Increased efflux of drug
- Reduced affinity for 50S ribosome
- Enzyme inactivates macrolides (erythromycin esterase)
Is cross-resistance common for macrolides?
Yes
Is cross-resistance common for aminoglycosides?
No
How can bacteria become resistant to fluoroquinolones?
- Alter DNA gyrase
- Decreased uptake
- Increased efflux
Is cross-resistance among quinolones common?
Yes
Bacteria that obtain ____ from the environment are resistant to sulfonamides
Folate
How can a bacteria become resistant to sulfonamides?
Altered dihydropteroate synthase
How can a bacteria become resistant to trimethoprim?
Altered dihydrofolate reductase
Why is cotrimoxazole resistance rare?
Bacteria must have simultaneous resistance to both sulfonamide and trimethoprim drug
What are some potential solutions to infections caused by resistant superbugs?
- Knowledge about resistant infections
- Infection control
- Vaccination
- Appropriate antibiotic use
- Discover and develop new antibiotics
- When treating, treat as early as possible and kill the pathogen
How is tuberculosis acquired?
Person-to-person transmission of airborne droplets of organisms from an active case to a susceptible host
What is the physical evidence of tuberculosis?
A tiny, fibrocalcific nodule at the site of infection (may or may not be present)
What is latent tuberculosis?
Positive tuberculin skin test but no disease
What is active tuberculosis?
Clinical signs and symptoms w/ radiographic and bacteriological evidence
What are signs and symptoms of tuberculosis?
- Pulmonary cavitation
- Myobacteria dissemination
- Presence of bacteria in sputum
- Malaise, anorexia, weight loss, fever
- Increased sputum
- Extrapulmonary sx (liver, bone marrow, spleen, kidneys, fallopian tubes)
Is M. tuberculosis considered fast or slow growing?
Slow
What is M. tuberculosis resistant to?
Drying, most antibiotics, and host killing
M. tuberculosis has ____ survival
Intracellular
What is the most important portion of M. tuberculosis for resistance?
Cell envelope
What occurs in the primary infection of tuberculosis?
- Most often asymptomatic
- Regional lymph node spread and bacteremia
- Infection is controlled w/ development of cellular immunity
- Positive TST
What effect does the tuberculosis disease have on the body?
Lowered immune defenses and possible re-infection
Where does tuberculosis reactivation most often occur?
In lungs; can occur in lymph nodes, pleural space, kidneys, gut, and CNS
If a px has ____ TB they will be infectious
Pulmonary
Which px are more likely to have reactivated TB?
Px w/ weakened immune systems
What is TB therapy based on?
Stage (latent or active)
What are the first line drugs for TB?
- Isoniazid
- Rifampin
- Pyrazinamide
- Ethambutol
Where is mycolic acid found?
Mycobacteria cell wall
What are mycolic acids?
Beta-hydroxy fatty acids w/ a long alkyl side chain
___ is the most important drug for TB tx and prophylaxis
Isoniazid
What is the mechanism of isoniazid?
Inhibits mycolic acid synthetase => mycobacterial cell death
What are adverse effects of isoniazid?
- Hepatic toxicity
- Peripheral neuropathy
- Rash
Is isoniazid bactericidal or bacteriostatic?
Bactericidal to actively growing bacilli
What is significant about isoniazid?
A prodrug that is converted to active form by bacterial catalase peroxidase
What is rifampin effective against?
Several gram positive and gram negative as well as M. tuberculosis
What is the mechanism of rifampin?
Inhibits DNA-dependent RNA polymerase => inhibition of RNA synthesis and mycobacterial cell death
Does rifampin bind mammalian RNA polymerase?
No
What is pyrazinamide converted to and by which enzyme?
Converted to active pyrazinoic acid by pyrazinamidase
What is the mechanism of pyrazinamide?
Inhibits mycolic acid synthesis => mycobacterial cell death
What is pyrazinamide effective against?
Dormant and semi-dormant mycobacteria is acidic environments
What is the mechanism of ethambutol?
Inhibits arabinosyl transferase => inhibition of arabinogalactan chain elongation, inhibition of mycobacterial cell wall synthesis, and reduction of mycobacterial cell growth
Is ethambutol bacteriostatic or bactericidal?
Bacteriostatic
What is isoniazid used for in the tx of TB?
- Bactericidal in extracellular areas w/ high oxygen concentration
- Important at preventing resistance by killing off rapidly growing bacilli
What is rifampin used for in the tx of TB?
Only drug that is bactericidal in fibrotic areas
What would be needed in rifampin wasn’t used?
18 months of tx
Which drug is essential is more advanced stages of TB?
Rifampin
What is pyrazinamide used for in the tx of TB?
Important in sterilizing semi-dormant bacteria
When does pyrazinamide lose its activity?
As inflammation resolves
What is ethambutol used for in the tx of TB?
Primarily used to prevent rifampin resistance when primary isoniazid resistance may be present
When is ethambutol not used?
In renal failure and in children
What is the goal of the intensive phase of TB tx?
Quickly kill the rapidly dividing organism to control disease and render px non-infectious and prevent emergence of drug resistance
What is the goal of the continuation phase of TB tx?
Sterilize lungs by killing dormant and semi-dormant organisms to prevent relapse
How long does each phase of TB tx last?
- Intensive phase = 0-8 weeks
- Continuation phase = 2-6 months
What drugs does the intensive phase include?
- 4 drugs for 8 weeks
- Normally 7 days a week, but minimum 5 days a week
- Isoniazid, rifampin, pyrazinamide, and ethambutol (can be dropped if organism pansensitive)
What drugs does the continuation phase include?
2 times/week isoniazid and rifampin
What is the tx for latent tuberculosis?
Isoniazid daily for 9 months or rifampin daily for 4 months
What is multi-drug resistant TB?
Resistant to rifampin and isoniazid and/or other drug
When does multi-drug resistant TB most often occur?
In px w/ weakened immune systems (patients w/ HIV or immunosuppressed px)
What is extensively-drug resistant TB?
- Resistant to rifampin and isoniazid
- Resistant to any quinolone
- Resistant to any injectable 2nd line agent
Why is extensively-drug resistant TB so bad?
Makes TB essentially untreatable
How can a bacteria become rifampin resistant?
Alteration in DNA-dependent RNA polymerase
What causes isoniazid resistance?
Decreased drug uptake
What are the possible treatments when a px is isoniazid resistant?
- Rifampin, pyrazinamide and ethambutol for 6-9 months
- Rifampin, pyrazinamide, and streptokinase for 6-9 months
- Rifampin and ethambutol for 12 months
What causes pyrazinamide resistance?
Loss of pyrazinamidase, causing decreased conversion to pyrazinoic acid, so mycolic acid synthesis occurs and mycobacterial cells survive
What causes ethambutol resistance?
Mutations in bacterial arabinosyltransferase gene, causing arabinogalactan elongation to continue, allowing mycolic acid synthesis and mycobacterial cells survive
What is the tx for MDR-TB?
- Combinations of 5-7 drugs:
- Isoniazid, rifampin, pyrazinamide, ethambutol
- Protein synthesis inhibitors (cycloserine, capreomycin, kanamycin)
- DNA synthesis inhibitor (fluoroquinolones, aminosalicylic acid)
- Metabolite synthesis inhibitor (ethionamide)
What is the mechanism of bedaquiline?
Inhibits mycobacterium ATP synthase
What is bedaquiline used for?
MDR-TB when in combination w/ rifampin and pyrazinamide
Is bedaquiline useful against latent infections?
Unknown
