Antimycobacterials Flashcards
Mycobacterium has its own family, Mycobacteriaceae. Mycobacteria includes pathogens known to cause serious diseases in mammals, including TB and Leprosy. Tx of infections caused by mycobacteria is complicated by numerous factors, including:
- Limited information about the mechanisms of antimycobacterial drug actions
- Mycobacteria are intrinsically resistant to most antimicrobials
- Intracellular location of mycobacteria
- Chronic nature of mycobacterial disease, associated with chronic use and therefore toxicities
- Patient compliance
Chemotherapy of mycobacterial infections almost always is associated with what?
Combination therapy
–delays the emergency of resistance and enhance antimycobacterial efficacy
First mycobacterium we will focus on is Tuberculosis caused by Mycobacterium Tuberculosis. What are some features?
Lungs = major site of infection
Spread through air when ppl who have an active infection cough, sneeze or transmit saliva through air
Most infections are asymptomatic and latent and about 1 in 10 latent infections progress to active disease.
Describe mycobacterium tuberculosis in terms of organism
Small, aerobic, non motile bacteria
Divides slowly (requires months of tx)
Have a cell wall so gram +
Now going into the treatment of TB, this involves use of anti-mycobacterial drugs. Effective tx is very difficult due to the unusual structure and chemical composition of the cell wall. How is latent vs active TB treated?
Latent TB: single drug
Active TB: tx with combination therapy
5 to 10% of infected persons who do not receive tx for latent TB will develop TB disease
Persons at high risk for developing TB disease fall into what two categories?
- Persons who have been recently infection with TB
2. Persons with medical conditions that weaken the immune system
Persons who have been recently infected with TB include?
- Close contacts of a person w/infectious TB
- Persons who have immigrated from area w/high TB
- Children less than 5 who have a + TB test
- Groups with high rates of TB transmission (homeless HIV)
- Persons who work or reside with people who are at high risk for TB in facilities or institutions (hospitals, homeless shelters, jails)
Persons with medical conditions that weaken the immune system include?
- Babies and young children often have weak immune systems
- HIV
- Substance abuse
- Silicosis
- DM
- Severe kidney disease
- Low body weight
- Organ transplants
- Head and neck cancer
- Medical tx with steroids
- specialized tx for RA and Crohns Disease
What are the goals of TB therapy?
To kill mycobacteria
To prevent emergency of drug resistance
To eliminate persistent mycobacteria from the host’s tissues to prevent relapse
What are the 1st and 2nd line drugs for TB?
1st Line: Isoniazid, Rifamycins, Ethambutol, Pyrazinamide
2nd Line: Streptomycin, Ethionamide, Levofloxacin, Amikacin
–initiation of therapy usually involves three or four drug combo regiment depending on the known or anticipated rate of resistance to isoniazid
What is Directly Observed Therapy (DOT)?
DOT: regimens are recommended in non compliant patients and in drug resistant TB
What are the standard regiments for empiric tx of pulmonary TB?
Initial Phase:
Drugs: Isoniazid, Rifampin, Pyrazinamide and Ethambutol (duration 8 weeks)
or
Drugs: Isoniazid, Rifampin, Ethambutol
(duration 8 weeks)
Continuation Phase:
Drugs: Isoniazid and Rifampin (duration: 18 weeks)
or
Drugs: Isoniazid and Rifampin (duration: 31 weeks)
–depends on drug resistance profile and immune status of patient
What are the drug regiments for tx of latent TB?
Isoniazid: 6-9 months
Rifampin: 4 months
Lets discuss each individual drugs. First is Isoniazid. What is the MOA?
Analogue of Pyridoxine (Vit B6)
–pro drug activated by mycobacterial catalase peroxidase (KatG)
–active form of drug targets enzymes that are involved in mycolic acid synthesis (component of cell wall)
–enzymes: enoyl acyl carrier protein reductase (AcpM) and B-ketoacyl-ACP synthase (KasA)
Bactericidial: actively growing organisms
Resistance is a big problem and emerges rapidly if isoniazid is used alone. Resistance occurs due to chromosomal mutations resulting in?
- Deletion of KatG
- Changes in binding sites on acyl carrier protein reductase
- Overexpression of the acyl carrier protein reductase
What is the spectrum of activity and clinical applications?
Single most important drug used in TB
For latent infections given as a single drug
What are the pharmacokinetics of isoniazid?
Orally, IV or iM
Liver metabolism via acetylation
Fast acetylators is 60-90 minutes (higher dosage for equal therapeutic effects)
Slow acetylators is 3-4 hours
What are adverse effects and contraindications for isoniazid?
Neurotoxic effects: corrected by supplementing with pyridoxine
Hepatotoxicity
CYP450 inhibitor: increase plasma levels of drugs
Lupus like syndrome: anti nuclear antibodies
Contraindications:
Safe in pregos but risk of hepatitis so need to give pyridoxine to all prego women
Next drug in the treatment of TB is Rifamycins (rifampin and rifabutin). What is the MOA and resistance?
Bactericidal against intracellular and extracellular mycobacteria and many other organisms
–block transcription by binding to the beta subunit of bacterial DNA dependent RNA polymerase = inhibition of RNA synthesis
Resistance:
point mutations in rpoB (gene for beta subunit of RNA polymerase) = decrease affinity for drug
decreased permeability
What is the spectrum of activity and clinical applications of Rifamycin?
Combo therapy for TB
Tx of latent infection :given as sole drug in isoniazid intolerant patients
In leprosy: given monthly delays the emergency of resistance to dapsone
Used for prophylaxis of meningitis in exposed individuals and also in combo with vancomycin for MRSA and PRSP
Rifabutin is preferred in tx of TB patient with HIV
What are the pharmacokinetics of Rifamycin?
Orally or parenterally
Well distributed (including CSF)
Enterohepatic cycling and both parent drug and metabolites (orange in color) are excreted in feces
Inducer of Cytochrom P450 enzymes and increases the elimination of many drugs (rifampin stronger induced)
what are adverse effects of Rifamycin as well as pregnancy use?
AE:
Light chain proteinuria
GI distress
CYP450 inducer
Orange Colored Secretions: urine, tears Sweat
Pregnancy: Rifampin is safe but not enough data on rifabutin
Next drug for TB is Ethambutol, what is the MOA and resistance?
Inhibits arabinosyl transferases (encoded by emb gene) (involved in the synthesis of mycobacterial cell wall components)
Resistance strains emerge due to mutations in the emb gene
What is the spectrum of activity and clinical applications of Ethambutol?
Used in combo for tx of TB ( M. Tuberculosis and M. Kansaii)
