Antimicrobial part 3 Flashcards
Mycobacteria are rod-shaped background
• aerobic bacteria that
grow slowly—their cell walls contain mycolic acids
•These pathogens produce lipophilic cell walls that
stain poorly with a Gram stain—once stained, these
bacilli do not lose color when made acidic—thus the
name Acid Fast Bacilli
•These infections cause slow-growing granulomatous
lesions—and can occur anywhere in the body
Drugs used for Myobacteria
Ethambutol Isoniazid [INH]—prototype drug Pyrazinamide Rifabutin Rifampin Rifapentine
Second line drugs for TB
Aminosalicylic acid Bedaquiline Capreomycin Cycloserine Ethionamide Aminoglycosides/Fluroquinolones/Macrolides
Chemo for TB
-M. tuberculosis is slow growing and requires treatment for months –years -LTBI can be treated for 9 months with INH or 12 once a week higher doses of INH + Rifapentine -Active TB has to be treated with several drugs for several months -Multi-drug resistant TB is typically treated for 2 years
EXTREMELY DRUG
RESISTANT [XDR]
TUBERCULOSIS
• This is a bacilli that is resistant to INH and Rifampin and is resistant to any fluoroquinolone and at least 1 of 3 injectable 2nd line agents— Amikacin, Kanamycin or Capreomycin
HOW DO WE
DEAL WITH
DRUG
RESISTANCE??
Resistance in M. tuberculosis, when it is treated with one drug—so multiple drug therapy is used to suppress resistant strains
⬇️
1st line agents—INH, Rifampin, Ethambutol and Pyrazinamide are the DOC and highly efficacious with tolerable SE profilesRifabutin or Rifapentine can replace Rifampin in certain scenarios
⬇️
Active disease ALWAYS requires multiple drugs—3 or more with proven in vitro activity against the isolate
⬇️
Clinical improvement occurs quickly—weeks, but therapy is continued much longer to kill persistent organisms and
prevent relapse
⬇️
Standard therapy is INH, Rifampin, Ethambutol and Pyrazinamide for 8 weeks, then INH and Rifampin for 16
more weeks
What is 2nd line therapy for MDR-TB—disease resistant to
INH and Rifampin—
is treated with an aminoglycoside [Streptomycin, Kanamycin or Amikacin] or Capreomycin [all of these are
injectables], a quinolone [Levofloxacin or Moxifloxacin], Ethambutol and Pyrazinamide [if sensitive to these] and one or more of these—Cycloserine, Ethionamide or PAS
Isoniazid: MOA
• Prodrug—activated by mycobacterial catalase
peroxidase [KatG]
• Target enzymes that are essential for the synthesis
of mycolic acid
• Inhibiting this acid leads to destruction of the tubercular cell wall
Isoniazid: Antibacterial spectrum
• Specific to M. tuberculosis
• M. kansasii may be susceptible at higher drug
dosages
• Most nontubercular Mycobacteria are resistant to INH
• Drug works well on rapidly growing bacilli and intracellular organisms
Isoniazid: Resistance
• Resistance follows chromosomal mutations
incapable of prodrug activation
• Acyl carrier mutated proteins
• Over expression of the target enzyme InhA
• Cross resistance can occur between INH and Ethionamide
Isoniazid: Pharmacokinetics
• Readily absorbed after oral dose
• Food impairs absorption—especially high fat foods
• Drug diffuses into all body fluids, cell and caseous
materials [necrotic tissue that looks lie cheese produced
in the tubercular lesions]
• Drug levels in CSF is the same as in the serum
• INH undergoes N-acetylation and hydrolysis
• INH acetylation is genetically regulated, with fast
acetylators having a 90” serum ½ life, while slow
acetylators have a 3-4° serum ½ life
• Excretion is from glomerular filtration and secretion as
metabolites
• Slow acetylators excrete more of the parent compound
Isoniazid: ADEs
• Hepatitis
• If hepatitis is not recognized and INH is continued, death
can be the result
• Chance of hepatitis increases with age, in those who are
also on Rifampin and in those who drink ETOH daily
• Peripheral neuropathy—paresthesias of hands and
feet—due to a relative Pyridoxine deficiency—daily
supplementation with B6 is mandatory
• Convulsions—in those prone to seizures
• Rash and fever signal hypersensitivity
• INH inhibits breakdown of Carbamazepine and
Phenytoin—so SE of these drugs of these can be
amplified
RIFAMYCINS—
RIFAMPIN,
RIFABUTIN,
RIFAPENTINE
🟣Group of similar macrocyclic antibiotics that are considered 1st line for TB
🟣Rifampin has broader coverage than does INH and can be used for several bacterial infections
🟣Resistant strains can occur rapidly—so it is never given as monotherapy for TB
Rifampin: MOA
• Blocks RNA transcription by interfering with the
ß subunit of mycobacterial DNA-dependent RNA
polymerase
Rifampin: Antimicrobial spectrum
- Bactericidal for intracellular and extracellular mycobacteria, including M. tuberculosis, M. kansasii and M. avium complex [MAC]
- Effective for many Gram + and Gram –pathogens and is used to prevent meningitis in those exposed to Meningococci or H. influenzae
- Highly active against M. leprae
Rifampin: Resistance
• Caused by mutations in affinity for the bacterial DNA-dependent RNA polymerase gene for the drug
Rifampin: Pharmacokinetics
- Absorption is adequate after oral dose
- Distribution occurs in all body fluids and organs
- Concentrations attained in the CSF are variable—10 to 20 percent of blood concentrations
- Taken up by the liver and undergoes enterohepatic recycling
- Can induce liver CYP 450 enzymes and transporters—causing many drug interactions
- Rifampin undergoes autoinduction—causing shortened elimination ½ life over the 1st 2 weeks of dosing
- Elimination of the drug and its metabolites is via the bile and feces—a small amount is excreted in the urine
- Urine/feces/other secretions will become orange-red in color; contact lens will be stained
Rifampin: ADEs
- Nausea
- Vomiting
- Rash
- Hepatitis and death from liver failure [rare]
- Use cautiously in alcoholics, older patients and in those with chronic liver disease
- Modest increase in chance of liver dysfunction when given with INH and Pyrazinamide
- When dosed intermittently at high dose, flu-like syndrome can occur—fever, chills, muscle aches that can progress to ARF, hemolytic anemia and shock
Rifampin: Drug Interactions
- Induces phase I CYP 450 enzymes and phase II enzymes—it can decrease the ½ life of co-administered drugs that are metabolized by these enzymes
- HIV PIs
- Methadone
- OCP
- Prednisone
- Propranolol
- Quinidine
- Sulfonylureas
- Voriconazole
- Warfarin
- This decreased ½ life may mean increasing the dose of the other drug, switch to a drug not affected by Rifampin or change Rifampin to Rifabutin
RIFABUTIN
🟣Derivative of Rifampin—preferred to treat TB in those that are HIV + on PIs or several NNRTIs
🟣It is less potent inducer of CYP 450 enzymes, thus less drug interactions
🟣ADEs similar to Rifampin, but can also cause uveitis, hyperpigmentation and neutropenia
RIFAPENTINE
🟣Has a longer ½ life than Rifampin
🟣With INH, can be used weekly in those with LTBI and in
selected HIV negative patients with minimal pulmonary TB
PYRAZINAMIDE
🟣Synthetic, oral agent used short-term with INH, Rifampin and Ethambutol
🟣MOA is unknown
🟣Must be hydrolyzed by pyrazinamidase to pyrazinoic acid
🟣Active against TB in acidic lesions and
in macrophages
🟣Distributes throughout body, penetrates CSF
🟣Can contribute to liver dysfunction
🟣Causes uric acid retention [but gout uncommon]
🟣Most benefit occurs early in treatment—so agent is only used 8 weeks in a 24
week regimen
ETHAMBUTOL
• Bacteriostatic and first line for mycobacteria
• Inhibits arabinosyl transferase—an enzyme important for the synthesis of mycobacterial cell wall
• Used with INH, Pyrazinamide and Rifampin pending cultures and susceptibility
• Distributes well throughout body, but CSF penetration is variable—question if it is adequate for TB meningitis
•Parent drug and metabolites are excreted in the urine
•ADEs—optic neuritis—which affects vision and ability
to see red and green
• Risk increases with higher doses and in those with CKD
• Visual acuity and color discrimination should be checked
before prescribing and periodically during therapy
•Uric acid excretion is decreased—caution in those
with a history of gout
Ethambutal: ADE
Optic neuritis with blurred vision, red-green color blindess
– est baseline visual acuity and color vision; test monthly
Isoniazid: ADE
Hepatic enzyme elevation, hepatitis, peripheral neuropahy
–take baseline hepatic enzyme measurements; repeat if abnormal or pt at risk or symptomatic. Clinically significant interaction with phenytoin and carbamazepine
Pyrazinamide: ADE
Nausea, hepatitis, hyperuricemia, rash, joint ache, gout (rare)
–take baseline hepatic enzymes and uric acid measurements; repeat if abnormal or patient is at risk or symptomatic
Rifampin: ADE
Hepatitis, GI upset, rash, flu lie syndrome, significant interaction with several drugs
–take baseline hepatic enzyme measurements and CBC; repeat if abnormal or patient is at risk or symptomatic. warn pt that urine and tears may turn red-orange in color
ALTERNATIVE SECOND LINE DRUGS
These agents are less effective and more toxic than 1st line agents**
Streptomycin Para-Aminosalicylic Acid Capreomycin
🟣Streptomycin 🟣Para-Aminosalicylic Acid 🟣Capreomycin 🟣Cycloserine 🟣Ethionamide 🟣Fluoroquinolones 🟣Macrolides 🟣Bedaquiline
Streptomycin
• Aminoglycoside
• One of 1st TB drugs
• Action greatest for extracellular organisms
• If isolate is resistant to Streptomycin—can be treated with Kanamycin or Amikacin [bacilli remain sensitive to
these agents
Para-Aminosalicylic Acid
- Works by folic acid inhibition
* Largely replaced by Ethambutol, but remains important part of many MDR-TB regimens
Capreomycin
- Parenterally administered polypeptide that inhibits protein synthesis very much like aminoglycosides
- Reserved to treat MDR-TB
- Careful monitoring of renal function and hearing is needed
Cycloserine
• Oral TB drug that disrupts D-alanine incorporation into
bacterial cell wall
• Distributes well throughout body fluids and CSF
• Excreted unchanged in the urine
• Accumulation in those with CKD
• ADEs—CNS disturbances [lethargy, difficulty concentrating, anxiety, SI] and seizures have been seen
Ethionamide
- Structural analog of INH—disrupts mycolic acid synthesis
- MOA is not identical to INH, but some overlap in resistance patterns
- Widely distributed throughout the body and CSF
- Metabolism is in the liver to active and inactive metabolites
- ADEs limit its use—nausea, vomiting, hepatoxicity, hypothyroidism, gynecomastia, alopecia, impotence and CNS have been reported
Fluoroquinolones
- Moxifloxacin and levofloxacin have a role in MDR-TB
* Some NTM are also susceptible
Macrolides
- Azithromycin and Clarithromycin are used in regimens for several NTM—including MAC
- Azithromycin may be preferred for those at risk for drug interactions as Clarithromycin is both a substrate and an inhibitor of CP 450 enzymes
Bedaquiline
• ATP synthase inhibitor
• Approved to treat MDR-TB
• Given orally
• Active against many types of mycobacteria
• BB warning for QTc prolongation, monitoring of EKG is necessary
• Elevated LFTs has been seen, so these must be monitored
• Metabolized by CYP 450 3A4
• Administration with strong CYP 450
3A4 inducers [such as Rifampin] should be avoided
