Download antimicrobials part 3 and more Study notes Pharmacology in PDF only on Docsity!
Antimicrobial Therapies Part 3
Antimycobacterials / Antifungals (Ch 32/33) Background on Mycobacteria and Tuberculosis Mycobacteria are slow-growing, rod-shaped aerobic bacteria with mycolic acid in their cell walls, making them acid-fast bacilli. These pathogens cause slow-growing granulomatous lesions that can occur anywhere in the body. Mycobacterium tuberculosis causes latent and active TB, and is a leading infectious cause of death worldwide, with a quarter of the global population infected. There is an increasing occurrence of nontubercular Mycobacterium species,
including M. aviumintracellulare, M. chelonae, M. abscessus, M. kansasii, and M.
fortuitum.
Mycobacterium leprae is the cause of leprosy. Drugs: Ethambutol Isoniazid [INH]—prototype Pyrazinamide Rifabutin Rifampin Rifapentine *Remember RIPE ( R ifampin, I soniazid, P yrazinamide and E thambutol) * Second line: Aminosalicylic acid Bedaquiline Capreomycin Cycloserine Ethionamide Aminoglycosides/Fluroquinolones/Macrolides
Tuberculosis
treatment requires months to years due to the slow-growing nature of M.
tuberculosis.
Latent TB infection (LTBI) can be treated for 9 months with isoniazid (INH) or 12 weeks with high-dose INH plus Rifapentine. Active TB requires treatment with multiple drugs for several months, and multi- drug resistant TB (MDR-TB) is typically treated for 2 years. Extremely drug-resistant (XDR) TB - bacilli is resistant to INH, Rifampin, any fluoroquinolone, and at least one injectable second-line agent (Amikacin, Kanamycin or Capreomycin). Active disease always requires multiple drugs (3 or more) o with proven in vitro activity against isolate First-line agents (INH, Rifampin, Ethambutol, Pyrazinamide) o are the drugs of choice due to efficacy and tolerable side effects.
o Standard therapy involves INH, Rifampin, Ethambutol, and Pyrazinamide for 8 weeks, followed by INH and Rifampin for 16 more weeks. o Rifabutin or Rifapentine can replace Rifampin in certain scenarios
Resistance in M. tuberculosis can occur when treated with a single drug,
necessitating multiple drug therapy to suppress resistant strains. Clinical improvement is rapid, but therapy continues longer to kill persistent organisms and prevent relapse. After susceptibility information is available, the regimen can be tailored. Second-line therapy for MDR-TB involves: o an injectable aminoglycoside or Capreomycin, o a quinolone, Ethambutol o and Pyrazinamide (if sensitive) o and one or more of other agents: Cycloserine, Ethionamide, or PAS. o For XDR-TB , Clofazimine and Linezolid may be used. Patient adherence can be low due to long therapy durations, making DOT (Directly Observed Therapy) a successful strategy.
First-Line Antitubercular Drugs Isoniazid (INH) Isoniazid is a pro drug activated by mycobacterial catalase peroxidase (KatG) and inhibits mycolic acid synthesis --> leading to cell wall destruction.
It is specific to M. tuberculosis, though M. kansasii may be susceptible at higher
doses. Most nontubercular mycobacteria are resistant to INH. INH works well on rapidly growing bacilli and intracellular organisms. Resistance to INH can occur: o via chromosomal mutations affecting prodrug activation o acyl carrier proteins o overexpression of the target enzyme InhA. o Mycobacteria can downregulate Kat G Cross-resistance can occur between INH and Ethionamide. Pharmacokinetics: INH is readily absorbed orally, but food impairs absorption o It diffuses into all body fluids and caseous materials, with CSF levels matching serum levels. INH undergoes genetically regulated N-acetylation, affecting its half-life. Adverse effects (ADEs): o hepatitis (risk increases with age, concurrent Rifampin use, and daily alcohol consumption)—can be fatal o peripheral neuropathy (due to pyridoxine deficiency, requiring B supplementation) o Convulsions- in pt’s w/ epilepsy o hypersensitivity reactions. o Can cause INH induced lupus o Metabolic? Anion gap Remember ADEs : [INH] Injury to Nerves and Hepatocytes INH inhibits the breakdown of Carbamazepine and Phenytoin, potentially amplifying their side effects.
Rifamycins (Rifampin, Rifabutin, Rifapentine) Rifamycins are a group of macrocyclic antibiotics considered 1st^ line for TB. Rifampin (RIFADIN)has broader coverage than INH and can treat other bacterial infections, but is never given as monotherapy for TB due to rapid resistance development. (MOA): Rifampin blocks RNA transcription by interfering with the beta subunit of mycobacterial DNA- dependent RNA polymerase. B actericidal for intracellular and extracellular mycobacteria
including M. tuberculosis, M. kansasii, and M. avium complex (MAC).
Rifampin is also effective against many Gram + and Gram - pathogens used to prevent meningitis in exposed individuals.
It is highly active against M. leprae.
Resistance to Rifampin is caused by mutations in the gene for the bacterial DNA- dependent RNA p olymerase. Pharmacokinetics: Rifampin is adequately absorbed orally and distributes widely. CSF concentrations are variable. It undergoes enterohepatic recycling and induces liver CYP 450 enzymes and transporters, leading to many drug interactions. Rifampin undergoes autoinduction, shortening its elimination half-life over the first two weeks. Elimination is via bile and feces; urine and other secretions turn orange-red. ADEs: nausea, vomiting, rash, and rare hepatitis/liver failure. Use cautiously in alcoholics, older patients, and those with chronic liver disease. Intermittent high-dose therapy can cause a flu-like syndrome. Drug Interactions: Rifampin induces CYP 450 enzymes, decreasing the ½ life of many co-administered drugs: HIV PIs • Methadone • OCP • Prednisone • Propranolol • Quinidine • Sulfonylureas • Voriconazole • Warfarin
Pyrazinamide Pyrazinamide (generic only) is a synthetic, oral agent used short-term with INH, Rifampin, and Ethambuto l. MOA is unknown, but it must be hydrolyzed to pyrazinoic acid. It is active against TB in acidic lesions and within macrophages. Pharmacokinetics: It distributes throughout the body and penetrates the CSF. ADEs include uric acid retention (though gout is uncommon) and potential contribution to liver dysfunction. It is most beneficial early in treatment and is typically used for only 8 weeks in a 24-week regimen.
Ethambutol Ethambutol (MYAMBUTOL) is bacteriostatic and a first-line agent for mycobacteria. MOA is inhibiting arabinosyl transferase, an enzyme crucial for mycobacterial cell wall synthesis. Think Ethambutol “at the wall” as in cell wall where inhibition occurs It is used with INH, Pyrazinamide, and Rifampin pending culture and susceptibility results. Pharmacokinetics: It distributes well, but CSF penetration is variable, questioning its adequacy for TB meningitis. Parent drug and metabolites are excreted in the urine. ADEs: optic neuritis , affecting vision and color discrimination; red/green blindness (risk increases with dose and CKD). Visual acuity and color vision should be checked periodically. It decreases uric acid excretion, requiring caution in patients with a history of gout. Can precipitate gout attacks Hepatotoxic-leads to liver necrosis
Alternative Second-Line Antitubercular Drugs Streptomycin is an aminoglycoside whose action is greatest for extracellular organisms. If resistant to streptomycin, Kanamycin or Amikacin can be used. Para-Aminosalicylic Acid (PAS) works by folic acid inhibition and remains important in MDR-TB regimens, though largely replaced by Ethambutol. Capreomycin is a parenteral polypeptide that inhibits protein synthesis, similar to aminoglycosides, and is reserved for MDR-TB. Careful monitoring of renal function and hearing is needed. Cycloserine is an oral drug that disrupts D-alanine incorporation into the bacterial cell wall, distributing well into CSF. ADEs include CNS disturbances and seizures. Ethionamide is a structural analog of INH that disrupts mycolic acid synthesis, with some overlap in resistance patterns. ADEs limit its use. Fluoroquinolones (e.g., Moxifloxacin, Levofloxacin) have a role in MDR-TB, and some NTM are susceptible. Macrolides (e.g., Azithromycin, Clarithromycin) are used in regimens for several NTM, including MAC. Bedaquiline is an ATP synthase inhibitor approved for MDR-TB, given orally. It has a black box warning for QTc prolongation and requires EKG monitoring.
TEST YOUR KNOWLEDGE
35 y/o male with a history of substance abuse has been on Methadone for 13 months. Two weeks ago he had a + PPD, and a CXR showed a right UL infection. He started on standard 4 drug therapy. He is now in the ER complaining of withdrawal symptoms. Which of the following antimycobacterial agents is likely to have caused his acute withdrawal?
- Ethambutol • INH • Pyrazinamide • Rifampin • Streptomycin
- Rifampin is a potent inducer of CYP 450 dependent drug metabolizing enzymes • Duration of action of Methadone is dependent upon liver clearance, so enhanced drug metabolism will shorten the duration and increase likelihood of withdrawal symptoms in those on Methadone maintenance • None of the other agents induce CYP 450 enzymes 42 y/o old man who is HIV + was diagnosed with active TB. He is currently stable on HIV regimen of 2 PIs and 2 nucleoside reverse transcriptase inhibitors [NRTIs]. What is the most appropriate regimen to prescribe for this patient?
- Rifampin + INH + Pyrazinamide + Ethambutol
- Rifabutin + INH + Pyrazinamide + Ethambutol
- Rifapentine + INH + Pyrazinamide + Ethambutol
- Rifampin + Moxifloxacin + Pyrazinamide + Ethambutol
- Amikacin + Moxifloxacin + Cycloserine + Ethambutol *Rifabutin is recommended instead of Rifampin in those co-infected with HIV—it is less of an inducer of CP 450 enzymes than Rifampin • Rifabutin is a CYP 450 3A4 substrate and bidirectional interactions can occur • Other meds, such as PIs, may affect the concentration of Rifabutin, requiring a dose adjustment • E is incorrect as these are not 1st line drugs Which of the following is true regarding the treatment of Hansen’s Disease?
- Clofazimine should not be used in those with G6PD deficiency
- Peripheral neuropathy is a common ADE with Clofazimine
- Clofazimine may cause skin discoloration over time
- The risk of Erythema Nodusum leprosum is increased in those on Clofazimine *Clofazimine is a phenazine dye and will cause bronzing of the skin, especially in fair skinned individuals • This will occur in the majority of patients—it is not harmful but may take several months to years to fade after finishing the meds
*these compare ionized microorganisms from the patient samples to a reference database 90% of C. auris is resistant to Fluconazole, 30% is resistant to Amphotericin B and 5% are resistant to echinocandins
*residual damage can persist if high dosed. Function returns when med DC’d. Loading pt w/ NS bolus prior to dose and use of liposomal formulations of Amphotericin minimize renal damage.
