Drug Therapy: Tuberculosis PDF

Drug Therapy: Tuberculosis  Principles of Drug Therapy for Tuberculosis (TB)  TB requires prolonged therapy with multiple agents  Risk of decreased adherence and emergence of drug resistant bacteria Multidrug resistant TB (MDR-TB): resistance to both isoniazid...

Drug Therapy: Tuberculosis  Principles of Drug Therapy for Tuberculosis (TB)  TB requires prolonged therapy with multiple agents  Risk of decreased adherence and emergence of drug resistant bacteria Multidrug resistant TB (MDR-TB): resistance to both isoniazid and rifampin Extensively drug resistant TB (XDR-TB): resistance to both Isoniazid and Rifampin and to all fluoroquinolones, and at least one injectable second line agent  Treatment regimens for active TB must contain two or more drugs  If the patient is not allergic, and the infecting organisms are not resistant, isoniazid and rifampin are almost always included  Measures to Promote Adherence  Nonadherence is the most common cause of treatment failure and drug resistant TB  Directly Observed Therapy (DOT)  Dosing in the presence of an observer, usually someone from the health department  Intermittent dosing schedules: daily versus 2-3 X/week  DOT combined with intermittent dosing promotes adherence and decreases risk of resistance  Treatment for Drug-Sensitive TB  Induction phase - Two months duration  Four agents: isoniazid, rifampin, pyrazinamide, ethambutol  Daily, twice weekly, or three times weekly dosing schedules  Goal is to eliminate actively dividing extracellular tubercle bacilli  Continuation phase - Four months duration  Two agents: isoniazid and rifampin  Daily, twice weekly, or three times weekly dosing schedules  Goal is to eliminate intercellular persisters Treatment for Drug-Sensitive TB  Landmark TB Trial in October 2020  Results indicated that a FOUR month daily treatment regimen of high dose, or “optimized”, Rifapentine with Moxifloxacin is as safe and effective as the existing standard six-month daily regimen.  https://www.niaid.nih.gov/news-events/landmark-tb-trial-identifies- shorter-course-treatment-regimen? utm_campaign=+44501618&utm_content=&utm_medium=email&utm _source=govdelivery&utm_term=  Resistant Infections  Single agent resistant infections - Resistance to either isoniazid or rifampin  Treatment is with the other three drugs  Duration of treatment 18-24 months  Usually responds well to treatment  MDR and XDR TB - Much harder to manage  Treatment is prolonged - 24 + months  Initial therapy may require 5-7 agents  Uses second and third line agents - more toxic/less effective  Prognosis is poorer  TB and HIV Coinfections  The incidence of TB is higher in the population of patients with HIV  Prolonged duration of TB treatment and more aggressive treatment is required in patients with HIV because patients with HIV are immunosuppressed  Rifampin is a cornerstone of TB treatment  Protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are cornerstones of HIV treatment  But… rifampin should not be given with protease inhibitors and NNRTIs because the effectiveness of these HIV treatments are diminished with rifampin  Net effect is that patients are denied optimal treatment for one of their infections  There is no good answer  Latent TB treatment  Treatment for latent TB is lengthy and there is risk for drug toxicity  Testing and treatment limited to those who really need it  People suspected of having recently acquired the infection  Those at risk for progressing for latent to active TB due to immunocompromise  Two equally effective treatment options available in the U.S.  Isoniazid daily for nine months – total # of doses is 270  Isoniazid plus rifapentine taken weekly for three months – total # of doses is 12  Ruling out active TB before starting treatment for latent TB is critical to prevent undertreatment and emergence of resistant bacilli  First-Line Agents  Isoniazid  Rifampin  Rifampentine  Rifabutin  Pyrazinamide  Ethambutol  Usually a combination of 3-4 are used to decrease risk of resistance Second-Line Agents  Always used in combination with first line agents  Generally less effective, more expensive, and more toxic than first-line drugs  Principle indication: resistance to a first-line agent  Used in combination with first-line agents to treat severe pulmonary TB and disseminated TB  Isoniazid (Isotamine - INH) Primary agent for treating active and latent TB  Superior with regard to cost, efficacy, toxicity, patient tolerance, and ease of use  Should be taken by all patients with isoniazid sensitive strains of TB who can tolerate the drug  Metabolism and Excretion  Inactivated in the liver by acetylation  Excreted in the urine primarily as inactive metabolites  Preparations  Tablets, syrups, or solutions for IM injection  Available in fixed dose combinations with rifampin (Rifamate) and with rifampin and pyrazinamide (Rifater)  Fixed dose products aid compliance  Isoniazid: Adverse Effects  Hepatotoxicity  Instruct patient to report signs of hepatitis  Withdrawn if hepatitis develops or AST exceeds 3-5 X baseline  Caution using with alcoholism or preexisting liver disease  Peripheral neuropathy caused by isoniazid induced B6 deficiency  Instruct patients to report numbness and tingling, pain and burning, clumsiness and unsteady gait  Treatment is B6 (pyroxidine)  Increased risk with alcoholism and diabetes - may see peripheral neuropathy prophylaxis with daily low dose B6 in these patients  Others: CNS manifestations, GI symptoms, anemia, urinary retention, allergic  Isoniazid: Drug/Drug Interactions  Drug/Drug interactions  Ingesting with rifampin, rifapentine, rifabutin, or pyrazinamide) increases the risk of hepatotoxicity  Strong inhibitor of cytochrome P450 isoenzymes which can raise the levels of some other drugs  Phenytoin most concerning  Monitor for S/S phenytoin excess: ataxia, incoordination  Ifphenytoin levels increased, Isoniazid dose should remain unchanged and phenytoin dose should be decreased  Rifampin (Rifadin)  Equals isoniazid in importance as an anti TB drug  Bactericidal to M. Tuberculosis  Induces hepatic drug-metabolizing enzymes, including those responsible for its own inactivation causing half-life to decrease over time  Best taken on an empty stomach  Hepatitis is most common adverse effect  Discolors body fluids orange  Available as an oral capsule; in two fixed-dose combinations (see isoniazid slides) and for IV administration (as a powder to be reconstituted)  Rifampin Drug/Drug Interactions  Induces cytochrome P450 isoenzymes which can hasten the metabolism of many other drugs.  Of special concern:  Contraceptives  Warfarin  Certain protease inhibitors and NNRTIs for treating HIV infection  Drugs Related to Rifampin  Rifapentine (Priftin)  Long-acting analogue of rifampin,  Same MOA, adverse effects, and drug interactions as rifampin.  Best absorbed when given with food  Rifabutin (Mycobutin)  Close chemical relative of rifampin  Preferred to rifampin in patients with HIV infection  Risk of uveitis  Other First-Line Agents  Pyrazinamide  Part of initial combination therapy - along with rifampin, isoniazid, and ethambutol - for active TB caused by drug sensitive bacilli  Adverse effects: hepatotoxicity, non-gouty poly-arthralgias (pain in multiple joints).  Ethambutol  Bacteriostatic  Adverse effects: dose related optic neuritis … clears upon discontinuation of treatment. Drug should be withdrawn if this occurs  New Anti-TB Agent: Bedaquiline  First unique anti-TB drug to be developed in 40+ years  Works faster and better than all other ant-TB drugs  Does not accelerate the metabolism of other drugs so useful for patients taking drugs for HIV  Black Box Warning: Prolongs QT interval, risk of hepatotoxicity  Use only If no other effective treatment  Administer under DOT and instruct patient to take with food.