molecular detection of tuberculosis and rifampin resistance.
Goals of TB Treatment - Curry International Tuberculosis ...nid... · 3 Initial Phase (2-month):...
Transcript of Goals of TB Treatment - Curry International Tuberculosis ...nid... · 3 Initial Phase (2-month):...
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Rupali Jain, PharmD, BCPSUniversity of Washington Medical Center
University of Washington, Clinical Associate Professor School of Pharmacy
June 2015
• Discuss the rationale for multiple drugs• Explain the rationale for intermittent therapy • Discuss the rationale for individual drugs in a
multi-drug regimen• Explain key pharmacologic features of
anti-TB drugs
Goals of TB Treatment
Eradication M. tuberculosis infection Prevention of the development of drug resistance Preventing relapse of disease Prevention of M. tuberculosis transmission
Combination therapy is required to achieve these objectivesDirectly observed therapy (DOT) is very important to facilitating adherence and preventing drug resistance
Blumberg et al. Am J Respir Crit Care Med 2003; 167:603.Hopewell PC et al. Lancet Infect Dis 2006; 6:710.WHO. Treatment of tuberculosis guidelines (4th edition).
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Rationale for Multiple Drugs
Past observation of treatment failure with individual drugs due to rapid emergence of drug resistanceMutation rate to first line anti-TB drugs (10-7Mutation rate to first line anti TB drugs (10to 10-10)Likelihood of bacilli developing resistance to 2 or more anti-TB drugs is the product of the individual mutation rates
Gillespie et al. Antimicrob. Agents Chemother. 2002, 46(2):267.Zumla et al. N Engl J Med. 2013 Feb 21;368(8):745-55.
Four Drug Combination Rifampin (RIF, R) or Rifabutin Isoniazid (INH, H )Pyrazinamide (PZA, Z)Ethambutol (EMB, E)(The so-called “RIPE” regimen or HREZ)
Designed to prevent secondary development of resistance to RIF in populations with a high rate of primary resistance to INH (≥ 4%)
Blumberg et al. Am J Respir Crit Care Med 2003; 167:603.WHO. Treatment of tuberculosis guidelines (4th edition).
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Initial Phase (2-month):Isoniazid + Rifampin + Pyrazinamide + Ethambutol○ EMB may be discontinued as soon as the results of drug
susceptibility testing confirm INH and RIF susceptibility
Pulmonary TB Disease Treatment Regimens
Continuation Phase (4-7 months):INH + RIF x 4 months (if isolate is fully susceptible) = total duration is 6 months
INH + RIF x 7 months (total 9 months) if:○ Patients with cavitary pulmonary disease with (+) sputum
culture after 2 months
○ If initial treatment did not include PZA
Directly Observed Therapy (DOT)Intermittent therapy facilitates DOTNonadherence to anti-TB regimen is the most common cause of …
Treatment failure RelapseRelapse Emergence of drug resistance
WHO ~ DOTS strategy results in a cure rate of > 80% and a default rate of < 10%
Frieden et al. Bulletin of the World Health Organization, 2007, 85:407–409.Hopewell et al. ISTC 12. Lancet Infectious Diseases, 2006, 6:710–725.United Nations Millennium Development Goals Report 2011. 2011, p. 51
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http://www.rxkinetics.com/antibiotic_pk_pd.html
How can we give medications twice a week?
Some anti-TB drugs have a post-antibiotic Effect (PAE)A l d PAEA prolonged PAE may allow wider dosing intervals without the loss of therapeutic efficacy
Chan et al. Antimicrob Agents Chemother. 2001 Dec;45(12):3631-4Blumberg et al. Am J Respir Crit Care Med 2003; 167:603.
WHO. Treatment of tuberculosis guidelines (4th edition).
Post-Antibiotic Effect (PAE)PAEs allows for a drug concentration to fall below the MIC, yet continue to suppress mycobacterial growth
PAE for RIPE (RIF + INH + EMB + PZA) >120 hours
PAEs ~ RIF + INH contribute predominantly to the effects of anti-TB combinations
Maintaining continuous inhibitory drug concentrations is NOT necessary to kill or inhibit growth of M. tuberculosis
Chan et al. Antimicrob Agents Chemother. 2001 Dec;45(12):3631-4
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Initial 4-drug regimens with 2-3 doses per week are effective (only given by DOT)O kl i i h
Intermittent Treatment – Who qualifies?
Once-weekly continuation phase:Used for HIV-negative patientsNon-cavitary drug-susceptible TBNot for children, pregnant women, extrapulmonary TB
First-Line Antituberculosis Drugs
Isoniazid (INH)Rifampin (RIF)Rifabutin Rifapentine (RPT)Pyrazinamide (PZA)Ethambutol (EMB)
Mitchison et al. Int J Tuberc Lung Dis. 2012 Jun;16(6):724-32. Zumla et al. N Engl J Med. 2013 Feb 21;368(8):745-55.Drugs for Tuberculosis. Treat Guidel Med Lett. 2012 Mar;10(116):29-36.References 1-3, 5, 9-17
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Dosing Drug Daily, mg/kg
(total dose)*3days/wk,mg/kg (total dose)
2days/wk, mg/kg (total dose)
INH 5 (300) 15 (900) 15 (900)RIF 10 (600) 10 (600) 10 (600)RIF 10 (600) 10 (600) 10 (600)Rifabutin 5 (300) 5 (300) 5 (300)RPT -- -- 10 (600)PZA 15-30 (2000) 50-70 (3000) 50-70 (4000)EMB 15-25 25-30 50
*Dose in mg/kg, maximum daily dose in parenthesis
References 1-3, 5, 9-17, and Doug Black, PharmD, UW School of Pharmacy
60 year old cachectic looking male referred to Public Health DOT for recent diagnosis pulmonary TB. He was started on RIPE earlier this week.
PMH:Di b t
Medications:LisinoprilGlyburide
DiabetesAlcoholism
Can you identify risk factors for INH drug toxicities in this patient?
Over the counter Pain pills for back painASA daily
Isoniazid (INH)
Discovered anti-TB properties ~ 1945Causes the greatest early reduction in colony forming units found in the sputumMechanism of Action:Mechanism of Action:
INH is a prodrug activated by mycobacterial KatG catalase-peroxidaseINH also blocks InhA, a key enzyme involved in fatty and mycolic acid synthesis
References 1-3, 5, 9-17
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Isoniazid (INH)
Role Antibiotic Activity RenalDosing
Absorption
Critical ~ Bactericidal activity No Oral: 90%TB and LTBI
ConcentrationDependent Killing(AUC/MIC)(Peak/MIC)
Inhibits mycolic acid synthesis
Take 1 hour before or 2 hours after meals (or antacids)
May take with small snack
References 1-3, 5, 9-17
Isoniazid (INH)Metabolism T ½ (h) Supplied
Hepatic acetylation under genetic control
0.7-4 h
0.7 -2 h
Tablets (100mg,300mg)
Inhibitshepatic CYP2C19, CYP3A4
Weak MAO inhibitor
Rapid acetylators
2.3-3.5 hSlow acetylators
Syrup (50mg/5ml)(contains Sorbitol)
Solution for Injection (100mg/ml)
References 1-3, 5, 9-17
MetabolismHepatic acetylation under genetic control“Fast acetylators” t ½ < 2 hours (may require a higher dose to get same therapeutic effect)
Caucasians: 50% Asians: 80-90%
“Slow acetylators” t ½ ~ 3-4 hours (↑ risk neurotoxicity and hepatotoxicity)
Egyptian: 80-90%European, North American: 40-70%Asian: 10-30%Canadian Eskimo: 5%
References 1-3, 5, 9-17
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Isoniazid (INH)Adverse Effects Monitoring
Asymptomatic ↑ ALT ~12-15%
Rash ~ 2%Fever ~ 1.2%
Overt hepatotoxicity ~ 1%-2.7% (↑w/RIF PZA)
LFTs ~ Symptoms: fatigue, nausea, malaise, anorexia or nausea, RUQ pain
baseline and monthly if symptoms of hepatotoxicity(↑w/RIF, PZA)
Neuropathy ~ <0.2%B6 25-50mg/day
CNS ~ restlessness, insomnia, dysarthria, seizures
Lupus-like syndrome ~ 20% develop ANAs
symptoms of hepatotoxicity
Occur within first 2-3months of therapy
Discontinue if transaminases ↑ > 3 X ULN + Symptoms(nausea
OR ↑ > 5 X ULNReferences 1-3, 5, 9-17
Drug-Drug InteractionsINHHypoglycemics(Glimepiride, Glypizide, Metformin)
Monitor glucose, may ↑ BG
APAP ↑ hepatotoxicity Anticoagulants ↑ anticoagulant effectBenzodiazepines ↑ toxicity BZDsCarbamazepine ↑ toxicity of bothCarbamazepine ↑ toxicity of bothDisulfiram (Antabuse) Psychotic episodesHaloperidol ↑ toxicity antipsychotics Ketoconazole ↓ efficacy of ketoconazole Dilantin ↑ toxicity antiepilepticTheophylline ↑ toxicity theophyllineValproate ↑ hepatic and CNS toxicity
References 1-3, 5, 9-17
Can you identify risk factors for INH drug toxicity in this patient?
60 year old cachectic looking male referred to Public Health DOT for recent diagnosis pulmonary TB. He was started on RIPE earlier this week. PMH:Diabetes
Medications:LisinoprilMetformin
Alcoholism
INH Hepatotoxicity: age, concomitant hepatotoxic drugs (OTC tylenol), DM, alcoholism, possibly race
INH neuropathies: malnourished, DM, alcoholism
MetforminOver the counter Pain pills for back painASA daily
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Rifampin (RIF)
Appeared as new drug of choice for TB ~ 1970Introduction of RIF into TB regimens allowed for gtrue short-course treatment of 6-9 monthsMechanism of Action:
Binds to rpoB portion of bacterial polymerase and inhibits mycobacterial DNA-dependent RNA polymerase, blocking bacterial RNA synthesis
References 1-3, 5, 9-17
Rifampin (RIF)Role Antibiotic Activity Absorption
Critical for TB and LTBI
Bactericidal activity
Concentration
Oral: 90% -95%
Dependent KillingProlonged effect(AUC/MIC)(Peak/MIC)
Blocks bacterial RNA synthesis
Food (high fat) delays absorption
Best on empty stomach same as INH
References 1-3, 5, 9-17
Rifampin (RIF)
Metabolism T ½ (h) Supplied
Hepatic: 60%-80%
Intestinal Wall: 30%-45%
2-3 h Capsules (150mg, 300mg)
Injection solution ~Intestinal Wall: 30% 45%
Induces CYP3A4, 1A2, 2C9, 2C19, and 2D6
Induces PGP, UGT
↓ Levels of many drugs
Injection solution reconstitution (600mg)
References 1-3, 5, 9-17
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Adverse Effects MonitoringPruritus +/- rash ~ 6%
Hypersensitivity ~ 0.3%
GI nausea, anorexia, abdominal pain
Flulike syndrome
Consider serumTDM
No routine monitoring needed
Consider baseline LFTs, bili bi lk li
Rifampin (RIF) References 1-3, 5, 9-17
Hyperbilirubinemia ~ 0.6%
Hepatotoxicity ~ <1%-2.7% (↑w/INH, PZA)
TCP, hemolytic anemia, acute renal failure, TTP ~ <0.1%
Orange discoloration of body fluids (sputum, urine, sweat, tears, contact lenses)
bilirubin, alkaline phosphatase, CBC
New medications!
Case A 44 year old homeless man is sent to the ER from his methadone clinic with fever and cough. He is HIV+ with a CD4 count of 200, not on Anitretroviral medications. He smokes 1 ppdcigarettes, does not drink, and has been on methadone maintenance for 5 years. He denies yother drug use.
His CXR shows a RUL infiltrate. AFB smear is positive. PPD is 12mm. He is admitted for treatment of pulmonary TB and started on RIPE. His methadone is continued.
Rifampin and opiates
Induction of P450 CYP3A4 by rifampin can decrease serum opiate levels by 30-65% and has been associated with appearance of withdrawal symptoms.
Patients on methadone will likely require increased doses while on rifampin. Once TB treatment completed will need close monitoring to avoid sedation or overdose.
Work with Pain management services as you titrate methadone…it also prolongs the Qtc
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Drug-Drug InteractionsRifampinHypoglycemic(sulfonylureas)
↓ efficacy of antidiabetics, RIF also ↑ intestinal glucose absorption ~ monitor glucose
Anticoagulants ↓ anticoagulant effect
Diltiazem ↓ DILT effect
Antidepressants ↓ antidepressants effect
Fluconazole ↓ fluconazole effect
Beta-Blockers ↓ beta blockade Itraconazole ↓ itraconazole effectContraceptives ↓ OCP effect Haloperidol ↓ haloperidol effectContraceptives ↓ OCP effect Haloperidol ↓ haloperidol effectCorticosteroids ↓ steroid effect Methadone ↓ methadone effectCyclosporine ↓ CsA effect, ↑ RIF Phenytoin ↓ phenytoin effectProtease Inhibitors ↓ PI effect, ↑ RIF Verapamil ↓ verapamil effectDelavirdine ↓ effect DLV Tetracyclines ↓ TCNs effectEfavirenz Slightly ↓ effect EFV,
↓ RIFTMP-SMX Possible RIF toxicity
Digoxin ↓ DIG levels Chloramphenicol ↓ chloramphenicol effect
References1-3, 5, 9-17, http://www.heartlandntbc.org/training/archives/tbnucama_20120719_1040.pd
RifabutinCritical for treatment of TB
May be used in place of RIF for the treatment of HIV co-infected patients on PIs, some NNRTIs (etravirine, rilpivirine)I ff ti RIF h d iIs as effective as RIF when used in combination therapyAlso used in some patients with solid organ transplants
Mechanism of action ~ same as RIF
References 1-3, 5, 9-17
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Rifabutin
Doses must be adjusted when administered with antiretroviral therapy (ARVs)Renal dose adjustment NOT required but someRenal dose adjustment NOT required, but some sources recommend renal dose adjustment
T ½ ~ 45 hours (much longer than RIF)Supplied:
Capsules (150mg)
References 1-3, 5, 9-17
RifabutinAdverse Effects Drug Interactions & MonitoringGI nausea, anorexia, abdominal pain ~ 3%
Polyarthralgias ~ 1-2%
Weak inducer and substrate of CYP3A4
Induces CYP ~ 40% of RIF
Hepatotoxicity ~ <1%
Orange discoloration of body fluids
Drug-drug interactions similar to RIF, but to a lesser degree
Consider TDM
Serum levels effected by inhibitors and inducers, i.e. PIs, NNRTIs, and other drugs
References 1-3, 5, 9-17
Rifapentine (RPT)
Useful for continuation phase in TB treatment of HIV negative patients with noncavitary disease
Recently studied for daily dosing ~ 5days/week in TB treatment
Approved for LTBI dosed weekly with INH for 3 months Prolonged t ½ (~ 13-14 hours) permits weekly dosing25-O-desacetyl metabolite is active t ½ (~ 13-24 hours)
References 1-3, 5, 9-17
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Rifapentine (RPT)
Mechanism of action ~ same as RIFSupplied:
Tablets (150mg)Tablets (150mg)Induces CYP enzymes ~ 85% of RIFDrug-drug interactions similar to RIFAbsorption:
Food improves concentrations
References 1-3, 5, 9-17
Pyrazinamide (PZA)
Appeared as potential TB drug ~ 1952Bactericidal activity in acidic pH, effective against semi-dormant organisms
PZA in 1st 2 months of therapy with RIF + INH allows total treatment duration to be shortened from 9 months to 6 months
Helps to prevent resistance from emerging
References 1-3, 5, 9-17
Pyrazinamide (PZA)
Mechanism of Action:Synthetic prodrug converted by mycobacterial pyrimidase to pyrazinoic acid (POA)POA accumulates in bacteria causing lethalPOA accumulates in bacteria, causing lethal membrane damageParticularly effective in killing dormant bacilli Targets the ribosomal protein S1, an essential protein involved in the ribosome translation
References 1-3, 5, 9-17
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Pyrazinamide (PZA)
Role AntibioticActivity
RenalDosing
Absorption
C iti l f B t i id l R l d O l lCritical for TB treatment
Bactericidal Renal dose adjustment requiredCrCl < 30ml/min
Oral: nearly complete
May be taken with food
References 1-3, 5, 9-17
Pyrazinamide (PZA)
Metabolism T ½ (h) Supplied
Hepatic metabolism 9-11 h Tablets pvia hydrolysis
But is prolonged in renal or hepatic disease
(500mg)
References 1-3, 5, 9-17
Pyrazinamide (PZA)
Adverse Effects MonitoringHepatotoxicity
GI anorexia and nauseaBaseline LFTs, SCr., and uric acid
Nongouty polyarthralgia ~ 40% receiving daily doses
Asymptomatic hyperuricemia Rash, photosensitive dermatitis
Follow-up LFTs in patients with underlying liver disease
Follow-up renal function in renal impairment
References 1-3, 5, 9-17
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Ethambutol (EMB)
Discovered ~ 1961Important for treatment of TB
Included in regimen primarily to prevent emergence of RIF resistance, when primary INH resistance is suspected Least potent first-line drug
Mechanism of Action:Inhibition of arabinosyltransferases, embcAB, involved in cell wall synthesis
References 1-3, 5, 9-17
Ethambutol (EMB)Role Antibiotic
Activity RenalDosing
Absorption
Critical TB Bacteriostatic Renal dose Oral: treatment activity adjustment
required CrCl < 30ml/min
80%
May be taken with food
References 1-3, 5, 9-17
Ethambutol (EMB)
Metabolism Elimination T ½ (h) Supplied
Hepatic Oxidation:8-15%
Urine:50%unchanged
Feces:20% unchanged
2.5 -4 h
Prolonged half-life of 7-15 h end stage renal disease
Tablets (100mg, 400mg)
References 1-3, 5, 9-17
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Ethambutol (EMB)
Adverse Effects MonitoringRetrobulbar neuritis ~ 1%-5%, dose-dependent and increased with renal impairment
Consider serum TDM
Baseline SCr.
Blurred vision
Red-green color blindness
Follow-up renal function in impairment
Baseline visual acuity test and color discrimination
Question patients at monthly visit about visual changes
Drug-Drug Interactions
PZAEthionamide ↑ risk of hepatotoxicity Rifampin ↑ risk of severe hepatic injury
EMBAluminum-containingAntacids
↓ EMB serum concentrations
Ethionamide ↑ GI distress, headache, confusion, neuritis, and hepatotoxicity
References 1-3, 5, 9-17
Second-Line Antituberculosis Drugs
Fluoroquinolones Linezolid CycloserineStreptomycin
Second-line agents are indicated for the treatment of…
D i t t TBStreptomycinAmikacin/KanamycinEthionamidep-Aminosalicylic acid (PAS)Capreomycin
Drug-resistant TBFor patients who are intolerant or allergic to 1st line drugsWhen 1st line agents are not available
References 1-3, 5, 9-17
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Fluoroquinolones
Levofloxacin, moxifloxacin, and gatifloxacin (outside US) may be used to treat TBBeing studied to possibly replace EMB or INH in 4 drug regimen or to shorten durationINH in 4 drug regimen or to shorten duration of therapy by 2 months Mechanism of Action:
Inhibit mycobacterial DNA gyrase or topoisomerase II, preventing cell replication and protein synthesisBactericidal, concentration dependent killing
References 1-3, 5, 9-17
Fluoroquinolones
Antibiotic Activity Dosing Absorption Adverse Effects
Bactericidal activity
LevofloxacinDaily ~ 500-1000mg PO or
Oral: 90% GI upset ~ 5%-6%
Dry eyes, ↓ visual
ConcentrationDependent KillingProlonged effect(AUC/MIC)(Peak/MIC)
500 1000mg PO or IV adults
Renal dose adjustment required
MoxifloxacinDaily ~ 400mg PO or IV adults
Take 2 hours before antacids with aluminum, magnesium, or calcium, iron, vitamins, sucralfate, dairy products
Dry eyes, ↓ visual acuity ~ 1% - 6%
Headache
Rash
QT Prolongation ~ 0.1% - < 2%
Tendinopathy
References 1-3, 5, 9-17
Linezolid
Being used in combination with other anti-TB drugs for MDR-TB (esp. failed regimen) and g ( p g )XDR-TBMechanism of Action:
Oxazolidinone that interferes with mRNA binding to the mycobacterial ribosome 50S at the initiation of translation
References 1-3, 5, 9-17
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Linezolid
AntibioticActivity
Dosing Absorption Adverse Effects
Bactericidal activity
Most advocate 600mg daily or 300mg twice
May be taken with food
Limiting factor ~ ↑ myelosuppression, peripheral, and optic
Time Dependent Killing(T>MIC)
300mg twice daily
Is sufficient for treatment of slow-growing M. tuberculosis
Avoid tyramine containing foods
Caution with drugs that increase serotonin (MAOIs)
peripheral, and optic neuropathy (twice daily dosing)
Rarely lactic acidosis
Nausea, diarrhea
Headache
References 1-3, 5, 9-17
BedaquilineNewly approved diarylquinoline, Dec 2012
Fast-tracked approval: indicated as part of combination therapy in adults (≥ 18 years) with pulmonary multi-drug resistant tuberculosis(MDR-TB). Reserve bedaquiline for use when an effective treatment regimen cannot otherwise be provided.
NOT indicated for the treatment of latent, extra-pulmonary or drug-sensitive tuberculosis or for the treatment of infections caused by non-tuberculous mycobacteria.Black Box warnings!
Time to Sputum-Culture Conversion in the Modified Intention-to-Treat Population.
Diacon AH et al. N Engl J Med 2014;371:723-732.
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Black Box Warning• An increased risk of death was seen in the
Bedaquiline treatment group (9/79, 11.4%) compared to the placebo treatment (2/81, 2.5%) in one placebo controlled trial.
• Only use Bedaquiline when an effective treatment regimen cannot otherwise by provided.g y p
• QT prolongation can occur with bedaquiline. Use with drugs that prolong the QT interval may cause additive QT prolongation
• CDC has provisional guidelines for use and safety monitoring (www.cdc.gov)
• Useful practical guide for clinicians
BedaquilineAntibioticActivity
Dosing Absorption Adverse Effects
Bacteriostatic activity
400mg once daily for two weeks, then
May be taken with food
Black Box warning:QT prolongation and increased death
Inhibitsmycobacterial ATP synthase
,200mg orally three times weekly for a total of 24 weeks
Nausea, arthralgia, and headache
Monitoring: LFTs at baseline and monthly
Bedaquiline
Metabolism Elimination T ½ (h) Supplied
Hepatic Oxidation: CYP 3A4
Urine:<0.001%unchanged
24-30 hours, but terminal half-life of 4 5 months
Tablets 100mg
CYP 3A4
Metabolite: M2/M3 also metabolized by CYP 3A4
unchanged
Feces:majority
4-5 months
Consider continuing background regimen for 4-5months after stopping bedaquiline
References 1-3, 5, 9-17
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Drug-Drug InteractionsBedaquilineRifampin Rifampin reduced Bedaquiline
concentrations by 50%Avoid concomitant use
Ketoconazole ( and other CYP 3A4
Increased bedaquiline exposure by 22%Avoid concomitant use for more than 14
inhibitors) daysAlso increase risk of Prolonged QTc
INH, PZA, ETB, kanamycin, Ofloxacin
No interactions seen
Kaletra (lopinavir/ritonavir)
Kaletra increased Bedaquilineconcentrations by 22%
Nevirapine No adjustments required
Conclusions
PAEs are an attractive feature of anti-TB drugsIntermittent therapy is an option, but make sure it is appropriate and the best option for your patient Monitor for….
Adherence to therapyDrug-drug interactionsDrug-disease interactions Adverse effects and intolerances
Questions
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Acknowledgement
Caroline Pitney, PharmDCindy Lee, PharmD
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Antimicrobial Chemotherapy. In: Brooks GF, Carroll KC, Butel JS, Morse SA, Mietzner TA, eds. Jawetz, Melnick, & Adelberg's Medical Microbiology. 26th ed. New York: McGraw-Hill; 2013. http://www.accesspharmacy.com.offcampus.lib.washington.edu/content.aspx?aID=57034158. (Accessed May 20, 2013).
16. Trevor AJ, Katzung BG, Kruidering-Hall MM, Masters SB. Chapter 47. Antimycobacterial Drugs. In: Trevor AJ, Katzung BG, Kruidering-Hall MM, Masters SB, eds. Katzung & Trevor's Pharmacology: Examination & Board Review. 10th ed. New York: McGraw-Hill; 2013. http://www.accesspharmacy.com.offcampus.lib.washington.edu/content.aspx?aID=56983976 (Accessed May 20 2013)=56983976. (Accessed May 20, 2013).
17. Peloquin CA.Therapeutic drug monitoring in the treatment of tuberculosis. Drugs. 2002;62(15):2169-83.
18. Burman WJ, Goldberg S, Johnson JL, et al. Moxifloxacin versus ethambutol in the first 2 months of treatment for pulmonary tuberculosis. Am J Respir Crit Care Med 2006; 174:331.
19. Conde MB, Efron A, Loredo C, et al. Moxifloxacin versus ethambutol in the initial treatment of tuberculosis: a double-blind, randomised, controlled phase II trial. Lancet 2009; 373:1183.
20. Dorman SE, Johnson JL, Goldberg S, et al. Substitution of moxifloxacin for isoniazid during intensive phase treatment of pulmonary tuberculosis. Am J Respir Crit Care Med 2009; 180:273.
21. Devasia RA, Blackman A, Gebretsadik T, et al. Fluoroquinolone resistance in Mycobacterium tuberculosis: the effect of duration and timing of fluoroquinoloneexposure. Am J Respir Crit Care Med 2009; 180:365.
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References 22. Diacon AH, Donald PR, Pym A, et al. The diarylquinoline TMC207 for
multidrug-resistant tuberculosis. N Engl J Med. 2009 Jun 4;360(23):2397-405.23. Diacon AH, Dawson R, von Groote-Bidlingmaier et al. 14-day bactericidal
activity of PA-824, bedaquiline, pyrazinamide, and moxifloxacin combinations: a randomised trial Lancet. 2012 Sep 15;380(9846):986-93.
24. Villemagne B, Crauste C, Flipo M, Baulard AR, Déprez B, Willand N. Tuberculosis: the drug development pipeline at a glance.Eur J Med Chem. 2012 May;51:1-16. doi: 10.1016/j.ejmech.2012.02.033. Epub 2012 Feb 25G S G f f25. Grosset JH, Singer TG, Bishai WR. New drugs for the treatment of tuberculosis: hope and reality.Int J Tuberc Lung Dis. 2012 Aug;16(8):1005-14. doi: 10.5588/ijtld.12.0277.
26. Shaw KJ, Barbachyn MR.The oxazolidinones: past, present, and future.Ann N Y Acad Sci. 2011 Dec;1241:48-70. doi: 10.1111/j.1749-6632.2011.06330
27. Field SK, Fisher D, Jarand JM, Cowie RL. New treatment options for multidrug-resistant tuberculosis. Ther Adv Respir Dis. 2012 Oct;6(5):255-68. Epub 2012 Jul 4.
28. Walter ND, Strong M, Belknap R, Ordway DJ, Daley CL, Chan ED. Translating basic science insight into public health action for multidrug- and extensively drug-resistant tuberculosis. Respirology. 2012 Jul;17(5):772-91. doi: 10.1111/j.1440-1843.2012.02176.x.