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


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)


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%


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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


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


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


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)


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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


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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)


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


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)


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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


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


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


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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


Pyrazinamide (PZA)

Metabolism T ½ (h) Supplied

Hepatic metabolism 9-11 h Tablets pvia hydrolysis

But is prolonged in renal or hepatic disease

(500mg)


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


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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


Ethambutol (EMB)Role Antibiotic

Activity RenalDosing

Absorption

Critical TB Bacteriostatic Renal dose Oral: treatment activity adjustment

required CrCl < 30ml/min

80%



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)


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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


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


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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


Fluoroquinolones

Antibiotic Activity Dosing Absorption Adverse Effects


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


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


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Linezolid

AntibioticActivity

Dosing Absorption Adverse Effects


Most advocate 600mg daily or 300mg twice


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


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


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


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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

References10. Drugs for Tuberculosis. Treat Guidel Med Lett. 2012 Mar;10(116):29-36 11. Khan FA, Minion J, Pai M, Royce S, Burman W, Harries AD, Menzies D.

Treatment of active tuberculosis in HIV-coinfected patients: a systematic review and meta-analysis. Clin Infect Dis. 2010 May 1;50(9):1288-99. doi: 10.1086/651686

12. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. http://aidsinfo nih gov/ContentFiles/AdultandAdolescentGL pdf (Accessedhttp://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. (Accessed May 20, 2013).

13. Peloquin CA, Namdar R. Chapter 121. Tuberculosis. In: Talbert RL, DiPiro JT, Matzke GR, Posey LM, Wells BG, Yee GC, eds. Pharmacotherapy: A Pathophysiologic Approach. 8th ed. New York: McGraw-Hill; 2011. http://www.accesspharmacy.com.offcampus.lib.washington.edu/content.aspx?aID=8003007. (Accessed May 20, 2013).

14. Gumbo T. Chapter 56. Chemotherapy of Tuberculosis, Mycobacterium AviumComplex Disease, and Leprosy. In: Brunton LL, Chabner BA, Knollmann BC, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 12nd ed. New York: McGraw-Hill; 2011. http://www.accesspharmacy.com.offcampus.lib.washington.edu/content.aspx?aID=16678373. (Accessed May 20, 2013).

References 15. Brooks GF, Carroll KC, Butel JS, Morse SA, Mietzner TA. Chapter 28.

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.

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