Diabetes Tb New

7/31/2019 Diabetes Tb New

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Double Trouble:

Diabetes and Tuberculosis


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Definitions

Latent Tuberculosis Infection (LTBI)

Persons are infected with M. tuberculosis, but do

not have active TB disease.

Active TB Disease

Persons infected with M tuberculosis bacteria that

progress from latent TB infection.


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Transmission ofM. tuberculosis

Spread by airborne route; droplet nuclei

Transmission affected by

Infectiousness of patient Environmental conditions

Duration of exposure

Most exposed persons do not becomeinfected


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TB Patient Characteristics That Increase Risk for

Infectiousness

Coughing

Undergoing cough-inducing or aerosol-

generating procedure

Failing to cover cough

Having cavitation on chest radiograph


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TB Patient Characteristics That Increase Risk for

Infectiousness

Positive acid-fast bacilli (AFB) sputum smear

result

Disease of respiratory tract and larynx Disease of respiratory tract and lung

or pleura

Inadequate TB treatment


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Characteristics of Infectiousness

Infectiousness related to

Cough >3 weeks

Cavitation on chest radiograph

Positive sputum smear results

Respiratory tract disease involving lung, airway, orlarynx

Failure to cover mouth and nose when coughing Inadequate treatment

Undergoing cough- or aerosol-producing procedures


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Antituberculosis Drugs

Isoniazid

Rifampin

Pyrazinamide

Ethambutol

Rifabutin*

Rifapentine

Streptomycin

Cycloserine

p-Aminosalicylic acid

Ethionamide

Amikacin or kanamycin*

Capreomycin

Levofloxacin* Moxifloxacin*

Gatifloxacin*

First-Line Drugs Second-Line Drugs

*Not approved by the U.S. Food and Drug Administration for use in the

treatment of TB


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Treatment Regiments for LTBI

Drugs Months ofDuration

Interval MinimumDoses

INH 9*Daily 270

2x wkly 76

INH 6Daily 180

2x wkly 52

RIF 4 Daily 120

*Preferred

INH=isoniazid; RIF=rifampin


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Treatment for TB Disease

TB treatment regimens must contain multiple

drugs to which M. tuberculosis is susceptible

Treating TB disease with a single drug can lead

to resistance

Also, adding a single drug to a failing regimen

can lead to drug resistance


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Treatment for TB Disease

Preferred regimen Initial phase: 2 months isoniazid (INH), rifampin (RIF),

pyrazinamide (PZA), and ethambutol

Continuation phase: 4 months INH and RIF

In patients with cavitary pulmonary TB and positiveculture results at end of initiation phase,continuation phase should be 7 months

TB patients with HIV who are taking anti-retrovirals(ARVs) should be managed by TB/HIV diseaseexperts TB treatment regimens might need to be altered


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When to Consider Treatment Initiation

Positive AFB smear

Treatment should not be delayed because of

negative AFB smears if high clinical suspicion:

History of cough and weight loss

Characteristic findings on chest x-ray

Emmigration from a high-incidence country


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Other Examinations to Conduct When

TB Treatment Is Initiated

Counseling and testing for HIV infection

CD4+ T-lymphocyte count for HIV-positive

persons

Hepatitis B and C serologic tests, if risks

present


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Other Examinations to Conduct When

TB Treatment Is Initiated

Measurements of aspartate aminotransferase

(AST), alanine aminotransferase (ALT),

bilirubin, alkaline phosphatase, serum

creatinine, and platelet count

Visual acuity and color vision tests (when

EMB used)


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Algorithm to Guide Treatment ofCulture-Negative TB

Give continuation- phasetreatment

of INH/RIF dailyor twice weekly for

2 months

NO YES

Wasthere

symptomaticor chest x-ray

improvement after2 months oftreatment?

NO YESIsinitial

culturepositive?

Continue

treatment for culture-positive TB

Discontinue treatment

Patient presumed tohave LTBI

Treatment completed


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Role of New Drugs

Rifabutin: For patients receiving medications

having unacceptable interactions with

rifampin (e.g., persons with HIV/AIDS)

Rifapentine: Used in once-weekly

continuation phase for HIV-negative adults

with drug-susceptible noncavitary TB and

negative AFB smears at completion of initialphase of treatment


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Role of New Drugs

Fluoroquinolones (Levofloxacin,

Moxifloxacin, Gatifloxacin): Used when

-first-line drugs not tolerated;

-strains resistant to RIF, INH, or EMB; or

-evidence of other resistance patterns with

fluoroquinolone susceptibility


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Common Adverse Reactions to

Drug TreatmentDrug Adverse Reaction Signs and Symptoms

Any drug Allergy Skin rash

Ethambutol Eye damage Blurred or changed vision

Changed color vision

Isoniazid,Pyrazinamide,

or

Rifampin

Hepatitis Abdominal painAbnormal liver function test

results

Fatigue

Lack of appetite

Nausea

Vomiting

Yellowish skin or eyes

Dark urine


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Drug Treatment

Drug Adverse Reaction Signs and SymptomsIsoniazid Peripheral

neuropathyTingling sensation in hands andfeet

Pyrazinamide Gastrointestinalintolerance

Arthralgia

Arthritis

Upset stomach, vomiting, lackof appetite

Joint aches

Gout (rare)

Streptomycin Ear damage

Kidney damage

Balance problems

Hearing loss

Ringing in the ears

Abnormal kidney function testresults


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Drug Treatment

Caused by Adverse Reaction Signs and Symptoms

Rifamycins

Rifabutin

Rifapentine Rifampin

Thrombocytopenia

Gastrointestinalintolerance

Drug interactions

Easy bruising

Slow blood clotting

Upset stomach

Interferes with certainmedications, such as birthcontrol pills, birth control

implants, and methadonetreatment


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Rifampin

MOA

Inhibits mycobacterial and bacterial RNA synthesis

Bactericidal and broad spectrum:

mycobacteria, gram(+), gram(-) bacteria Increases in vitro activity of INH and SM

Resistance

Mutations in the target, DNA-dependent RNA

polymerase, reduce binding of RIF to the

polymerase


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PK

Rapid absorption, Cp 2-4h; 8 mg/L

Food decreases rate, extent

Distributes to most body fluids CSF levels 10-20% of plasma

Metabolism: deacetylated; enterohepatic

circulation w/ significant reabsorption

T 3-5 hours

Dose: 10 mg/kg (up to 600mg) po daily

Rifampin


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Rifampin

Adverse effects

GI distress, rash, elevated liver tests

Hepatotoxicity

Discoloration of urine, tears, saliva, feces Rare hypersensitivity reaction; ARF; thrombocytopenia

Drug interactions

Potent inducer of CYP 3A4, 2C9, 2C19

Lower levels: NNRTIs, maraviroc, etravirine,

carbamazepine, phenytoin, warfarin,OAD


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Isoniazid

MOA

prodrug; mycobacterial catalase-peroxidaseconverts INH to an active metabolite

Inhibits biosynthesis of mycolic acids (MAs).MAs + polysaccharide (arabino galactan),

form part of cell wall.

Resistance Mutations in at least 5 genes e.g. katG- codes

for catalase-peroxidase.

Petri, Goodman and Gilman, 11th ed


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Isoniazid

PK

Readily absorbed; Cp 1-2h; 3-5 mg/L

Food decreases rate & extent

Distribution: all body tissues/fluids,

therapeutic CSF levels w/ inflammed meninges

Metabolism: acetylation (primary) & hydrolysis

T 1-4 hours (depends on acetylation status)

Dose: 5mg/kg (up to 300mg) po daily


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Isoniazid

Adverse effects

Hepatitis, elevated transaminases, rash, fever,jaundice,peripheral neuritis (malnutrition, DM, anemia increaserisk)

Drug Interactions Stavudine, didanosine (neuropathy)

INH inhibits CYP 3A4

Elevated carbamazepine, phenytoin levels

Comments Pyridoxine 25-50mg po daily to prevent neuropathy

Avoid EtOH


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Ethambutol

MOA

Inhibition of arabinogalactan & lipoarabinomannan

synthesis; inhibits RNA synthesis impairing cellmetabolism

& multiplication; disrupts formation of cell wall Active against actively dividing bacilli; primarily

bacteriostatic; cidal at higher doses

Resistance

Single amino acid substitutions in embA gene

Dose 15-25 mg/kg po daily

Separate from antacids


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Pyrazinamide

MOA

PZA = pyrazinoic acid (POA) by a pyrazinamidase.

Targets mycobacterial fatty acid synthase I gene (involved in mycolic

acid biosynthesis)

POA lowers pH

prevents growth of TB

Mainly static; can be cidal (concentration and TB-susceptibility

dependent)

Effective within macrophages, most effective early in treatment

Resistance Loss of pyrazinamidase activity; decreased formationof active moiety

Develops quickly if used as monotherapy


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Pyrazinamide

MOA

Suppressive in vivo; cidal in vitro

Does not readily enter living cells; intracellular organisms escape

Inhibition of protein synthesis

Resistance

Ribosomal protein mutation

Develops gradually over course of therapy

As monotherapy 80% at 4 months

PK

Rapid absorption after IM injection; Cp at 30-90 min; 15-30ug/mL Poor distribution into cells, CSF, or respiratory secretions; Vd 0.25

L/kg

Clearance: renal; T ~2-3 hours


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Ethionamide

MOA

structural analog of INH inhibits mycolic acid synthesis disruptingformation of cell wall

Susceptible organisms and liver convert ethionamide to ethionamideS-oxide (active moiety)

Static or cidal (concentration and TB susceptibility dependent) No cross-resistance with cycloserine, PAS, SM

Resistance

Mutations in inhA gene

Develops quickly if used as monotherapy

Possible cross-resistance with INH (documented, but infrequent);mutations in catalase-peroxidase are not involved


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Ethionamide

Adverse Effects

GI: Abdom pain, N/VD, metallic taste, anorexia,

elevated liver tests (transient)

CNS: dizziness, drowsiness, HA,

Other: paresthesias (give with pyridoxine) vision

changes, rash, hypothyroidism

Drug Interactions

Stavudine, didanosine (risk of PN)

Cycloserine (inc seizure risk in patients with sz d/o)

EtOH, psychotic reactions reported


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Aminosalicylic Acid

PAS

MOA

Similar to sulfonamides, impairs folatebiosynthesis

Bacteriostatic; activity only against M.tb

Resistance develops slowly

PK

Readily absorbed, Cp 1.5-2h; 7.5 mg/L

Distributed throuout TBW; high pleuralconcentrations, low CSF levels

Clearance: >80% excreted unchanged in urine


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Aminosalicylic Acid

PAS

Dose: 50 mg/kg po q8h (12 G/day max)

Dose after meals (gastric irritant)

Adverse Effects

GI: anorexia, N/D, abdominal pain

Hypersensitivity (5-10%): fever, abrupt or gradual,

malaise, joint pain, sore throat, various skin eruptions

Leukopenia, agranulocytosis, eosinophilia,lymphocytosis, thrombocytopeniaoccasional

hemolytic anemia

Drug interactions

Probenecid decreases renal excretion


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Cycloserine

MOA

Inhibits cell wall synthesis; structural analog ofDalanine

(involved in cell-wall synthesis)

Resistance

No cross resistance with other agents

PK

Rapid absorption (70-90%), Cp 3-4 h; 20-35 ug/mL Wide distribution; CSF levels ~= plasma

Renal clearance, 65% unchanged in urine


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Cycloserine

Dose: 250mg po bid initially, up to 500mg bid

Adverse effects

Neuropsychiatric toxicities (HA, vertigo,

nervousness, tremor, irritability, confusion,psychosis, twitches, seizures)

Drug interactions/cautions

EtOH increases seizure risk. Contraindicated if

seizure d/o

Depression (suicide risk)


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Capreomycin

MOA

Cyclic peptide.

4 active components-capreomycins IA, IB, IIA,IIB

Polypeptide complex w/ toxicities

Resistance: mutation in tlyA

PK: fe 50-60%, T 3-6 hours

Dose: 15 to 20 mg/kg IM daily or up to 1G x 60-

120 days, f/b 1 G 2-3 times/week


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Capreomycin

Dose (renal impairment):

ClCr


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Other

Linezolid

In vitro activity against M. tuberculosis

Resistance: ribosomal RNA mutation

Interferon-y

Activates macrophages to kill M. tuberculosis

Can give via aerosol; wide pulmonarydistribution


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Drug Interactions

Relatively few drug interactions substantiallychange concentrations of antituberculosisdrugs

Antituberculosis drugs sometimes change

concentrations of other drugs

-Rifamycins can decrease serumconcentrations of many drugs, (e.g., most of

the HIV-1 protease inhibitors), tosubtherapeutic levels, OAD

-Isoniazid increases concentrations of somedrugs (e.g., phenytoin) to toxic levels


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Prevention of TB in persons with

DMPersons with diabetes mellitus (DM) who are atincreased risk of tuberculosis (TB) should bescreened for latent TB infecti on (LTBI)

TST or IGRA should be done at time of DMdiagnosis

Patients with DM who are found to have LTBI should

be encouraged to take INH for 9 months Patients with DM on INH should receive vitaminB6 to prevent INH induced neuropathy


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Screening for DM in persons with TB

Every patient with TB over the age of 18 should

be screened for DM

A fasting plasma glucose > 125 mg/dl = DM

A random plasma glucose > 200 mg/dl = DM

A Hemoglobin A1c > 6.5% = DM

Abnormal glucose values should be repeated in

patients who have no symptoms of DM


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Screening for DM in persons with TB

Glucose should be repeated after 2-4 weeks of

TB Rx or if symptoms of hyperglycemia

develop

Rifampin can markedly elevate glucose levels

Use the same criteria to diagnose DM as at initial

evaluation

Ask about polyuria/polydipsia at TB clinic visits


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Management of DM in patients receiving

TB treatment

Use the frequent contact with the patient duringTB treatment to help manage his/her DM in theTB clinic

There should be a glucose meter in every TB clinic andblood glucose should be frequently checked in theclinic for those with DM

All clinical staff should reinforce lifestyle changes at TBclinic visits

If available, refer persons with diabetes to a diabetesspecialty clinic or clinician comfortable with treatingDM


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Management of DM in patients

receiving TB treatment

DOT workers should encourage lifestyle changes

at every encounter

Dietary changes and physical activity are most

important in this effort

Use available structured diabetes education

materials i.e. NDEP available at:

www.YourDiabetesInfo.org

Consider delivering DM meds with TB meds via DOT
http://www.yourdiabetesinfo.org/http://www.yourdiabetesinfo.org/


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Treatment of TB in persons with DM

Ensure that TB treatment is appropriately

adjusted in persons with DM

Check creatinine for diabetic nephropathy

May need to adjust frequency of PZA and EMB

administration

Give B6 to prevent INH induced peripheral

neuropathy


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Ensure that TB treatment is appropriatelyadjusted in persons with DM

Persons with DM have a relative immune suppressionand often a higher burden of disease

Consider extending treatment to 9 months for personswith DM and caviatary disease OR delayed sputumclearance.

Upon completion of therapy, obtain smear and culture

for AFB

Follow up the patient at 6 months and one year aftertreatment completion


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Observe closely for treatment failure

Be aware of poor absorpti0on of some TB meds in

DM

Manage the many interactions between TB and DMmeds

There may be a slight increase in diabetic retinopathy

in persons with DM

Special Treatment Situations


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Renal Insufficiency and End-Stage

Renal Disease Renal insufficiency complicates management

of TB because some antituberculosis

medications are cleared by the kidneys Dosage should not be decreased because

peak serum concentrations may be too low;

smaller doses may decrease drug efficacy

l


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Dosing interval of antituberculosis drugs

should be decreased

Most drugs can be given 3 times weekly after

hemodialysis; for some drugs, dose must be

adjusted

Special Treatment SituationsRenal Insufficiency and End-Stage

Renal Disease

S i l T Si i


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Hepatic Disease

Must consider regimens with fewer hepatotoxicagents for patients with liver disease

Recommended regimens:

1) Treatment without PZAInitial phase (2 months): INH, RIF, and EMB

Continuation phase (7 months): INH and RIF

2) Treatment without INH

Initial phase (2 months): RIF, PZA, and EMB

Continuation phase (4 months): RIF, EMB, and PZA

S i l T Si i


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Hepatic Disease

Recommended regimens: (continued)

3) Regimens with only one potentially

hepatotoxic drug

RIF should be retained

Duration of treatment is 12-18 months

4) Regimens with no potentially hepatotoxic drugs

Duration of treatment is 18-24 months


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Treatment Failure

Defined as positive cultures after 4 months oftreatment in patients for whom medicationingestion was ensured

Single new drug should never be added to a

failing regimen; it may lead to acquiredresistance to the added drug

Add at least three new drugs (e.g.,fluoroquinolone, ethionamide, and an injectable

drug: SM, amikacin, kanamycin, or capreomycin)to the existing regimen being cognizant of thepossibility of drug resistance


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References

Centers for Disease Control and Prevention. Guidelines

for preventing the transmission ofMycobacterium

tuberculosis in health-care settings, 2005. MMWR 2005;

54 (No. RR-17): 1141.http://www.cdc.gov/nchstp/tb/pubs/mmwrhtml/

Maj_guide/infectioncontrol.htm

Errata (August 2006) available online

http://www.cdc.gov/nchstp/tb/pubs/mmwrhtml/Errata_table.pdf

ddi i l id li
http://www.cdc.gov/nchstp/tb/pubs/mmwrhtml/%20Maj_guide/infectioncontrol.htmhttp://www.cdc.gov/nchstp/tb/pubs/mmwrhtml/%20Maj_guide/infectioncontrol.htmhttp://www.cdc.gov/nchstp/tb/pubs/mmwrhtml/Errata_table.pdfhttp://www.cdc.gov/nchstp/tb/pubs/mmwrhtml/Errata_table.pdfhttp://www.cdc.gov/nchstp/tb/pubs/mmwrhtml/Errata_table.pdfhttp://www.cdc.gov/nchstp/tb/pubs/mmwrhtml/Errata_table.pdfhttp://www.cdc.gov/nchstp/tb/pubs/mmwrhtml/%20Maj_guide/infectioncontrol.htmhttp://www.cdc.gov/nchstp/tb/pubs/mmwrhtml/%20Maj_guide/infectioncontrol.htm


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Additional TB Guidelines CDC. Prevention and Control of Tuberculosis in Correctional and Detention Facilities:

Recommendations from CDC.MMWR 2006; 55 (No. RR-09): 144.

CDC. Guidelines for the investigation of contacts of persons with infectious tuberculosis:recommendations from the National Tuberculosis Controllers Association and CDC.MMWR 2005; 54 (No. RR-15): 1-37.

CDC. Guidelines for using the QuantiFERON-TB Gold Test for detecting Mycobacteriumtuberculosis infection, United States. MMWR 2005; 54 (No. RR-15): 49-55.

CDC. Controlling tuberculosis in the United States: recommendations from the American

Thoracic Society, CDC, and the Infectious Diseases Society of America. MMWR 2005; 54(No. RR-12): 1-81.

CDC. Guidelines for infection control in dental health-care settings2003. MMWR 2003;52 (No. RR-17).

CDC. Treatment of tuberculosis. American Thoracic Society, CDC, and Infectious DiseasesSociety of America. MMWR 2003; 52 (No. RR-11).

CDC. Guidelines for environmental infection control in health-care facilities:recommendations of CDC and the Healthcare Infection Control Practices AdvisoryCommittee (HICPAC).MMWR 2003; 52 (No. RR-10).

Documents

Diabetes Tb New