Double Trouble: Diabetes and Tuberculosis

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.

Transmission of M. tuberculosis
Spread by airborne route; droplet nuclei Transmission affected by
Infectiousness of patient Environmental conditions Duration of exposure

Most exposed persons do not become infected

TB Patient Characteristics That Increase Risk for Infectiousness Coughing Undergoing cough-inducing or aerosolgenerating procedure Failing to cover cough Having cavitation on chest radiograph

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

Characteristics of Infectiousness
Infectiousness related to
Cough >3 weeks Cavitation on chest radiograph Positive sputum smear results
Respiratory tract disease involving lung, airway, or larynx Failure to cover mouth and nose when coughing Inadequate treatment Undergoing cough- or aerosol-producing procedures

Antituberculosis Drugs
First-Line Drugs Isoniazid Rifampin Second-Line Drugs Streptomycin Cycloserine

Pyrazinamide
Ethambutol Rifabutin*

p-Aminosalicylic acid
Ethionamide Amikacin or kanamycin*

Rifapentine

Capreomycin
Levofloxacin* Moxifloxacin*

Gatifloxacin*
* Not approved by the U.S. Food and Drug Administration for use in the treatment of TB

Treatment Regiments for LTBI

Drugs Months of Duration Interval Minimum Doses

INH INH RIF

*Preferred

9* 6 4

Daily

270

2x wkly
Daily 2x wkly Daily

76
180 52 120

INH=isoniazid; RIF=rifampin

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

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 positive culture 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 disease experts
TB treatment regimens might need to be altered

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

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

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)

Algorithm to Guide Treatment of Culture-Negative TB

NO

Is initial culture positive?

YES

NO

Was there symptomatic or chest x-ray improvement after 2 months of treatment?

YES

Continue treatment for culturepositive TB

Discontinue treatment Patient presumed to have LTBI Treatment completed

Give continuation- phase treatment of INH/RIF daily or twice weekly for 2 months

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 initial phase of treatment

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

Common Adverse Reactions to Drug Treatment

Drug Any drug
Ethambutol

Adverse Reaction Signs and Symptoms Allergy Skin rash

Eye damage Blurred or changed vision Changed color vision Abdominal pain Abnormal liver function test results Fatigue Lack of appetite Nausea Vomiting Yellowish skin or eyes Dark urine

Isoniazid, Hepatitis Pyrazinamide, or Rifampin

Common Adverse Reactions to Drug Treatment

Drug Isoniazid Adverse Reaction Peripheral neuropathy Pyrazinamide Gastrointestinal intolerance Signs and Symptoms Tingling sensation in hands and feet Upset stomach, vomiting, lack of appetite

Arthralgia
Streptomycin Arthritis Ear damage

Joint aches
Gout (rare) Balance problems Hearing loss Ringing in the ears

Kidney damage

Abnormal kidney function test results

Common Adverse Reactions to Drug Treatment

Caused by Rifamycins Rifabutin Rifapentine Gastrointestinal intolerance Rifampin Drug interactions Adverse Reaction Signs and Symptoms Thrombocytopenia Easy bruising Slow blood clotting Upset stomach

Interferes with certain medications, such as birth control pills, birth control implants, and methadone treatment

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

Rifampin
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
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

Isoniazid
MOA prodrug; mycobacterial catalase-peroxidase converts 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

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

Isoniazid
Adverse effects Hepatitis, elevated transaminases, rash, fever,jaundice, peripheral neuritis (malnutrition, DM, anemia increase risk) Drug Interactions Stavudine, didanosine (neuropathy) INH inhibits CYP 3A4 Elevated carbamazepine, phenytoin levels Comments Pyridoxine 25-50mg po daily to prevent neuropathy Avoid EtOH

Ethambutol
MOA Inhibition of arabinogalactan & lipoarabinomannan synthesis; inhibits RNA synthesis impairing cell metabolism & 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

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

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

Ethionamide
MOA structural analog of INH inhibits mycolic acid synthesis disrupting formation of cell wall Susceptible organisms and liver convert ethionamide to ethionamide S-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

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

Aminosalicylic Acid PAS

MOA Similar to sulfonamides, impairs folate biosynthesis Bacteriostatic; activity only against M.tb Resistance develops slowly PK Readily absorbed, Cp 1.5-2h; 7.5 mg/L Distributed throuout TBW; high pleural concentrations, low CSF levels Clearance: >80% excreted unchanged in urine

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

Cycloserine
MOA Inhibits cell wall synthesis; structural analog of Dalanine (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

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)

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 60120 days, f/b 1 G 2-3 times/week

Capreomycin
Dose (renal impairment): ClCr <80 10mg/kg q24h ClCr <50 14 mg/kg q48h ClCr <10 7 mg/kg q72h Adverse effects Hearing loss, tinnitus, transient proteinuri, cylindruria, nitrogen retention (severe kidney failure rare) Eosinophilia (common) Leukocytosis, leucopenia, rash, fever Pain at injection site

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 pulmonary distribution

Drug Interactions
Relatively few drug interactions substantially change concentrations of antituberculosis drugs Antituberculosis drugs sometimes change concentrations of other drugs -Rifamycins can decrease serum concentrations of many drugs, (e.g., most of the HIV-1 protease inhibitors), to subtherapeutic levels, OAD -Isoniazid increases concentrations of some drugs (e.g., phenytoin) to toxic levels

Prevention of TB in persons with DM

Persons with diabetes mellitus (DM) who are at increased risk of tuberculosis (TB) should be screened for latent TB infecti on (LTBI) TST or IGRA should be done at time of DM diagnosis

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 vitamin B6 to prevent INH induced neuropathy

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

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

Management of DM in patients receiving TB treatment

Use the frequent contact with the patient during TB treatment to help manage his/her DM in the TB clinic
There should be a glucose meter in every TB clinic and blood glucose should be frequently checked in the clinic for those with DM All clinical staff should reinforce lifestyle changes at TB clinic visits If available, refer persons with diabetes to a diabetes specialty clinic or clinician comfortable with treating DM

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

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

Treatment of TB in persons with DM

Ensure that TB treatment is appropriately adjusted in persons with DM
Persons with DM have a relative immune suppression and often a higher burden of disease Consider extending treatment to 9 months for persons with DM and caviatary disease OR delayed sputum clearance. Upon completion of therapy, obtain smear and culture for AFB Follow up the patient at 6 months and one year after treatment completion

Treatment of TB in persons with DM

Observe closely for treatment failure
Be aware of poor absorpti0on of some TB meds in DM Manage the many interactions between TB and DM meds There may be a slight increase in diabetic retinopathy in persons with DM

Special Treatment Situations 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

Special Treatment Situations Renal Insufficiency and End-Stage Renal Disease

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 Situations Hepatic Disease

Must consider regimens with fewer hepatotoxic agents for patients with liver disease Recommended regimens:
1) Treatment without PZA Initial 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

Special Treatment Situations 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

Treatment Failure
Defined as positive cultures after 4 months of treatment in patients for whom medication ingestion was ensured Single new drug should never be added to a failing regimen; it may lead to acquired resistance 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 the possibility of drug resistance

References
Centers for Disease Control and Prevention. Guidelines for preventing the transmission of Mycobacterium 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

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 Mycobacterium tuberculosis 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 Diseases Society 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 Advisory Committee (HICPAC).MMWR 2003; 52 (No. RR-10).