Tuberculosis treatment in special situations

Dr. Onur Fevzi ERERİzmir Göğüs Hastalıkları ve Cerrahisi

Eğitim ve Araştırma Hastanesi

Contents

1. TB treatment in pregnancy and breastfeeding

2. TB treatment in chronic renal failure (CRF)

3. TB treatment in chronic liver disease

4. TB treatment and diabetes mellitus

5. TB treatment in silicosis

Where do you work ?

1. University hospital

2. Teaching hospital

3. Goverment hospital

4. Dispensary

5. Private

What do you suggest? Pregnancy and TB

35 year old female patients. No previous TB treatmentShe has cough for a month. Health status is good.She is pregnant for 4 months (Invitro fertilization method)Two sputum smears were positive for AFPHer gynecologist recommended her not to take any medication during pregnancyWhat do you suggest ?1) Postpone TB treatment to the third trimester2) Postpone TB treatment until labor.3) Recommend medical aborts 4) 2 HRZE + 4 HR5) 2 HRE + 7 HR

Pregnancy and TB

The most lethal infectious disease among women in the world is TB with 1 million deaths per year. It occurs in 15-49 years old women that 80% of deaths due to TB. This fact suggest that TB is an important health problem among fertile women.

There are many different opinions about TB and pregnancy since Hippocrates.

It is believed for centuries that enlargement of uterus helps closing of cavities in the lung and hormonal changes due to pregnancy help to improve TB

The opposite hypothesis is proposed in the 19 th century. Because of the belief that pregnancy worsened TB. Women with TB were not allowed to marry , get pregnant, have children or to breastfeed.

Nowadays, when pregnant and non-pregnant women with TB are compared, TB treatment results are not different

111 pregnant and TB 51 pregnant 51 TB Patients are followed up for 2-5 years Results;

Pregnancy had no effect on TB Pregnancy duration, premature birth and other

obstetrical complication and congenital abnormalities were not different among these groups.

Tripathy S.N., Tripathy S.N. Int J Gynaecol Obstet. 2003 Mar;80(3):247-53.

Extrapulmonary TB is seen more frequently in women Nonspecific complaints such as fatigue, lack of appetite

are attributed to pregnancy Tendency of avoiding to use radiological methods in

pregnancy TB diagnosis is delayed in pregnant women

Delay in diagnosis of TB is the most important cause of ; Aborts Toxemia Difficult labor Low birth weight Low APGAR score

•Llewelyn M, Sriskandan S, Terrazzini N, et al. Tuberculosis diagnosed during pregnancy: a prospective study from London. Thorax. 2000;55(2):129-32.•Ormerod P. Tuberculosis in pregnancy and the puerperium. Thorax 2001;56:494–499•Bjerkedal T, Bahna SL, Lehmann EH. Course and outcome of pregnancy in women with pulmonary tuberculosis. Scand J Respir Dis 1975;56:245–50.•Jana N, Vasishta K, Jindal SK, et al. Perinatal outcome in pregnancies complicated by pulmonary tuberculosis. Int J Gynecol Obstet 1994;44:119–24.•Jana N, Vasishta K, Saha SC, Ghosh K. Obstetrical outcomes among women with extrapulmonary tuberculosis. N Engl J Med. 1999;341(9):645-9.

Pregnant women with TB who were early diagnosed and had appropriate treatment had similar perinatal results like non-pregnant women

Figueroa-Damien R, Pregnancy and tuberculosis: influence of treatment on perinatal outcome.Am J Perinatol 1998;15:303–6.

Compliance problems for TB treatment in pregnancy

Pregnant women may not want to take their drugs. Nausea and vomiting in pregnancy may cause problems

for taking TB drugs Tendency of treatment interruption. Health care providers should give pregnant women the

impression of being trust worthy, importance of treatment should be explained and TB treatment should be completed.

DOT is the most important method for compliance DOT should be performed by health care providers

instead of family members.

DrugRisk

categorizations in pregnancy

İsoniazid C

Rifampisin C

Ethambutol B

Pyrazinamide C

Streptomycin D

Provided by FDA; A: No risk B: Risk ratio had not been approved by animal experiments and studies in pregnantC: Has a potential riskD: Data for fetal risk if it has a life threaten condition, drug may use X: Certainly not use

Önerilen rejim

ATS 2 HRE / 7 HR

WHO 2 HRZE / 4 HR

Health Ministry (Turkey) 2 HRZE / 4 HR

Recommendation for TB treatment in pregnancy

It is important to start treatment as soon as possible in pregnancy for good maternal and fetal resultsIt is accepted that first line drugs can be used safely in pregnancy except streptomycinPyridoxine is recommended in pregnant Liver function test (LFT) should be measured in every two weeks in the first ( weeks and monthly afterwards.K vitamin should be given to avoid newborn heamorigical disease due to rifampisin

Drug Safety in breastfeedingConcentration

in milk %

İsoniazid

Hemolysis in glucose 6 phosphates insufficiency in new born. B6 is advised to prevent neuropaty in new born

6.4-25

Rifampisin Safe 0.57-7.3

Ethambutol Safe 2.8-6.9

Pyrazinamide Not known 0.75-1.5

Streptomycin Safe, Poor GES absorption 0.95-22.5

The transfer of first line TB drugs into human milk is low.However This level in milk does not protect baby from TB or cause side effects. Smear positive puerperant should be separated from her newborn

Newborn from mother with active TB

X-ray ve Tuberculin skin test (TST)

If the baby is sick, treat No disease

H prophylaxis

After 3 months evaluate for TB

TST (-)BCG

TST (+)

No disease,Prophylaxis continue to 6th month

evaluate for TB

What do you suggest? Renal failure and TB

45 years old male patients. He has hemodialysis 3 times / week for 5 years.He had swelling in his neck for 2 months. Biopsy specimen shows TB lymphangitis.Which regimen do you suggest?

1) 2 HRZE + 4 HR before dialysis2) 2 HRZE + 4 HR after dialysis3) 2 H3R3 Z3E3 + 4 HR before dialysis 4) 2 H3R3 Z3(E)3 + 4 H3R3 after dialysis

Renal failure and TB

In renal failure, risk of TB is higher due to decreased of cellular immunity.

Many investigations indicate that to develop 10-70 times more in hemodialysis and peritoneal dialysis patients than normal population.

Diagnosis is more difficult in CRF because of nonspecific clinical findings and extra-pulmonary TB

Factors influencing TB treatment in CRF

Medical pharmacokinetics; Drug metabolism proportion in kidneys and excretion

by HD and PD affects blood drug levels and changes efficiency and toxicity.

Accompanying diseases; Hepatitis C and B D.M Protein energy malnutrition Other opportunistic infection

Interaction with other drugs

DrugPharmacokinetic

propertiesCrCl* < 30 ml/min or hemodialysis

İsoniasideMetabolized in liver (acetylization)

Can be used. 5 mg/kg/day (max. 300 mg/day or 900 mg /3days in a week) . Pyridoxin 25 mg /day recommended.

Rifampisin

Metabolized in liver (cytocrom p450). 30% excreted in urine (not changed)

Can be used. 10 mg/kg/day (max. 600mg /day or 600 mg/3 days in a week)

PyrazinamideMetabolized in liver but metabolites excreted kidneys.

Dose interval should be increased. 25-35 mg/kg/3days in a week, daily use is not recommended

Ethambutol Excreted by kidneys

If it is essential, serum levels should be measured and dose interval should be increased. 15-25 mg/kg/3 days in a week, daily use is not recommended.

AminoglycosidesExcreted by kidneys

If it is essential, serum levels should be measured and dose interval should be increased. 15-25 mg/kg/3 days in a week, daily use is not recommended.

There is no randomized controlled study about treatment in CRF

Today, many guidelines are based on characteristics of pharmacological and case reports.

Treatment regimen of new cases with CRF

Regimen

WHO 2 HRZ / 4 HR

Health Ministery (Turkey)

KrKl>30 ml/min; 2 HRZE / 4 HRKrKl<30 ml/min; 2 HRZ3E3 / 4 HR

2 (HRZE)3 / 4 (HR)3

• E: Close monitoring for optic neuritis and drug serum level monitorization• Pyridoxine 25 mg/day should be added.• Drugs should be administered after HD with DOT.

What do you suggest? Liver disease and TB

55 years old alcoholic cirrhosis patients is diagnosed to have smear (+) TB.During the first week of standard TB treatment (HRZE), LFT rises 5 times normal levels and treatment is stopped.The same treatment regimen is initiated gradually. However hepatotoxicity is seen and treatment stopped again.For about 2 weeks LFT is as bellows:ALT: 180 u AST: 170 u T.bil: 2.0 mg D. Bil: 1.2mgWhat is your suggestion ?

1) 2 HRES + 6 HR2) 2 HES + 10 HE3) 9 RE4) 12 REFqCs5) Refer to specialized center

Liver disease and TB

Hepatotoxicity due to TB treatment is very common in this group.

It may be fatal, because of limited liver function It is very difficult to differentiated to undulation in LFT

between liver disease and drug induced hepatitis. Abnormal LFT at the beginning of TB treatment must be

differentiated. The follow up and treatment of these patients must be

done by specialized center

H, R, Z are related with hepatotoxicity Z is most hepatotoxic drug. R causes cholestatic

jaundice. Ethionamid, prothionamid and PAS are hepatotoxic Fluoroqunilones are rarely hepatotoxic.

LFT is not directly correlated with metabolism of drugs in liver.

In the existence of ascites, drug distribute in ascites and half-life period is prolonged.

In the existence of ascites, drug serum levels must be monitored

The following situations are related with hepatotoxicity without chronic liver diseases;

Hepatitis carrier History of acute hepatitis Excessive alcohol consumption Old age Extensive lung infiltrations Low serum albumin level Abscent of HLADQA1*0102 allele and existence of

HLA-DQB1*0201 allele

In chronic liver disease; ALT < 3 x ULN ; standards regimen

(with close clinical and laboratory fallow up) If hepatotoxicity occurs during treatment is

stopped and referred specialized center.

ATS 2003 guidelineATS 2006 Hepatotoxicity ofAntituberculosis Therapy

guideline**

WHO 2003 guideline

without H;6 RZE or

2 RZE + 10 RE

without Z;2 HRE + 7 HR

2 HRES + 6 HR or

9 RE or

2 HES + 10HE

without Z;2 HRE + 7 HR

cirrhosis;12-18 REFqCs*

one hepatotoxic drug *;12-18 REFqCsI encephalopathic liver

disease;18-24 EFqCsI*no hepatotoxic drug*;

18-24 EFqSX

H: İsoniazid, R: Rifampisin, Z: Pyrazinamide, E: Ethambutol, S: Streptomycin, FQ: Fluoroquinolon, Cs:, I: Injectable agent (amikasin, capreomisin,streptomisin, kanamisin), X : Oral minör anti TB drug (Cycloserin, because of no hepatotoxicity) *: No safety and effiency data about these regimens. Refer to specialized center. **: At beginning of treatment ALT > 3 x ULN. This situation not due to TB

What do you suggest ?Diabetes mellitus and TB

62 years old female patient. She has type II D.M for 10 years She takes oral antidiabetic drugs.She has complaint of cough and sputum for 1 month.Sputum smear for AFP positive (2 times). Laboratory findings:Blood glucose: 320 mg/dl, Urine: glucose (++). No aseton and keton What do you suggest?

1) Outpatient, 2 HRZE + 4 HR , increasing dosage of oral antidiabetic drugs2) Outpatient, 2 HRZE + 7 HR , increasing dosage of oral antidiabetic drugs3) Inpatient, 2 HRZE + 4 HR, convert to insüline.4) Inpatient, 2 HRZE + 7 HR, convert to insüline.

Effects of D.M to TB

Especially, decrease in the number and functions of T lymphocytes cause decrease in cellular immunity.

It is observed that hyperglycemia also decreases the intracellular bactericidal activity of leukocyte

Increased glycerol due to fat metabolism also increases the growth rate of TB bacilli

Eventually, TB is seen 1.5-7.8 times more frequently in D.M patients than in non DM patients

Effects of D.M to TB

The tissue concentration of TB drugs can not be achieved because of decreased GES drug absorbtion and hyperglicemic status.

Effect of TB to D.M

Relationship between D.M and TB is not one side TB causes hyperglycemia and insulin resistance by

affecting blood glucose regulation. TB treatment can have negative effects on beta cells

functions and cause a hidden DM in non DM patients. In D.M patients , it may also cause exogen insulin need.

TB and D.M

In case of abnormal LFT, biguanid and sulfonylurea drugs are not recommended.

R, induces the hepatic enzymes that metabolize sulfonylurea drugs.

H, has an antagonist effect on sulfonylurea. R, has an negative effect on glycemic control by causing

hypercortizol and increase the intestinal absorption of glucose

TB and D.M

If D.M is good controlled the result of Tb treatment at the standard regimen and duration are as same as non D.M.

It is recommended to convert the oral anti diabetic therapy to insulin to type II D.M patients and to give intensive insulin therapy in type I D.M patients.

For glycemic control and compliance to TB therapy, hospitalization is recommended.

Pyridoxine must be added.

What do you suggest?Silicosis and TB

36 years old male patient worked 10 years in the stone quarry.20 pocket-year of cigaretteDiagnosed as silicosis two years ago and stop working.Increasing cough complaint in for two month.Sputum smear for AFP is positive What do you suggest ?

1) 2 HRZE + 4 HR2) 2 HRZE + 7 HR3) 2 HRZES + 1 HRZE + 5 HRE4) 2 HRZE + 10 HR

Silicotuberculosis

Risk of TB is 2.8-30 times more in silicosis. Primary pathology;

Alveolar macrophages functions are blocked by silica Local defense mechanism are decreased

Relapse has become an important problem in the modern therapy ages.

*Cowie RL. The epidemiology of tuberculosis in gold miners with silicosis. Am J Respir Crit Care Med 1994; 150:1460-1462.*Westerholm P, Ahlmark A, Maasing R, Segelberg I. Silicosis and risk of lung cancer or lung tuberculosis: a cohort study. Environ Res 1986; 41: 339-350.

In South Africa, in 167 silicosis patients of total 549 TB patients

5 HRZS treatment regimen In 5 years follow up relapse was seen 1.55 times

more in silicotuberculosis group.

Cowie RL et al. Silicotuberculosis: long-term outcome after short-course chemotherapy. Tuber Lung Dis. 1995;76(1):39-42

In 1987 , Taiwan, prospective study, 2 HRZS + 7 HR regimen, TB patients with silicosis

5 % treatment failure 5% relapse in two years %90 treatment success

Lin TP, Suo J et al. Short-course chemotherapy of pulmonary tuberculosis in pneumoconiotic patients. Am Rev Respir Dis. 1987 ;136(4):808-10

In 1991 , Hong Kong , 240 Chinese silicotuberculosis patients

6 months; 2 (HRZS)3 + 4 (HR)3

8 months; 2 (HRZS)3 + 6 (HR)3

randomized in the two groups . 3 years follow up after treatment

6 months 22 % relapse 8 months 7 % relapse

Hong Kong Chest Service/tuberculosis Research Centre, Madras/British Medical Research Council.A controlled clinical comparison of 6 and 8 months of antituberculosis chemotherapy in the treatment of patients with silicotuberculosis in Hong Kong. Am Rev Respir Dis. 1991;143(2):262-7.

It is recommended lengthen the continuous phase to make the total treatment duration 9 months for preventing relapse in silicotuberculosis.

Önerilen rejim

T.C. Sağlık Bakanlığı 2 HRZE / 7 HR

Conclusion

Patient centered and multidisciplinary approach and treatment is the basis of therapy of TB in special situations.

Changes in the therapy must be concluded by pulmonary physicians especially working in this area.

1. I’m confused about TB treatment 2. I learnt new things about TB treatment

3. Good coortons 5. It’s over now4. I’m happy to come here

LAST QUESTION