IN THE MANAGEMENT OF

By

Dr. Soji Ige FWACPSenior Lecturer

College of Medicine, University of IbadanPulmonologist

University College Hospital, Ibadan,

INTRODUCTION

• Prior to 1950s the mainstay of management was bedrest, fresh air, sunshine (where available)

• and in suitable cases, surgical intervention– resection of tuberculosis lesions– more commonly the active management depended

on ‘collapse therapy’, collapsed therapy ‘rested’ diseased lung and might take the form of artificial pneumothorax, pneumoperitoneum. Collapse of the lung by pleural plombage in which the pleural & hence the underlying lung, were compressed by implanted material (e.g lucile balls or mineral oil).

Drugs

• Schatz and Waksman in 1944 discovered streptomycin, which heralded a new era of tuberculosis chemotherapeutics

• PAS by Lehmann, followed by INH in 1952Controlled Clinical Trials on Early Drugs• British Medical research Council - World 1st

control clinical trialTreated Group Control Group

51% showed radiographic improvement7% diedAll patients deteriorated after 3 months

8% showed radiographic improvement21% dieadAll patients deteriorated after 3 months

Conclusion: Mycobacterial resistance to strep emerged after 3 months of treatment

• Development of PAS and Isoniazid– Study

– Strep. And PAS or– Strep. and INH or– PAS and INH, prevented the emergence of drug-resistant

organisms

• Report from Edinburgh in 1958 showed that combination theraphy with Strep, PAS and INH, prevent the emergence of drug-resistant organisms and to effect a 100% cure– These early regimens are for 18 months or 2 years

Drugs (Continued)

Comes with the passage of time and the introduction of new drugs

Short Course Chemotherapy

Principles of Modern ChemotherapyFour different populations of bacterial exist within tuberculous lesions

and each is particularly accesible to the action of a different

antitubeculosis drug

a)rapidly growing bacilli e.g in cavity walls (Active cavity with neutral pH)

- INH/RIF/SM - bactericidal

b & c) Slowly growing population as in cells (macrophages) and solid caseous tissue (persisters) RIF/PZA/INH

RIF and PZA are potent sterilizing agents.

PZA is particularly effective against bacilli in an acid (presumably intracellular) environment pH< 5.6

d) a fourth population of totally dormant bacilli not killed by any drug

Principles of Modern Chemotherapy of Tuberculosis

Inadequate Rx:

Treatment Failure

INHRIFSM

Slowly multiplying intracellular and in

closed caseous lession

Actively multiplying extracellular bacilli

RIFINHPZA

Adequate Rx: sterilizing action

Adequate Rx: bactericidal

action

Lasting cure of tuberculosis

Elimination of ‘persisters’

Elimination of

extracellular

Inadequate Rx:Late growth of

‘persisters’

Relapse

• First-line drugs - RIF, INH, Ethambutol, PZA, SM

• Second-line drugs – Cycloserine

• Ethionamide• Prothionamide

– Aminoglycoside• capreomycin• kanamycin• viomycin

– Fluoroquinolone• Ciprofloxacin• Ofloxacin

Classification of Antituberculous Drugs

Newer Drugs

• Rifambutin

• Rifapentin

Chemotherapy Regimen for Pulmonary Tuberculosis

Standard 6-month short-course chemotherapy2SHRZ/4RH2EHRZ/4RH

Standard 9-month short-course chemotherapy2SHR/7RH2EHR/7RH

• The relevance of compliance and the strategies that can be employed to guard against the emergence of drug resistance organisms is important

• This is called by the provision of DOTS (directly observed therapy short-course)

Relapse rates with different 6-month chemotherapy regimens in patients with drug-sensitive bacilli

Initial Continuation No. of Follow-up RelapseReference Phase Phase Subjects (Months) %

Singapore Tuberculosis Service/ 2SHRZ 4HRZ 84 6 0British Medical Council [86] 2SHRZ 4HR 80 6 1

Singapore Tuberculosis Service/ 2SHRZ 4H3R3Z3 97 24 1British Medical Council [96] 1SHRZ 5H3R3 94 24 1

2HRZ 4H3R3 109 24 1

Algerian Working Group/British 2EHRZ 4HR 229 24 4Medical Council Co-operative Study

Third East African/British Medical 2SHRZ 4TH 89 6 9Research Council Study [98)

Tanzania/British Medical Research 2SHRZ 4TH 105 24 3Council Study [99]

Snider et al. [100] 2SHRZ 4H2R2 56 24 22HRZ 4H2R2 116 24 3

E, ethambutol; H, isoniazid; R, rifampicin; S, streptomycin; T, thiacetazone; Z, pyrazinamide.Subscript indicate degree of intemittency e.g H2 represents isoniazid twice weekly; numbers preceding letters indicate duration in months, e.g 4HR represents 4 months of therapy with daily isoniazid and rifampicin

Chemotherapy Regimen for Pulmonary Tuberculosis (continued)

Other non-standard 6-month regimens

2SHRZ/4H3R3

1SHRZ/5H3R3

2HRZ/4H3R3

• Studies from Singapore, Algeria, East Africa and Poland based on an intial 1 or 2 months four-drug phase of therapy followed by a variety of 4-month intermittent or daily regimens had satisfactory success rates

Treatment of Smear-negative Pulmonary Disease

• Standard short-course chemotherapy in developed countries

• National tuberculosis programmes in the developing world recommend the most appropriate regimens for smear-positive and smear negative cases in their own countries where the luxury of routine mycobacterial culture and sensitivity pattern determination is usually not available.

• In Nigeria we use:

– 2SHRZ/6TH; 2EHRZ/6TH before

– and now 2SHRZ/6EH; 2EHRZ/6EH

Empirical Treatment of Smear-negative Disease

• Where TB is suspected on clinical and radiological grounds but bacteriological proof is lacking

• Start standard short-course chemotherapy while awaiting the results of bacteriological cultures

• Complete treatment if the cultures prove positive or negative

• Treatment should stop in an unusual event of a clinical and radiological response to treatment is inappropriate (i.e usually too fast or too complete). In such cases a simple bacterial pneumonia may have responded to rifampicin

Such cases should be kept under review for 6 months if treatment is to be stopped

Assessing Treatment Response

• In patients with positive bacteriology, sputum status should be assessed monthly; by 2 months more than 85% of positive sputum culture should have converted to negative. Ideally drug sensitivity pattern should be checked.

• Failure to convert ring alarm bells about patients compliance and/or the emergence of drug resistant disease. Drug sensitivity pattern should be rechecked

• Clinically, after 1-4 weeks the patient should be feeling better, have gained weight and be free from fever, cough and sputum.

• Chest radiographic changes should have improved after 2 months and continue to improve over several months, eventually leaving residual fibrotic and/or cavitary change. CXR is also taken at the end of treatment

Assessing Treatment Response (Continued)

• Failure of clinical or radiographic appearances to change after 2-3 months should lead to concerns about compliance and/or drug-resistant disease monitoring of adverse reactions during standard short-course chemotherapy.

• Baseline measurement of visual acuity• FBC and platelets• Liver function test (bilirubin and liver enzymes)• Uric acid

EXTRAPULMONARY TUBERCULOSIS

• Lymph node tuberculosis

• Genitourinary tuberculosis

• central nervous system

• Miliary Tuberculosis

Standard 9-month chemotherapy or 6-month chemotherapy

Standard 6 or 9-month chemotherapy plus prednisolone 40mg OD for 6 months

Steroid to prevent ureteric stricture

Standard 6-month chemotheray

The continuation phase is prolonged duration of treatment is 9-12 months

Add prednisolone 1mg/1kg/day

Standard 6-month chemotherapy

Treatment in Special Situations

• Pregnancy

• Childhood

• HIV Infection– With the standard short-course chemotherapy,

relapse rates are no more common in HIV-positive than in HIV-negative patients if the continuation phase of treatment is prolonged to give a total duration of chemotherapy of 9 months.

– The rate of sputum culture conversion is similar in both groups

Streptomycin is ototoxic to the fetus and is contraindicated Because of difficulties

in monitorin for ocular toxicity, Ethambutol is best avoided

Drug Resistance and the Management of Diseases due to Drug-resistant Organisms

The three stages in the development and spread of drug-resistant tuberculosis

Colony of mycobacterium tuberculosis

Resistant mutants

Secondary (multiple) drug- resistance tuberculosis

Primary (multiple) drug- resistance tuberculosis

More primary (multiple) drug- resistance tuberculosis

Natural mutations

Selection of resistant strains by inadequate treatment

Transmissionin droplets

Further transmission

HIV infection Inadequate infection controlDiagnostic delay

(1)

(2)

(3a)

(3b)

Drug Resistance and the Management of

Diseases due to Drug-resistant Organisms (continued)

• There are 3 stages• The fourth contribution to the problem comes from

migration of patients with primary and secondary resistance into the control area.

• Tuberculosis patients with secondary drug-resistant tuberculosis may infect others who are then said to have tuberculosis that demonstrates primary resistance

• Such transmission is facilitated by HIV infection, where disease development and progression seem more rapid.

• Primary resistance. Like secondary drug resistance may be transmitted to others thus spreading drug-resistance disease within the community.

Treatment of Drug-resistant Disease

• The essence of success is to treat with at least two and preferably three drugs to which the organisms is known or believed to be sensitive until sputum cultures have been negative for at least 6 and possibly 12 months.

• Where disease is intractable, surgical resection may be of value

Summary

• The worst possible scenerio, one in which tubercle bacilli become increasingly resistant to multiple drugs resulting effectively in a return to the prechemotherapy era of tuberculosis with 50-80% mortality rates, will only be avoided if the long-established principles of treating tuberculosis are rigidly observed. At present, this means considering the need for DOT for every patient