Causative agent

Tuberculosis (TB) is an airborne disease caused by bacteria belonging to the Mycobacterium tuberculosis complex. The M. tuberculosis complex consists of M. tuberculosis and seven very closely related mycobacterial species (M. bovis, M. africanum, M. microti, M. caprae, M. pinnipedii, M. canetti and M. mungi). Most, but not all, of these species have been found to cause disease in humans but most TB disease is caused by M. tuberculosis. 

Transmission of Mycobacterium tuberculosis (M. tuberculosis) is carried in airborne particles, called droplet nuclei. Infectious droplet nuclei are generated when persons who have pulmonary or laryngeal TB disease cough, sneeze, shout or sing. Depending on the environment, these tiny particles can remain suspended in the air for several hours. Transmission occurs when a person inhales droplet nuclei containing M. tuberculosis, and the droplet nuclei traverse the mouth or nasal passages, upper respiratory tract, and bronchi to reach the alveoli of the lungs. The infectiousness of a person with TB disease is directly related to the number of bacilli they expel into the air.

 Various factors determine the probability of transmission and acquisition of infection. These include host factors many of which are poorly understood, factors related to the pathogen and environmental factors. 

Transmission of Mycobacterium tuberculosis is facilitated by exposure to a greater volume of droplet nuclei, in small enclosed spaces that are poorly lighted and ventilated and with long duration of contact and closer proximity to the infectious person.

Pathogenesis of TB

When a person inhales air that contains water droplets containing M. tuberculosis, most of the larger droplets become lodged in the upper respiratory tract (the nose and throat), where infection is unlikely to develop. However, smaller droplet nuclei may reach the small air sacs of the lung (the alveoli), where infection is more likely to become established

In the alveoli, some of the tubercle bacilli are killed, but a few multiply in the alveoli and enter the bloodstream and spread throughout the body. Bacilli may reach any part of the body. The areas where TB infection develops include the upper portions of the lungs, as well as the kidneys, brain and bone. Within 2 to 8 weeks of entry of the bacilli into the body, the body’s immune system usually intervenes, halting multiplication and preventing further spread of the tubercle bacilli. When infection is established but the TB bacilli are not actively replicating and there is no apparent disease, the person is said to have Latent TB Infection (LTBI). LTBI is a function of a complex host –pathogen relationship that is poorly understood currently. In simple terms during LTBI the individual’s immune system is able to keep the infecting bacilli under control and inactive through the development, production and activation of immune cells that surround the tubercle bacilli, forming a shell that acts as a fence and prevents the bacilli from replicating. People who have LTBI are NOT infectious i.e. they cannot spread the infection to other people. These people usually have a normal chest x-ray. It is important to remember that LTBI is not considered a case of TB. Major similarities and differences between LTBI and TB disease.

 Some people with LTBI progress on to develop TB disease.  In general, it is accepted that persons who progress from LTBI to active TB have failure of immunological mechanisms that have hitherto prevented multiplication of MTB. The risk that TB disease will develop following infection is higher for some people than for others.  Active TB disease that develops within a few months or years (1-2) after infection is labelled primary TB disease, while disease that develops many years (>2 years) after infection is called post primary or reactivated TB. The risk of developing TB disease following infection varies with various host factors such as concurrent infection with HIV, presence of diabetes mellitus, presence of chronic kidney and many others. In non HIV infected persons the lifetime risk of developing TB following infection is in the region of 10% which means that the majority of persons infected with MTB, currently estimated to be about a third of the world population, will never develop TB disease. 

Tuberculosis is a major public health threat in Zimbabwe. Tuberculosis Case Notification Rate (TB-CNR) was stable for several decades between the 60’s and 80’s at about 100/100,000, but this situation dramatically changed in the 90’s when TB-CNR increased year on year until 2002 when a peak was reached (450/100,000).  Since then the TB-CNR has been declining steadily with variations in the rate of decline on a year by year basis (212/100, 000 in 2015).

In 2015, 28 225 TB cases were notified to the NTLP of which, 40% were bacteriologically confirmed pulmonary TB (PTB) cases, 46% were clinically diagnosed PTB cases and 14% were extra–pulmonary TB cases (EPTB). The proportion of re-treatment cases increased from 6% of all notified cases in 2007 to 12% in 2014. As in the rest of the world, the population most affected by TB was the economically productive age group between 25 and 44 years.  In the population below 24 years, there were more females than males affected by TB and in the 25-34 years age group, rates of TB were similar in males and females, while in all other age groups TB rates were higher in males compared to females. There were district variations in TB case notifications   with districts in the Southern parts of the country more affected by TB compared to Northern districts. These variations in TB–CNR appeared to be related to variations in HIV prevalence. Tuberculosis case notification in children of ages 14 years and below, as a proportion of all notified TB cases, has averaged 5-6% in the last five years. 

The Zimbabwe NTLP has identified the following groups of people as the vulnerable or key populations for active TB:

 • Persons living with HIV Infection (PLHIV).

 • Children, especially those 5 years of age and below.

 • Current and ex-miners.

 • Persons living in correctional facilities including inmates, the officers who work in these facilities and their families.

 • Health Care Workers.

 • Persons living with diabetes mellitus.

 • Persons receiving immunosuppressive therapies.

 • Persons with chronic kidney disease.

 • Tobacco smokers.

 • Persons living in urban slums.

 • Persons living in remote rural areas with poor access to health services. 

In 2015, 96% of all TB cases were tested for HIV; 70% were HIV positive. Of the HIV positive TB cases, 96% were put on Cotrimoxazole Preventive Therapy (CPT) and 86% were commenced on anti-retroviral medicines. 

Tuberculosis prevention, care and control is based on the following key principles:

 1. Early and complete identification of incident TB cases with prompt initiation of effective treatment so as to reduce TB morbidity including clinical illness that may result from long term sequelae of TB, prevent death and stop transmission of the causative agent.

 2. Treatment of active TB disease with multiple medicines to prevent Mycobacterium tuberculosis from developing resistance to any medicine.

 3. Providing appropriate support to persons being evaluated for TB or on treatment for TB to ensure full adherence to diagnostic processes and treatment until completion, while avoiding processes or procedures that have the potential to increase diagnostic or treatment costs to the patient and/or his/her family.

 4. Providing an enabling environment, with adequate resources (human, financial, commodities and work environments) to ensure effective and efficient delivery of TB services.

  5. Proactively and routinely screening and testing groups of patients known to be at risk of active TB and promptly linking those found to have TB to care and treatment. 

6. Provision of Tuberculosis Preventive Therapy (TBPT) to individuals who are infected with Mycobacterium tuberculosis but, at the time of evaluation do not have clinical, radiologic and/ or bacteriologic evidence of active TB disease.

 7. Engaging multiple partners and stakeholders in the TB response including private health care providers, non-governmental organizations, community based organizations and communities themselves in the TB response.

 8. Vigorously pursuing efforts to eliminate poverty, which is the major driver of TB.

  9. Providing an environment for creativity and innovation to thrive with rapid adaptation of new ideas, approaches and practices. 

These principles have now been packaged into a comprehensive strategy called the End TB Strategy

Treatment of Drug Susceptible TB 

The AIMS of treatment are to:

• Cure the patient and ensure return to a full quality of life. 

• Prevent death from active TB or its complications.

• Prevent relapse of TB.

• Stop transmission of TB to others.

• Prevent the development and transmission of drug resistant TB

Tuberculosis treatment policies in Zimbabwe  

Practice Recommendations

• Diagnosis and treatment of TB is offered for FREE in Zimbabwe.

• Treatment of TB should be supervised (DOT) throughout its duration. 

• Both intensive phase (IP) and continuation phase (CP) must be completed.

• Multiple medicines preferably FDCs should be used to treat all forms of TB using standardised regimens. 

• Every patient is treated under a designated class with either medicines that currently belong to the first line group (for treatment of drug susceptible TB) or to the 2nd line group (for treatment of drug resistant TB) guided by DST results.

• All patients on treatment need to be monitored both clinically and with laboratory assessment in addition to receiving appropriate support throughout treatment.

• Documentation of every step of the management process is critical. 

Justification

As part of the efforts to end TB in Zimbabwe, TB diagnostic and treatment services are offered at all levels of delivery of health services free of charge. This is one of the strategies of reducing catastrophic costs to TB affected patients and their families.

 Treatment of TB should be supervised throughout its duration. The recommended approach is directly observed treatment (DOT) which requires a supporter to watch a patient swallowing the tablets. This ensures that the patient takes the right medicines, in the right doses and completes the treatment. The preferred order of DOT supporter is health workers, trained community health workers, trained family members/guardians. 

 NB: In highly motivated TB patients or those with special circumstances that impede DOT, self-administered treatment (SAT) can be employed. However, even when SAT is chosen every effort must be taken to ensure that the patient is fully aware of the obligation to adhere to treatment and to keep up with routine follow up and appointments. Video – observed treatment (VOT) is a new innovation that can be explored subject to guidance from NTLP.

Full TB treatment is delivered in two phases both of which must be completed:

 • Intensive Phase (IP): the initial, intensive phase is designed for rapid killing of actively growing bacilli and killing of semi- dormant bacilli. The duration of this phase is 2 months.

• Continuation phase (CP): this phase eliminates bacilli that are persistent and reduces the rate of failure and relapses. The duration is between 4 -6 months depending on the organ affected by the disease. It is important to use multiple medicines in the treatment of TB to avoid emergence of drug resistance. In a population of MTB bacilli that have never been exposed to anti-TB medicines, variable proportions of the bacilli will have spontaneous resistance mutations to any single drug, however, it is highly improbable that there will be bacilli that are resistant to multiple agents at the same time. If single medicines are used to treat TB, the bacilli with resistant mutations to the medicine used will be selected and allowed to replicate leading to failure of treatment. The three essential medicines for the treatment of drug susceptible TB are Isoniazid (H or INH), Rifampicin (R or Rif) and Pyrazinamide (Z or PZA) and they form the backbone of current short course chemotherapy (SCC) of TB. Ethambutol (E) is added in case there may be pre-existing resistance to one of these medicines.  

 The essential anti-TB medicines are available either as single medicine formulations or as fixed dose combinations (FDCs) that include two medicines (2-FDC), three medicines (3-FDC) or four medicines (4FDC). The FDCs available in Zimbabwe are Rifampicin, Isoniazid, pyrazinamide and ethambutol (RHZE); Rifampicin, Isoniazid and Pyrazinamide (RHZ) and Rifampicin and isoniazid (RH). While a recent systematic review has suggested that treatment with single drug formulations may confer some risk of acquired drug resistance, the risk appears to be small and thus the Zimbabwe NTLP has chosen to continue using FDCs for the following reasons: 

• FDCs reduce the pill burden (maximum of 5 instead of 15-16 tablets per day) and are thus more convenient for the patient.

• FDCs also simplify both treatment and supply management system for these medicines.

• Finally, FDCs reduce the risk of inappropriate treatment either through clinician error or selection by the patient of medicines to be taken on account of link between the medicine with an adverse event or even taste.  The number of FDC tablets to be taken by each patient is determined by the weight of the patient at the start of treatment with dose adjustment made as the patient’s weight band changes with treatment.

All patients are treated with first line medicines in standardized regimen combinations.   Standardized regimens have the following advantages over individualized prescription of medicines:

• Facilitate estimates of medicine needs, purchasing, distribution and monitoring.

• Reduce errors in prescription thereby reducing the risk of development of drug resistance.

• Facilitate staff training. 

• Reduce costs.

• Facilitate regular medicines supply when patients move from one area to another. Every patient should be treated with either first line (FLD) or second line medicines (SLD) as guided by DST results. First line drugs are used in patients whose DST results do not show resistance to at least rifampicin irrespective of whether they are new patients who have never taken anti-TB medicines or they were previously treated with one or more FLDs. Second line drugs are used for all patients whose DST results show resistance to R, either alone or in combination with other FLDs. 

All patients on treatment need to be monitored throughout treatment for adherence, treatment response, and development of adverse events and at the end of treatment be assessed for treatment outcomes. The progress of the patient, changes in clinical status, medication use and other clinical events should be documented at every stage using the patient TB treatment card. 

 INITIATION OF TREATMENT

 Patients who are confirmed to have TB bacteriologically or clinically should be started on appropriate treatment by the clinician (doctors and nurses) at the point of diagnosis for the convenience of the patient.  The patient must be notified and registered in the facility TB register. These patients should be monitored and followed up as recommended.

Treatment of drug susceptible TB in adults (FLDs) 

Intensive phase         2RHZE

Continuation phase   4RH

Treatment for Extra-pulmonary TB (EPTB) 

There have been no robust clinical trials to guide the choice of treatment regimens for EPTB. Experts recommend that most forms of EPTB are treated with the 2RHZE/4RH standard regimen.

Practice Recommendation

• Initiate TB treatment immediately upon making a diagnosis of TB.

• All new or retreatment TB cases with rifampicin resistance not detected on Xpert MTB /Rif testing are treated for 6 months with FLDs using the regimen 2RHZE/4RH.

• All patients with meningo-cerebral TB and skeletal TB, which are difficult to treat forms of EPTB should be treated for at least 8 months using the regimen 2RHZE/6RH. Clinical evaluation at end of such treatment may lead to extension of treatment for up to 12 months.

• All other cases of EPTB are treated with the six month 2RHZE/4RH standard regimen.

• Doses of anti-TB medicines are weight based and remember to adjust doses when the weight band of a patient on treatment changes.

• All new or retreatment TB cases with rifampicin resistance detected on Xpert MTB/Rif assay should be treated with Second Line Drugs and second line DST must be done to guide treatment regimens.

• Treatment of TB is generally ambulatory (treatment received at an outpatient or community basis) except for special situations requiring admission.

Patients with meningo-cerebral and skeletal TB where treatment may be extended for up to 12 months. This is primarily a result of the poor penetration of medicines to these disease sites and the consequences of either failure of treatment or recurrent disease should disease be insufficiently treated.  The Zimbabwe NTLP has chosen to treat intracranial and skeletal TB with an 8 months regimen consisting of 2RHZE/6RH with the provision that clinicians can extend treatment beyond 8 months if in the judgement of the clinician an adequate response to treatment has not been achieved by the end of the 8th month. 

Dosage of anti-TB medicines in adults

 The dose of anti-TB medicines is based on the WEIGHT of the patient. Note: Adjust dosage as soon as the patient weight band changes to avoid under- or over-dosage. Below are estimates of number of FDCs per KG body weight:

Weight based dosing of FLDs Patient’s weight Intensive phase for 2 months 2(RHZE) daily (Isoniazid 75mg + Rifampicin 150mg + pyrazinamide 400mg + Ethambutol 275mg).

 Continuation phase for 4 months i.e. 4 (HR) daily (Isoniazid 75mg+ Rifampicin 150mg)

25-39 KG :2 

40-54 KG :3 

55-70 KG :4 

70 KG +: 5 

Children weighing 25 kg and more should be treated using the adult treatment guidelines.

Children with severe malnutrition should be given medicines at the lower end of the dose range and closely watched for hepatotoxicity.

Tuberculosis in children is treated in a similar way to that in adults with a few exceptions. The dose per weight in children is higher than in adults. The recently revised and accepted WHO daily dosage (range) recommendations are:

Rifampicin:  15 mg/kg/d (10 to 20 mg/kg/day)

Isoniazid:  10 mg/kg/d (10 to 15 mg/kg/day)

Pyrazinamide:  35 mg/kg/d (30 to 40 mg/kg/day)

Ethambutol: 20 mg/kg/d (15 mg to 25 mg/kg/d)

Practice Recommendations

• All children with drug susceptible TB on DST (new or retreatments) are treated with FLDs in a similar way to adults using the regimen 2RHZE/4RH.

• In children with TB meningitis, osteo-articular TB and miliary TB, the continuation phase is prolonged for 10 months, thus the regimen used is 2RHZE/10RH.

• Commencement of TB therapy should be documented on the child health card for children under 5 years of age. 

• Monthly weight should be documented on the TB treatment card and child health card where applicable. Failure to gain weight may indicate poor response to therapy.

• The treatment doses should be adjusted as soon as the child’s weight band changes.

 •  The care giver and child should receive comprehensive information and education including the reasons why they must take the full course of treatment even if they are feeling better. 

• Remember some children require to be hospitalised and others require pyridoxine supplementation during treatment (see below).  

 Doses of paediatric formulations of anti TB medicines Weight Band Recommended Regimen Intensive Phase Continuation Phase

RHZ (75/50/150), E (100) , RH (75/50) 4-7kg 1 1 1 8-11kg 2 2 2 12-15kg 3 3 3 16-24kg 4 4 4  25kgs and above Adopt adult dosages 

Reasons for hospitalization in children

 Children with the following characteristics should be hospitalized

• Severe forms of TB such as TB meningitis (TBM).

• Severe malnutrition requires in-patient based nutritional rehabilitation.

• Signs of severe pneumonia such as chest in-drawing. 

• Other co-morbidities e.g. severe anaemia.

• Social or logistic reasons likely to interfere with adherence to anti-TB medicines e.g. severe alcoholism in a parent or guardian and lack of appropriate social support at the home environment.    • Neonates.  

• Severe adverse reactions such as hepatotoxicity.

Pyridoxine supplementation

 Isoniazid (INH) may cause symptomatic pyridoxine deficiency, which manifests as peripheral neuropathy. The NTLP recommends that all children on INH as part of the anti-TB treatment regimen or for TBPT should receive pyridoxine. It is however appreciated that the following categories of children are at an increased risk of developing peripheral neuropathy: 

• malnourished

• breastfeeding infants

• adolescents

• Children on high-dose INH therapy (>10mg/kg/day)

• children with diabetes mellitus

• Children with renal failure

• All pregnant women with TB should be treated in a similar way to non-pregnant women. Firstline anti-TB medicines are safe in pregnancy, except for streptomycin (which will be less often used as a first line medicine) which is ototoxic to the foetus.

• Note: Tuberculosis in pregnancy is associated with an increased risk of premature birth, low birth weight and perinatal death. For these reasons, women who develop TB should be strongly encouraged not to become pregnant while receiving treatment for TB and should be provided with appropriate contraception (using double protection as highlighted in the text box above)

Practice Recommendations

 • All pregnant women with TB should be treated with a similar regimen to women who are not pregnant (2RHZE/4RH). First Line Drugs(FLDs) are considered safe in pregnancy.

 • FLDs are safe in breast-feeding mothers

 • Breast feeding babies whose mothers are on treatment for pulmonary TB should be screened and tested for TB and only be initiated on preventive therapy using 6H (INH for SIX months) if active TB has been excluded. After completion of 6H, these babies should be vaccinated with BCG. 

 • Women in the child bearing age who are taking medicines for the treatment of TB should be advised to postpone getting pregnant until after the TB treatment is completed. Double contraception using a hormonal contraception and a barrier method should be recommended for such women. 

• Patients with chronic liver disease should not receive pyrazinamide. Both INH and Rif are also hepatotoxic but less so compared with PZA and may be used with caution in patients with mild pre-existing liver disease. In severe pre-existing liver disease, PZA, INH and Rif should be avoided. These patients may be treated with an injectable, ethambutol and a fluoroquinolone with or without the addition of cycloserine for a total of 9-12 months. All such patients should be treated under the supervision of a medical specialist. 

• Patients with renal failure can still use 2RHZE/4RH with adjusted doses and dosing intervals under specialist care.  Pyridoxine is given to prevent INH-induced peripheral neuropathy

Breastfeeding women

Full TB treatment is safe, and is the best way to prevent transmission of TB to the baby. If the mother has pulmonary TB then the baby should receive INH preventive treatment (10 mg/kg for 6 months) after TB screening using a symptom enquiry and a CXR with or without a TST. Once active TB is excluded, the child should be treated with 6H and pyridoxine.  On completion of 6H, BCG vaccination should be provided. Mother and baby should not be separated on account of TB. As far as possible, mother and child should stay together for the entire duration of treatment.

Women taking hormonal contraceptives 

Rifampicin reduces the efficacy of the contraceptive pill through induction of liver enzymes (cytochrome P450) which enhance the metabolism of many medicines including hormonal contraceptives. Therefore, providing an additional contraceptive method (dual protection) preferably a barrier method is recommended. However, this must be balanced against potential harms such as greater risk of acquisition of HIV for intrauterine implants/devices.  

Patients with liver disorders and established chronic liver disease

Provided there is no clinical evidence of chronic liver disease which is associated with increased risk of anti-TB drug induced hepatitis, patients with the following conditions can receive the usual short-course chemotherapy: hepatitis virus carriage, a past history of acute hepatitis, and excessive alcohol consumption. Patients with chronic liver disease should not receive pyrazinamide. Patients may receive less hepatotoxic medicines such as INH and Rifampicin but must be clinically and biochemically monitored (AST, ALT and bilirubin) with the medicines promptly stopped if there is evidence of worsening of the liver disease. If INH and Rif are used without PZA, the treatment should be extended to 9 months, with the regimen therefore being 2RHE/7RH. If PZA, INH and Rif cannot be used because of severe existing liver disease, an injectable, Ethambutol and a fluoroquinolone with or without Cycloserine (note the overlap of symptoms between the central adverse events of Cycloserine and hepatic encephalopathy) may be used with the treatment lasting up to 9-12months. 

NB: All TB patients with pre-existing liver disease should be managed under the care or guidance of a specialist physician while being monitored clinically and or by biochemical tests to rapidly identify evidence of deterioration that requires modification of treatment.

Acute hepatitis (e.g. acute viral hepatitis)

It may be prudent to defer treatment in some cases, while in others it may be necessary to continue with anti-TB treatment. All such patients should be referred to a specialist.

Patients with renal failure

Isoniazid, rifampicin and pyrazinamide are excreted almost entirely by the hepatobiliary system or metabolised into non-toxic compounds. However, the metabolites of PZA, including Pyrazinoic acid and 5 hydroxy-Pyrazinoic acid are excreted by the kidneys and therefore dose adjustment is necessary for PZA in patients with chronic kidney disease (CKD). In severe renal failure, give pyridoxine to prevent INH-induced peripheral neuropathy. Ethambutol is excreted by the kidneys, and should be avoided or used under specialist care. Below are the does adjustments that should be made when treating patients with CKD for TB.

Drug doses and dosing frequency in patients with CKD. CORRECTION

Drug Change in Frequency Recommended Dose and Frequency for Patients with creatinine clearance of <30ml/min or patients  receiving haemodialysis INH No 300 mg once daily Rif No 600 mg once daily PZA Yes 25-35 mg/Kg/dose  3 times/week ( not daily) Ethambutol Yes 20-25 mg/Kg/dose  3 times/week ( not daily) Levofloxacin Yes 750 -1000 mg/dose/ 3 times/week ( not daily) Moxifloxacin No 400 mg once daily Cycloserine Yes 250 mg once daily or 500 mg/dose 3 times/week Ethionamide No 250-500 mg/dose daily PAS No 4g/dose twice daily Streptomycin Yes 15 mg /Kg/dose 2-3 times/week ( not daily) Capreomycin Yes 15 mg /Kg/dose 2-3 times/week ( not daily) Kanamycin Yes 15 mg /Kg/dose 2-3 times/week ( not daily) Amikacin Yes 15 mg /Kg/dose 2-3 times/week ( not daily)

Thus, the regimen given to patient with CKD and drug susceptible TB remains 2HRZE/4HR but the dosing frequency for PZA and Ethambutol is adjusted to three times a week and not daily.

The key clinical practice points to remember when managing patients with TB and CKD are:

• Patients with CKD, on dialysis and following transplantation are at significantly increased risk of tuberculosis. As far as feasible these patients should be managed at the central level/highest level of care.

• All TB patients with concomitant CKD should be treated in the same way as patients without CKD, however medicines doses and dosing intervals need to be adjusted appropriately. 

• Patients with TB and CKD should be cared for by or under the leadership of medical specialists familiar with the management of both TB and CKD. 

• For patients with a creatinine clearance of 30 ml/min or less, dosing intervals should be increased to three times weekly for ethambutol, pyrazinamide and the aminoglycosides.

• For patients on haemodialysis, dosing intervals for ethambutol, pyrazinamide and the aminoglycosides should be increased to three times weekly to reduce the risk of drug accumulation and toxicity. All anti-TB medicines should be given after dialysis to avoid rapid clearance during dialysis.  

• Rifampicin in particular can interact with immunosuppressive medicines, increasing the chance of graft rejection, and doses of mycophenolate mofetil, tacrolimus and cyclosporin may need adjustment. Corticosteroid doses should be doubled in patients receiving rifampicin.

Following diagnosis and initiation of appropriate anti-TB treatment, it is the responsibility of Health Care Workers to retain patients in care until they finish their treatment successfully.

Practice recommendations 

• All TB patients must be enrolled, recorded and reported in the health information (recording and reporting) system used by the NTP

• All TB patients should receive treatment under Direct Observation Therapy.

• Adequate information about TB should be provided regularly to TB patients

• Identifying and managing adverse events due to anti-TB medicines must be prioritized.

• Immediate follow up measures for all patients who interrupt treatment must be instituted.

• Ensure patient centred support systems are in place throughout the course of treatment

• All TB patients must be enrolled, recorded and reported through the recording and reporting (health information and management) system used by the National TB and Leprosy Programme.

Tuberculosis is a chronic disease which requires long duration of treatment. Thus, in order to keep track of every patient and to report on him/her appropriately, every step of the management process should be documented. The TB treatment card should be used for this purpose.  Always capture the following key information:

o Personal details of the patient.

o Information about the diagnosis, classification and category of TB.

o Details of the treatment regimen and actual doses prescribed.

o Enter details of all clinical events that the patient experiences such as adverse events, inter-current illness, medication use, adherence to treatment, changes in medicine doses or dosing frequency etc.  

 Treatment of TB should be supervised throughout its duration. The recommended approach is DOT. The DOT observer should be chosen by the patient in consultation with the health care worker. The selected DOT observer should be a person who is trusted, reliable and acceptable to the patient and who is committed to supporting the patient over the entire period of treatment. In addition, the DOT observer should, if he or she is not a health care worker, be willing to be trained and accept supervision by the health care workers at the treating health facility. Adequate information about TB should be provided regularly to TB patients at diagnosis, prior to treatment initiation and during follow up visits as they receive their treatment. The information enhances their understanding of TB disease, helps them cope with the disease and its treatment and thus to remain in care. The information that should be provided to patients should focus on facts about TB to help dispel myths and misconceptions and should include the following:

 o The cause of TB

o Transmission of TB

o Symptoms and signs of TB

o Diagnosis of TB 

o Prevention of TB transmission 

o The treatment of TB including the medicines used and the length of treatment

o Common adverse reactions of anti-TB medicines and how they are managed 

o The association between TB and HIV

o The need for family and other contact screening and testing for TB 

o Drug resistance in TB and how the patient can avoid acquiring drug resistant TB

o The patient’s right and responsibilities 

 Identification and management of adverse events due to anti-TB medicines must be regularly carried out at every encounter with the patient through symptom enquiry and physical examination such as asking if the patient is nauseated or has vomited and looking at the eyes to see if there is jaundice. Patients must regularly be re-assured about adverse events so that they can develop and sustain confidence in the treatment and the ability of the health care worker and the health care system to “take care of things” should adverse events/reactions occur.  This will enhance the patient adherence to treatment

Immediate follow up measures for all loss to follow up patients must be instituted for those patients who miss their appointments or discontinue treatment for whatever reason. Actions to take include: reminder telephonic messages (SMS); direct phone calls and home visits by HCWs or community-based health workers to establish the reasons for the missed appointment or treatment interruption. All these interventions depend on obtaining and recording detailed information about the patient in the TB treatment card. 

In spite of efforts to prevent interruption of treatment, a proportion of patients (which should be minimal in a well- functioning TB prevention and care program) will still interrupt treatment for various reasons. A proportion of these patients will come back to care either on their own or following retrieval efforts by health care workers.

 Outlined below are the practice recommendations for patients who come back to care after a period of treatment interruption.

 • The first and essential step is to establish the reasons for the interruption of treatment and to attempt as far as feasible to address those reasons in order to prevent a recurrence of treatment interruption.  The most common reasons for treatment interruption include poor understanding of TB and its treatment, difficulties with coping with treatment schedules especially health facility based DOT due to distances and transport costs, negative attitudes of health care staff, feeling well and therefore assuming that treatment is no longer needed, perceived or experienced stigma and discrimination, experience of medicine adverse reactions/events and work schedules.

• Re-enforce patient education on TB and its treatment with an emphasis on adherence to treatment. 

• Continue treatment with anti-TB medicine if the treatment interruption lasted less than a month

• If the treatment interruption lasted more than a month, collect a sputum specimen and send it over to the laboratory for smear microscopy, the Xpert MTB/Rif assay and SL-LPA. 

o If the Xpert MTB Rif assay comes back positive for MTB but with no Rif resistance, restart treatment with first line medicines, recording this patient in the register as a re–treatment case. 

o If the Xpert MTB /Rif assay come back with a positive MTB result and Rif resistance start treatment for RR/MDRTB using the recommended short RR/MDRTB treatment regimen as results of the SL-LPA are awaited. Treatment should be adjusted accordingly when the SL-LPA results are received.

o If the Xpert MTB/Rif assay comes back negative for MTB consider the initial test results, the   amount of treatment that patient had received and thus the time point when treatment interruption occurred. Patient who had a negative Xpert at the beginning of treatment should not be continued on treatment but be investigated for other diseases. Those who have received more than 4 months of treatment may also not be re-treated while patients who have a negative Xpert but have clinical symptoms and radiological features compatible with TB should be re initiated on treatment and recorded as clinically diagnosed re treatment cases of TB.  

Ensure patient centred support systems are in place throughout the course of treatment. All patients on treatment for tuberculosis should have a psycho-social and economic assessment done to identify those who need to be provided with psychological and social support such as transport and food to prevent treatment interruption and to reduce treatment associated costs.

Steroids are beneficial as adjuvant therapy in some forms of TB disease. They work by targeting the host immune response, dampening it and thus reducing pathogen induced, host driven damage to the affected organ. On the other hand, corticosteroid therapy used in patients with TB without concurrent effective anti-TB therapy is hazardous.

Corticosteroid therapy is beneficial and improves outcomes in TB meningitis, TB pericarditis, patients with massive lymphadenopathy as part of paradoxical reaction if used concurrently with effective TB medicines. It is also useful in patients with severe hypersensitivity reactions to anti-TB medicines. 

Indications for steroids

• TB meningitis.

• TB pericarditis.

• Massive lymphadenopathy with pressure effects.

• Severe hypersensitivity reactions to anti-TB medicines.

• More rarely: hypo-adrenalism, renal tract TB (to prevent ureteric scarring), TB laryngitis with life threatening airway obstruction.

 For large TB pleural effusion with severe symptoms, urgent referral to a facility where the effusion can be drained using a chest tube and under water seal drainage system is critical. Drainage using needle and syringe should be avoided because of the risk of introducing air and infectious agents into the thoracic cavity. If the patient already has an empyema when the initial thoracocentesis is done, chest tube placement with under water seal drainage system should be carried out in addition to consultation with a surgeon for consideration of a decortication procedure to prevent massive pleural thickening and chest wall restriction.   

Doses for steroid therapy

Recommended doses for adjuvant steroid therapy Indication Prednisolone treatment TB meningitis 60 mg/d for 4 weeks then taper off.

Alternatively- Dexamethasone 8-12mg/d tapered over 6-8 weeks in cases of patients who cannot swallow prednisolone

TB pericarditis -Prednisolone 60 mg/d for 4 weeks, then 30 mg/d for 4 weeks then taper off over several weeks

Hypersensitivity reaction to TB medicines 20-80mg (average 60mg)/d tapering off over 2-8 weeks

Note: for children the dose of prednisolone is 1-2mg/kg for 4 weeks with appropriate dose tapering thereafter over 2-4 weeks. 

Practice Recommendations

 1.All TB patients on treatment must be monitored frequently for:  - Adherence - Response to treatment (bacteriologically and or clinically) - Adverse drug events (early identification and management)

2.Sputum smear microscopy is used to monitor response to treatment and is done at: a) end of 2 months of intensive phase, b) end of 5 months and c) end of treatment at 6 months.

3.Chest radiographs and Xpert MTB/Rif assays are only used for screening and diagnosis of TB respectively and NOT recommended for follow up and monitoring of TB treatment.

4.At the end of treatment, assessment of outcomes is mandatory for all TB patients.

5.All TB deaths should be audited (guided by death audit forms) within 7 days at the facility where it happened and reported to the next level within the next 7 days while the province will report quarterly to national level. 

Once a patient with TB is started on treatment, he/she must be followed up regularly. The frequency of monitoring depends on the level of care. At the health facility level, this is usually at every visit (two weekly or monthly depending on medicines refill schedules) by the clinician and daily by the DOT nurse 

While at the community level, the treatment supporter should monitor the patient daily during the intensive phase and at least weekly during the continuation phase.  Adherence to medicines as stated before, each patient must take the right regimen at the right dose for the right duration until end of treatment. It is not only the duty of the patient to take his/her medicines but it is also the duty of the health care system, particularly the facility health care workers who are treating the patient, to ensure this. Thus adherence to medicines is an on-going activity that the patient must be continually reminded of and supported to achieve. Every health care worker must use every contact with a TB patient to ensure that adherence to medicines is as near 100% as possible. Therefore, at every contact with the patient assess and support adherence by doing the following:

1. Ask the patient if he/she is taking the medicines. 

2. Carry out a pill count: ask the patient how many pills are left, request to see the tablets he/she has brought in and count them and compare with what was dispensed and what is expected to be remaining.

3. Ask what time he/she takes each medicine and whether he/she takes the medicines before meals or after meals.

4. Check and see if the patient is regularly obtaining treatment: review his/her tuberculosis treatment card and see if medicines were collected and taken at the scheduled times.

Response to TB Treatment

The primary aim of treatment is to cure the patient. Treatment should result in improvement/ decrease of the patient symptoms, resolutions of documented fever and gain in weight if there was significant weight loss due to the disease. These improvements should in most patients, begin to occur within two weeks of treatment. Most patients will be almost completely well within 1-2 months of being on treatment and any patient whose symptoms have not subsided and clinical status has not improved within that time should be evaluated for either a concurrent disease (such as, diabetes), a complication of the disease, poor treatment adherence or drug resistance. Meanwhile, clinicians should review results of the diagnostic tests and ensure that the diagnosis is correct. Monitoring the response to treatment involves clinical monitoring and bacteriological monitoring.

Clinical monitoring and bacteriological monitoring

Clinical monitoring must be done for all patients. For cases of TB where bacteriological monitoring cannot be done such as in most forms of EPTB, this is the only way of monitoring response to treatment. Clinical monitoring consists of re-taking the clinical history and performing physical examination as appropriate. Check the weight of the patient, ask about his/her well-being and ask if the previous symptoms are still present or not at each visit to the clinic. A patient who is doing well will progressively have increased energy, increased appetite, gain in weight, a decrease, if not disappearance, of symptoms and generally feel better.

Bacteriological monitoring 

This is done using sputum smear microscopy to monitor the response to treatment. In drug resistant TB cases, mycobacterium culture is also used for bacteriological monitoring. Examination of sputum smears for conversion from positive to negative is the best indicator that the treatment is being taken regularly and that it is effective. Xpert MTB/Rif assay is only used for diagnosis of TB and is not recommended for monitoring treatment response.

After 2 months of chemotherapy, more than 80% of new pulmonary bacteriologically confirmed cases should be smear-negative (seroconversion) and after 3 months, the rate should increase to at least 90%. NOTE: Routine use of chest radiographs in monitoring patient response to treatment is unnecessary, wasteful of resources and is not recommended. Chest radiographic shadows may not resolve at the same pace as symptoms and or mirror bacteriologic clearance. 

A positive sputum at the end of the intensive phase should trigger a review of the quality of supervision and support provided by the programme and adherence to treatment by the patient and if needed should trigger the provision of an appropriate remedy. This will, however, lead to prolongation or continued use of ALL four medicines used in intensive phase treatment awaiting results of repeat Xpert and LPA.

Schedule of sputum smear microscopy for monitoring patients on TB treatment Category Sputum examination, interpretation & action to take All Pulmonary TB cases, resistance ruled out on First Line Drug- Drug Sensitivity Test Examine sputum at end of months 2,5,6 months 

 If positive at: End of month 2 then:

• Continue RHZE.

• Assess and address issues with adherence.

• Send sputum specimen for culture and DST.

• Repeat Xpert looking out for rifampicin resistance and send a specimen for LPA. Refer to the Clinical Guidelines for the Management of Drug Resistant Tuberculosis for INH mono-resistance

End of month 5 or 6:

• Assess and record outcome as treatment failure.

• Close current patient's treatment card.

• Assess and address issues with adherence. 

• Send sputum specimen for culture and DST.

• Send specimen for LPA and repeat Xpert; looking out for rifampicin resistance.

• Switch to an appropriate SLD treatment regimen depending on DST results.  Extra-pulmonary TB cases, with no resistance suspected

• Clinical monitoring.

• If no change in clinical condition, re-evaluate and investigate further.

 Children

• Examine sputum at the end of months 2, 5, 6 in children who produce sputum.

• Manage as for adults above.

Adverse drug events monitoring

All patients on TB treatment must be monitored and managed appropriately for emerging adverse drug events.

The performance of the TB control programme may be assessed in various ways and at different levels but of paramount importance is the ability of the program to assess and record outcomes of every patient diagnosed, registered and treated for TB. Every patient must be accounted for and a treatment outcome recorded in the patient treatment card and in the facility register. Treatment outcome assessment shall be done for all patients at the end of the treatment. Accurate and complete recording of the treatment outcome in the TB treatment card and the TB register will enable the NTLP to monitor progress of individual patients, performance of individual health care facilities, districts and provinces and track Zimbabwe’s performance towards achieving national and international targets to which the country has committed.  Death audits

All TB deaths should be audited within 7 days at the facility where the patients were being treated and reported to the next level within the next 7 days. The district level should report to the provincial level within 7 days of receiving the death audit report from the health care facility while the provincial level should compile all the data and report quarterly to the national level. The NTLP will provide death audit forms and the reporting format to be used. Refer to chapter 17 on Monitoring & Evaluation for outcome case definitions Post TB treatment care  

While for a large proportion of TB patients the experience of the TB episode will lead to no significant illness after the TB is cured, for a significant proportion of patients, the episode of TB becomes the beginning of a journey characterised by chronic ill health and in some patients, premature deaths. National TB Control programs have hitherto not paid attention to the group of patients who develop long term complications of TB. Tuberculosis is associated with multiple, acute and chronic complications that are the result of structural, metabolic and vascular changes due to the disease. Despite successful cure

Practice Recommendations At the end of TB treatment:

• Pulmonary TB patients with significant lung damage and capitations on the initial CXR should have a follow up CXR at the end of treatment.

• Where available a spirometric lung function test should be carried out in patients whose end of TB treatment CXR shows significant lung damage.

• Appropriate plans should be made to link patients completing treatment for PTB who have significant lung damage visualized at the end of treatment CXR and or have significantly abnormal spirometric lung function test to chronic respiratory care.

• Patients with TB pericarditis should have a CXR and echocardiogram carried out.

• Patients with TB meningitis associated with neurological deficits should have a brain CT scan carried out

• Patients with osteo-articular TB should be evaluated for physical function to identify the need for rehabilitation.

• Patients with genito-urinary TB should have urea & electrolytes plus creatinine done. Ultrasound scan can also be performed where affordable. of TB, confirmed by the absence of MTB in the involved organ, chronic complications can arise such as lung scarring (fibrosis), bronchiectasis, chronic pulmonary aspergillosis, airway stenosis, chronic obstructive pulmonary disease (COPD), skeletal deformities, genito-urinary complications or focal neurologic deficits from healed tuberculomas.

Little is known about what drives the long term complications of TB. While delays in TB diagnosis may be associated with these complications, it appears that in some patients an exuberant and destructive immune response, determined by host-pathogen relationship may be playing a role. It is for this reason that several research groups are studying the immunological response to MTB and testing various host directed therapies to attempt to modify the immune response to MTB and make it less destructive. While this is going on, NTPs need to play their role by identifying patients who, at the end of TB treatment, require continued care to manage long term complications of TB. The Zimbabwe NTLP is among the pioneer TB control programs to include a statement and make a commitment to begin a systematic evaluation of patients at the end of TB treatment that goes beyond a search for bacteriological cure to identify patients who may be at risk of chronic morbidity post TB treatment. At this stage the burden and type of disease post TB treatment is not known and therefore elaborate plans for testing and providing care to these patients cannot be made. In the life time of the guidelines efforts will be made to attempt to define the burden and characteristics of post TB treatment chronic disease with a focus on the lung.

COPD Lung function test-spirometry

Shortness of breath, cough and wheeze- Bronchodilators (Long Acting Beta Agonists /Long Acting Muscarinic Agents (LABA/LAMA) 

Bronchiectasis-CXR, Lung function test (spirometry) High Resolution Chest CT Scan where available 

Persistent productive cough which is copious & purulent Recurrent haemoptysis- Physiotherapy; broad spectrum antibiotics when exacerbated by bacterial infection 

Chronic Pulmonary Aspergillosis (CPA) -CXR Chest CT Scan (where available) Aspergillus precipitins serology

Aspergilloma (mycetoma) in the residual cavities; Malaise, cough, recurrent haemoptysis-Antifungal drugs e.g. itraconazole Surgical excision 

Constrictive pericarditis -CXR, ECHO

Dyspnoea, oedema, fatigue, pleural calcification on CXR, changes in cardiac chamber sizes on ECHO -Refer for surgery e.g. pericardiectomy

Intracranial tuberculoma-Brain CT scan 

Stroke; epileptic seizures; cranial nerve palsies, motor deficits; cognitive impairment; hydrocephalus in children; etc.-Consider surgery/ anti-convulsant 

Obstructive uropathy-U&E+ creatinine; USS

Genitourinary symptoms of obstruction-Surgical treatment by urologists

Osteo-articular deformities -Clinical evaluation Various deformities Physiotherapy

Practice recommendations

 1. All PLHIV should be screened for active TB using the symptom enquiry (current cough, night sweats, loss of weight, fever and history of TB contact) and/or measurement of the BMI at every encounter with a health care worker and/or CXR (annually if possible or as indicated).

 2. All PLHIV with a positive enquiry to any one of the symptoms on the checklist (current cough, night sweats, fever, loss of weight and history of TB contact) and/or a BMI of less than 17 Kg/m2 should have a CXR taken (unless it is unavailable)

  3. All PLHIV with a positive enquiry to any one of the symptoms on the checklist (current cough, night sweats, fever, loss of weight and history of TB contact) and/or a BMI of less than 17 Kg/m2 and/or abnormal CXR should have specimen collected and submitted to the laboratory for Xpert MTB/Rif or Xpert MTB/Rif Ultra assay.

  4. All newly diagnosed HIV positive patients should submit one spot sputum sample for Xpert MTB/Rif or Xpert MTB/Rif Ultra to rule out active TB disease even if they have a negative symptom screen and or a BMI of >17.

 5. All PLHIV who are seriously ill and or have a CD4 T cell count of equal or less than 100 should have the Urine Lateral Flow - Lipoarabinomannan Assay (LF-LAM). 

 6. All PLHIV who have active TB excluded on symptom enquiry, measurement of BMI and CXR should be provided with TBPT preferably using isoniazid at 300 mg given once daily for six months (IPT/6H)

 7. All people with presumptive and diagnosed TB should be tested for HIV at first contact with a HCW.

 8. All presumptive and diagnosed TB patients who test negative for HIV should be linked with HIV prevention services.

 9. All TB patients who test HIV positive should be started on ART within 2-8 weeks of commencement of TB treatment.  HIV care should be provided preferably under the same setting and patients transferred for continuation of HIV care to the OI/ART clinic after completion of TB treatment.

 10. Patients co-infected with TB and HIV should be managed for both conditions concurrently with TB treatment taking precedence over ART initiation.

  11. All HIV infected persons with active TB should be initiated on anti-TB treatment promptly followed by Cotrimoxazole prophylaxis (CPT) and then an Efavirenz based ART regimen within 8 weeks of commencement of TB treatment.

  12. All HIV infected persons with active TB who have a CD4 T cell count of equal or less than 50 should be initiated on anti-TB treatment promptly and on an Efavirenz based ART regimen within 8 weeks of commencement of TB treatment.

  13. All HIV infected persons with intracranial TB who have a CD4 T cell count of equal or less than 50 cells/µl should be initiated on anti-TB treatment promptly and have their ART initiation delayed until after 8 weeks of commencement of TB treatment to reduce the risk of intracranial TB–Immune Reconstitution Inflammatory Syndrome (IRIS) which could end fatally.

14. All HIV infected TB patients should be given cotrimoxazole preventive therapy (CPT) for the whole duration of TB treatment.  

NB. Following observations made by the NAP, on occurrence of severe hepatic necrosis in 8 cases (4 of whom died) among PLHIV who had been on ART for longer than 3 years and had high CD4 T cell counts (unpublished), the TB/HIV subcommittee recommends that IPT SHOULD NOT BE PROVIDED to this target population due to high risks of severe hepatic reactions that could end fatally. With further characterization of these cases being done, an interim decision to exclude persons who fit this description will be upheld, in line with the TB and HIV

15. All children who are presumed to have TB should be screened for HIV with adherence to the principle of counselling, consent or assent and confidentiality.

16. All HIV infected children receiving treatment for TB should also receive supplementary pyridoxine.

17. Recommendations for ART in HIV infected children being treated for TB remain the same as those in adults.  

18. In patients receiving PIs for the treatment of HIV, rifabutin given at a dose of 150 mg once daily, should be substituted for Rifampicin. If Rifabutin is not available the doses of Ritonavir boosted Lopinavir (LPV/r) should be doubled or the doses of ritonavir increased to 400 mg twice daily (super boosting). Clinicians should be aware that both double dosing and super boosting are associated with increased risk of adverse drug reactions. 

 19. In children being treated for TB with a Rifampicin- based regimen, using a triple NRTI regimen (such as AZT+3TC+ABC) may be considered. This regimen may however be inferior in children with high plasma viral loads.

20. Bedaquiline is primarily metabolised by CYP3A4, therefore, its concomitant use with EFV and PIs for patients with XDR/MDR TB can interfere with drug concentrations and should be undertaken with extreme caution and close clinical, bacteriological and virological monitoring.  Therapeutic drug monitoring should be considered in these patients (note this capacity is available at the University of Zimbabwe).

 21. There is limited information on the use of EFV 400mg among TB patients on ART and as such an EFV 600mg based triple ART regimen once daily remains the recommended treatment regimen and dose of choice.  

22. Rifampicin is known to significantly lower plasma concentrations of Dolutegravir (DTG) and therefore, in patients receiving TB treatment with a Rifampicin based regimen, the dose of DTG should be increased from 50 mg once daily to 50 mg twice daily. 

Drug-resistant tuberculosis (DRTB) is confirmed through laboratory tests that demonstrates in-vitro growth of isolates of Mycobacterium tuberculosis in the presence of one or more anti-TB medicines. It can also be confirmed through molecular tests such the Xpert MTB/Rif assay, LPA or gene sequencing that detect mutations responsible for resistance to specific medicines (resistance conferring changes in the MTB’s genetic code, the DNA). Cases are classified in categories based on DST results of clinical isolates confirmed to be M. tuberculosis:

-Mono-drug resistance TB: resistance to one first-line anti-TB medicine only.

-Poly-drug resistance TB (PDR): resistance to more than one first-line anti-TB medicine other than resistance to both isoniazid and rifampicin.

-Multidrug resistance TB (MDR-TB): resistance to at least both isoniazid and rifampicin.

-Extensive drug resistance TB (XDR-TB): multi -drug resistance that additionally is resistant to any fluoroquinolone and to at least one of three second-line injectable medicines (capreomycin, kanamycin and amikacin).

-Rifampicin resistance TB (RR-TB): resistance to rifampicin detected using phenotypic or molecular (genotypic) methods, with or without resistance to other anti-TB medicines. It includes any resistance to rifampicin, whether mono-resistance, multidrug resistance, poly-drug resistance or extensive drug resistance.

These categories are not all mutually exclusive. When enumerating rifampicin-resistant TB (RR-TB), for instance, multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) are also included. While it has been the practice until now to limit the definitions of mono-resistance and polydrug resistance to first-line medicines only, future drug regimens may make it important to classify patients by their strain resistance patterns to fluoroquinolones, second-line injectable agents and any other anti-TB medicines for which reliable DST becomes available. 

Causes of DR-TB

1. Poor adherence to treatment due to experience of adverse events, lack of information, malabsorption
2. Misdiagnosis, medication stock outs, poorly trained staff, poor medication quality
3. Delayed diagnosis and treatment, improper empiric treatment, untreated HIV, nosocomial transmission, medication stock outs, lack of lab reagents, social barriers, poor adherence
4. Ongoing transmission, resistance amplification

Prevention of DR-TB

Treating a case of MDR-TB is more than 25 times the cost of treating an uncomplicated drug-susceptible case. In the Zimbabwean setting of high HIV burden, an untreated case of MDR-TB can infect large numbers of individuals, rapidly leading to significant outbreaks of MDR-TB with high case fatalities. Prevention of DRTB depends on 

• A robust TB control program that is able to treat successfully the largest possible proportion of identified new, previously untreated cases with first line medicines (a TB treatment success rate in excess of 90% for new cases) 

• Correct usage of first line medicines in terms of regimens and doses in both the public and private health care sectors 

• Rational use of anti-microbial medicines in general and anti-TB medicines in particular in both the public and the private sector.

• Ensuring the highest possible quality of all the anti-TB medicines used in the program in addition to optimised storage conditions.

• Ensuring every effort is made to promote and support full adherence to treatment for all patients treated with anti-TB medicines, both for first and second line medicines.

• Prompt and complete identification of patients with drug resistant TB and initiation of treatment with appropriate regimens and doses of second line medicines.  

NOTE: The priority is prevention of MDR-TB plus early identification and appropriate management of MDR-TB.

The National TB Control Programme will ensure that regular and sufficient stocks of quality controlled anti-TB medicines are available in the country at all times. Provincial Health Executive (PHEs) teams led by the PMDs, central hospitals and local authority health departments should ensure all TB patients identified in their jurisdiction are registered to facilitate correct estimation of annual anti-TB medicines requirements.

In the event that a health care worker presumes that a patient has MDR-TB, a sputum sample must be sent for Xpert MTB/RIF testing. Screening of household contacts should be conducted and appropriate health education on infection control provided. Infection control measures as outlined in the chapter on TB infection should also be implemented.

Serious limitations of the quality of evidence prevent drawing any recommendations on MDR-TB preventive therapy as a public health measure. Strict clinical observation and close monitoring of contacts of patients with MDR-TB for the development of active TB disease for at least two years is preferred over the provision of preventive treatment. All contacts of patients with MDR-TB should be screened for TB in more or less the same way as in contacts of patients with drug susceptible TB.  However even in the absence of symptoms and or a low BMI, it is recommended that contacts of MDR-TB cases have a CXR. The CXR should be repeated annually for two years in persons whose initial screening is negative for TB. The two year cut off is based on the risk of development of active TB following infection with MTB which is highest in the first two years.  Note: While clinical trials are underway to find an effective TBPT for persons latently infected with MTB that is MDR, currently such therapy does not exist. 

Principles of diagnosis of DR-TB 

Practice Recommendations

1. Rapid DST, of at least rifampicin using rapid molecular tests such as Xpert MTB/Rif rather than conventional culture and DST, should be carried out in all adults and children at the time of TB diagnosis. Bacteriological diagnosis of TB without DST should as far as feasible be avoided. 

2. For patients with confirmed rifampicin-resistant TB or MDR-TB, SL-LPA must be used as the initial test, instead of phenotypic culture-based DST, to detect resistance to fluoroquinolones and the injectable medicines used to treat MDR-TB.   

Principles of the care and control of DR-TB

1. To detect DR-TB cases early and

2. To promptly initiate appropriate therapy for patients with DR-TB  

3. To avoid the spread of DR-TB strains

  4. To select medicines and regimens for the treatment of DR-TB in a manner that prevents the emergence of further resistance to anti-TB medicines.  

 Classification of TB medicines for DR-TB treatment

A. Fluoroquinolones

 Levofloxacin, Moxifloxacin, Gatifloxacin (Lfx Mfx Gfx)

B. Second-line injectable agents

Amikacin Capreomycin/ Kanamycin (Am Cm Km)

C. Other core second-line agents

 Ethionamide / Prothionamide Cycloserine / Terizidone Linezolid Clofazimine (Eto / Pto Cs / Trd Lzd Cfz)

D. Add-on agents (not part of the core MDR-TB regimen) D1

Pyrazinamide Ethambutol High-dose isoniazid (Z E Hh)

D2 Bedaquiline Delamanid (Bdq Dlm)

D3 p-aminosalicylic acid Imipenem-cilastatin Meropenem Amoxicillin-clavulanate (Thioacetazone) (PAS Ipm Mpm Amx-Clv (T))

Practice recommendations

1. In the programme setting in Zimbabwe, all patients with RR-TB or MDR-TB who were not previously treated with second-line drugs and in whom resistance to fluoroquinolones and second-line injectable agents is excluded or is considered highly unlikely, a shorter MDR-TB regimen of 9–12 months will be used instead of the longer regimens unless there are contraindications for some medicines in the shorter regimen.

Subgroup considerations

 2. Rifampicin-resistant TB (RR-TB) without MDR-TB. In the programme setting in Zimbabwe, all patients, children or adult, with RR-TB in whom isoniazid resistance is not confirmed will be treated with the shorter MDR-TB treatment regimen. Resistance additional to MDR-TB.

 3. For patients infected with strains known or strongly suspected of being resistant to one or more drugs in the shorter MDR-TB treatment regimen (e.g. pyrazinamide), the shorter regimen will not be used, under routine programme settings in Zimbabwe, until more evidence becomes available about its performance in such a situation.

Based on the following treatment principles and advise from WHO

a) In patients with RR-TB or MDR-TB, a regimen with at least five effective TB medicines during the intensive phase is recommended, including pyrazinamide and four core second-line anti-TB medicines – one chosen from Group A, one from Group B, and at least two from Group C.

b)  If the minimum number of effective TB medicines cannot be composed as given above, an agent from Group D2 and other agents from Group D3 may be added to bring the total to five.

c) In patients with RR-TB or MDR-TB, it is recommended that the regimen be further strengthened with high-dose isoniazid and/or ethambutol

d) It is recommended that any patient – child or adult – with RR-TB in whom isoniazid resistance is absent or unknown be treated with a recommended MDR-TB regimen, either a shorter MDR-TB regimen, or if this cannot be used, a longer MDR-TB regimen to which isoniazid is added

The standard short treatment regimen for DR-TB treatment in Zimbabwe is: 4-6Km, Mfx high dose, Cfz, Z, E, H high dose, ETO / 5 Mfx high dose, Z, CFZ, E

The initial treatment plan for all patients treated with the short MDRTB regimen will be to have a 4 and 5 months intensive and continuation phases respectively. Treatment will be extended to a maximum of 6 months in the intensive phase if culture conversion has not occurred by the fourth month of treatment. Similar considerations will be used to extend the continuation phase of treatment for a maximum total treatment duration (intensive and continuation phases) of 12 months. If patients have not achieved culture conversion by month 5 they will be declared treatment failures. 

Regimen design steps for RR-TB patients who are not eligible for the Short Treatment Regimen (STR) 

The steps shown below which are recommended by WHO, will be used to design a treatment regimen for the RR-TB patients who are not eligible for the STR.

 Step wise selection of Second Line Drugs for constituting regimens to treat MDR-TB

Step 1: Choose either Bedaquiline or Delamanid (Group D2).  The choice of which drug (or potentially both drugs) is outlined in the section on ‘special considerations’ below.

Step 2: Choose a fluoroquinolone (Group A – Mfx or Lfx).  If only ofloxacin resistance from DST is known, Mfx or Lfx (high dose is preferred) can still be added to the regimen, but should not be counted as one of the effective drugs. Treatment with a later generation FQ (Mfx or Lfx) significantly improves RR-TB or MDRTB treatment outcomes; they should therefore always be included unless there is an absolute contraindication for their use. 

Step 3: Choose an injectable (Group B – Km, Cm, and Am).  If clinical history or DST suggests resistance to all SLID, or in case of a serious adverse event (hearing loss, nephrotoxicity), the injectable should not be used or should be promptly discontinued.  In children with mild forms of DR-TB disease, the harms associated with an injectable may outweigh potential benefits and therefore injectable agents may be excluded in this group. 

Step 4: Choose at least two Group C drugs (Lzd, Cfz, Eto, and Cs) thought to be effective as additional core second line drugs to BDQ/DLM, FQs, and SLID.  If efficacy is uncertain, the drug can be added to the regimen, but should not be counted as an effective drug.     

Step 5: Choose D1 drugs (PZA, INHhd, EMB) as add-on agents.  PZA is routinely added to most regimens.  High dose INH may further strengthen the regimen if DST shows INH sensitivity, or INH resistance is unknown.  D1 drugs are usually added to the core second-line drugs, unless the risks from confirmed resistance, pill burden, and intolerance or drug-drug interaction outweigh potential benefits. 

Step 6: Only choose D3 drugs if there are no other treatment options available due to highly resistant forms of DR-TB or multiple intolerances to other DR-TB drugs. 

The final individualized DR-TB regimen will consist of at least 5 drugs with confirmed or high likelihood of susceptibility from the following list: Bdq or Dlm, Lfx or Mfx, Km (Am, Cm), Eto, Lzd, Cfz, Cs, Z, Hhd, E.

Patients started on the shorter treatment regimen and are failing, have drug intolerance or return after interrupting treatment for two or more months should be switched to the longer individualised regimen.  Patients may be initiated on the shorter treatment regimen, after assessment, while awaiting SLLPA and treatment changed accordingly when results are available.

 If a shorter treatment regimen is unavailable or contraindicated, patients with RR/MDR-TB should be treated with an individualised regimen.  The injectable is used during the intensive phase, a minimum of 6 months, and should be used up to a minimum of 4 months after culture conversion. The total duration of treatment must be at least 20 months NB. All patients treated with Cycloserine (Cs) should receive Pyridoxine (50 mg for every 250 mg of Cs) in order to prevent neurological adverse events.  Organization of the DR-TB case management system

There are three main strategies for the delivery of DR-TB treatment i.e. hospitalization (institutional approach), clinic –based (OPD Model) treatment and community-based treatment.  Each patient must be assessed on an individual basis to choose the most appropriate care approach. The DMO is responsible in ensuring that this assessment is carried out. The assessment should include clinical and psychological condition of patient, home environment, infection control needs, distance from the health facility, transport logistics, availability of trained health care workers and community and family support potential.  

Hospitalization- Institutional approach: 

The main indications for hospitalization include the following: 

? Patients too ill (clinically or psychologically) to commence DR-TB treatment on an ambulatory basis.

? DOT and adherence support not guaranteed.

? Implementation of adequate infection control measures not feasible at home

? Patient monitoring cannot be implemented on an out-patient basis.  Where patients with DR-TB are admitted provisions for infection control must be strengthened and maintained at high levels according to the customised facility infection control plan. Patients may be referred to the provincial centre of excellence where clinical management dictates. Patients who meet the following criteria can be discharged for ambulatory care: 

? Patients whose clinical status has improved to the extent that he/she can be managed on ambulatory basis.

? Adequate infection control measures in the home are ensured.

? Adequate nutritional and social patient support is available to the patient. 

? Measures to ensure full implementation of DOT, adherence support and regular follow up have been put in place (including transport). 

? The receiving facility has been oriented and mentored on the patient's management. This may include a visit by health care workers from the facility to the district hospital.  A discharge summary must be completed and a month supply of drugs must be provided to the responsible facility. Recording forms for treatment adherence and reporting of adverse events, patient information and education materials must be provided also. The district should arrange transport to the patient's home. 

Clinic based (OPD Model) Treatment 

 This involves the patient visiting the clinic each day to receive DOT by the health care worker. Standard infection control measures must be implemented in facilities providing such DOT. 

Community Approach 

Trained community DOT observers may observe stable patients on treatment for DR-TB during the continuation phase. The specific tasks to be performed by these DOT observers are: 

? Direct observation of treatment on a daily basis

? Treatment literacy for DR-TB patients, including TB infection control and nutrition.

? Monitoring patients for side effects.

? Reminding patients of their follow-up dates.  These DOT observers are accountable to the DMO and are or should be supervised by the primary health care centre nurses. They should meet with the nurses at the supervising facility at least monthly to report on their activities. Additionally, they should refer to the supervising health facility any patients who are getting worse or who are experiencing new symptoms, which could be due to adverse events of the SLDs.  NB: Infection control is also very important for ambulatory care in the intensive phase. 

Patient Education

Adequate patient education and measures surrounding infection control include: 

? Education on cough hygiene, including use of surgical masks by patients.

? Suspension of school or work attendance until culture conversion or first two months of intensive phase.

? Ensure measures for adequate ventilation in the home. 

? Community and family education. 

Decision making in DR-TB management MUST always be made by the district team led by the DMO. The model of care for each patient must be regularly reviewed as there maybe changes in the clinical condition or social circumstances.

Patient Support systems

All patients on DR-TB treatment should have a psycho-social and economic assessment to identify those who need to be provided with psychological and social support such as transport and food to prevent treatment interruption and to reduce treatment associated costs.

Clinical and bacteriological monitoring of patients on the shorter DR-TB treatment regimen

Patients coming from neighbouring countries who have already been diagnosed with MDR-TB have to be registered, have their treatment reviewed and either modified or continued with appropriate monitoring.

Post treatment care

All patients completing treatment for pulmonary TB should have a chest x-ray to determine if long term post TB pulmonary care is needed.

This guideline discusses the TB infection control (TB-IPC) measures to reduce TB transmission in healthcare facilities, congregate settings and households. In the absence of appropriate infection control policy and practice, there is a high risk of transmission and spread of TB in healthcare settings, other congregate settings and in the community. The greatest risk of transmission occurs when TB patients remain undiagnosed and untreated. The most critical element or fundamental principle of infection control therefore is early diagnosis and prompt initiation of effective treatment of TB patients.

TB Infection Control in Healthcare Settings  

A plan to prevent transmission of TB in a health care facility should be part and parcel of the overall facility infection prevention and control (IPC) programme. The plan should be guided by the Zimbabwe National Infection Prevention and Control policy.  All health care facilities should develop and implement a facility specific TB infection control plan designed to:

 • Ensure prompt identification of presumptive cases of TB.

 • Appropriate, non-stigmatizing, immediate separation of presumptive cases or infectious TB cases from other patients.

 • Prompt testing of presumptive cases of infectious TB with rapid and specific tests such as the Xpert MTB/Rif assay.

 • Prompt initiation of treatment of bacteriologically confirmed cases of infectious TB

 • Appropriate, robust and sustained implementation of simple but effective environmental infection transmission prevention measures.

 • Judicious use of personal protective equipment (PPE)

 • Ensure continuous monitoring and periodic evaluation of the TB-IPC plan and its implementation.

 • Assess performance and achievements of monthly, quarterly and or annual targets. 

To develop a robust and specific TB-IPC plan it is critical to carry out a baseline TB infection control risk assessment to identify the risk areas and what needs to be done in the various units or departments of the facility using a standardised TB-IPC risk assessment tool.

The task of developing, implementing and monitoring the TB –IC plan should be done by the IPC Committee of the health facility.  Every health care facility, irrespective of size and portfolio of services offered should have such a committee in place whose tasks should include:

• Developing a written TB-IPC plan tailored to the specific health facility setting and needs. 

• Assigning from within the IPC committee a designated TB-IPC officer to take responsibility for training of HCWs at the facility, supporting facility HCWs to implement and adhere to TB-IPC measures outlined in the TB-IPC plan, regular monitoring of the implementation of the plan and reporting to the facility IPC committee in addition to other IPC tasks that the committee identifies.

• Monitoring the implementation of the TB-IPC plan at the health facility including the achievement of facility specific TB-IPC targets.

• Periodically evaluating the facility TB-IPC plan to identify failures and successes, the reasons for these outcomes and to identify measures including innovations and modifications to the IC plan that need to be undertaken to achieve the desired results and outcomes. 

Managerial and Administrative Controls

In health care settings, it is important to implement infection control measures designed to minimise the time that patients with possible TB symptoms (particularly cough) spend in clinics / health facilities. Ensure that those with a chronic cough are separated from other patients and investigated promptly and started as soon as possible on correct treatment if found to have TB.  It is encouraged that all health facilities carry out symptomatic screening of all patients, so that persons with chronic cough, are identified, separated and investigated (triaging).  The first and most important level of infection control is the use of administrative measures to prevent droplet nuclei from being generated, thus reducing the exposure of HCWs and patients to M. tuberculosis. Administrative controls are the cheapest and most effective interventions and they ensure early diagnosis and treatment of potentially infectious TB patients. These measures include:

• Setting up or strengthening facility IPC Committee

• Assessment of the risk of transmission of MTB in the various units or departments of the facility.

• The development of a health facility TB-IPC Plan or a unit SOP detailing what should be done, how it should be done and who should be responsible for each TB-IPC task. 

• Assigning responsibility and authority for the coordination and monitoring of adherence to the implementation of the infection control plan to the TB-IPC officer with mechanisms for reporting back to the IPC committee and the implementation of appropriate corrective action.

• Adequate training of HCWs and other staff to implement the plan.

• Administrative support for procedures contained in the plan, including quality assurance.

• Ensuring that patient waiting areas are not congested.

•  Ensuring that highly infectious or chronic TB patients (e.g. those failing treatment for MDR-TB) are reviewed by appointment with times scheduled at periods when facility patient volume is usually small.

• Implementing effective and efficient processes for the management of presumptive or confirmed TB patients including triaging, fast tracking of service delivery to potentially infectious patients (those who are coughing), isolation of potentially infectious TB patients and discharging patients when appropriate

 • Organising appropriate patient movement through the facility to reduce the risk of cross-infection   • Prompt initiation of appropriate anti-TB treatment as soon as the TB diagnosis is made.

 • Education of patients on TB and increasing community awareness including the use of cough hygiene to reduce the spread of infectious droplets into the environment. 

• Designing health facilities e.g. wards, out-patient department to ensure adequate ventilation.

 • Ensuring that HCWs who are at high risk of TB infection and progression to disease do not work in areas of the facility where exposure to MTB is very likely such as TB wards including wards for MDR-TB patients.

Five steps for managerial and administrative processes for patient management to prevent transmission of TB in Health Care Settings Step Action Description

 1 Screen Early recognition of presumptive or confirmed infectious TB cases should be done through questioning patients about cough (and TB) on arrival.

2 Educate Instruct presumptive or confirmed cases of infectious TB on cough etiquette and respiratory hygiene.

3 Separate Patients identified to be presumptive or confirmed cases of infectious TB should be separated from other patients and requested to wait in a separate well ventilated waiting area.

4 Provide prompt health services Triaging of patients with symptoms that could lead to the spread of infectious aerosols to the front of the line for the services they came for such outpatient consultation, TB/HIV counselling and testing services, and medical refills.

5 Investigate for TB or refer TB diagnostic tests should be done on site and if not available on site, the facility should have an established link with a TB diagnostic centre to which collected sputum specimens should be sent.

The following should also be part of the TB-IPC plan:

1. Using and maintaining environmental control measures.

2. Routine screening for TB using the TB screening tool (see Annex 3) and CXR/BMI among health care workers on an annual basis. This is best done as part of a health care worker wellness program (see annex 2).  

3. Training and educating staff on TB, TB prevention and care and the TB –IC plan.

4. Job relocation of staff who are at risk of developing TB following infection, from high to low TB exposure areas.

Environmental Control Measures

It is often not possible to completely eliminate the exposure to infectious droplet nuclei, but various environmental control methods can be used in high-risk areas to reduce the concentration of droplet nuclei in the air. Such measures include:

• Maximizing natural ventilation by keeping facility windows and doors open at all times when providing care to patients even during winter and night time and promoting cross ventilation (opening of windows or doors on opposite walls) and "stack effect", which increases airflow using indoor/outdoor temperature difference.

• Using open-air shelters with a roof to protect patients from sun and rain as waiting areas. 

• Avoiding patients crowding in narrow, poorly ventilated and lighted corridors as they wait for services.

• Controlling the direction of airflow e.g. with strategically placed fans, which also cause air mixing which increases the effectiveness of other environmental controls.

• Utilizing an open plan in patient waiting areas and wards to let in sunlight.  Sunlight is a natural source of ultraviolet light, which kills TB bacilli.

• Reducing crowding in patient waiting areas is very important. Waiting areas in open-air shelters should be favoured over enclosed corridors. 

• Organising sitting arrangements in consultation rooms to avoid airflow from patient to HCW.

• Attending to one patient at a time in the consultation room to minimise exposure to droplet nuclei.

Health staff should be mindful of the direction of airflow to ensure the patient is closest to the exhaust fans and the HCW is closest to the clean air source. Personal Respiratory Protection Personal respiratory protection protects HCWs, where concentration of droplet nuclei cannot be adequately reduced by administrative and environmental control measures. It protects the health worker from inhaling infectious TB droplet nuclei. When PPE is used the HCWs should wear N95 or FFP2 respirators to protect them from inhaling infectious air droplets. Respirators are worn by workers and visitors in high risk areas and situations. Patients with active TB should be encouraged to wear a surgical mask and practice cough etiquette to reduce the spread of infectious droplets (see Figure 15).  Surgical masks reduce the spread of microorganisms from the wearer. Personal respirators are useful only when managerial, administrative and environmental controls are in place. Performing a N95 fit test – Hold the mask in the palm of hand, with the cup facing upwards; place the mask on face covering the nose and mouth and secure the mask using the elastic bands. The top metallic margin should be above the nasal bridge; adjust the metallic section to tightly fit. Cup both hands over the mask gently and test the seal by exhaling forcefully after a deep breath. For a well-fitting mask, pressure build-up with no air blowing to your eyes or ears through the margins of mask should be felt. The mask should collapse on forceful inhalation.

The use of PPE should not replace, less expensive, administrative and environmental IPC measures. N95 masks are only indicated in specific settings, e.g. facilities nursing TB patients. All other infection control measures should be fully implemented; the use of personal protective equipment is the least effective of all infection prevention and control measures.

Protection of Health Workers All HWs should be screened for TB using a symptom screen, a BMI with a CXR on an annual basis and symptom screening every six months. This should be done free of charge and preferably as part of a routine medical evaluation as part of a health worker wellness program that also includes HIV testing and counselling services as well as screening for non-communicable diseases such as cancers, diabetes mellitus and hypertension. All presumptive TB cases (symptoms + BMI< 17 Kg/m2 +abnormal CXR) should submit a sputum sample to be tested for TB using the Xpert MTB/Rif or Ultra assay. 

TB Infection control is effective only if each person working in a facility understands the importance of TB infection control policies and his/her role in implementing them. All health facility staff, including medical and administrative staff, technicians and laboratory staff, laundry, cleaners and any other workers, should be targeted for training.

 Construction of health facilities according to TB Infection Control measures

 A multidisciplinary team should coordinate health facility demolition, construction, and renovation projects. During the developmental stages of health facility construction or renovation projects, the MoHCC should work closely with the Ministry of Public Works to proactively embed TB transmission minimising designs for the new or renovated facilities. The engagement of the NTLP in this process may be done through a coordinating mechanism that includes aerosolized infection transmission prevention experts. Mandatory adherence to agreements for limiting transmission of pathogens that primarily use the aerosolized route to establish infection, should be incorporated into construction contracts, with penalties for non-compliance and mechanisms to ensure timely correction of errors.

All the TB infection control measures described in this guideline apply also to medical services in refugee camps, correctional facilities and other congregated settings. This is because the spread of tuberculosis is worsened by the often poor living conditions in these settings such as overcrowding, malnutrition and HIV among inmates and residents of refugee camps. It is recommended that the following measures are routinely carried out:

• Regular TB screening of inmates and refugees to ensure early diagnosis of active TB and prompt initiation of appropriate treatment.

• Screening of all new inmates and new arrivals at a refugee camp using the TB screening tool and CXR (when available). All presumptive TB cases should submit a spot sputum sample for TB testing with the Xpert MTB/Rif or Ultra assay.

• Encourage all staff and their dependents working in congregated settings to undergo six monthly symptom screening and annual CXR screening as part of the comprehensive wellness programme.

• Separate inmates diagnosed with active TB from other inmates in an adequately ventilated area to prevent transmission to other inmates. Similar measures with appropriate modification may be carried out in refugee camps.

• Improvement in living conditions for inmates with special attention paid to reducing overcrowding. 

• Offer TB information and HIV testing and counselling to all staff and inmates.

• There should be particular attention paid to integrating prison and civilian TB services so that there is continuation of care after discharge from the correctional facility.

Reducing TB transmission in households

 The period of household transmission is greatest before the diagnosis of TB. Again, early case detection and prompt treatment is the key to reduction of TB in households. TB contact investigation should be undertaken. Information, education and communication messages including basic TB-IPC behaviour-change should be provided. Coughing etiquette and respiratory hygiene in the household before and after diagnosis of TB should be emphasised. Stigma reduction should not be forgotten. Environmental control measures to reduce exposure should be emphasized. Natural ventilation should be improved in households particularly in rooms where people with TB spend much time. Bacteriologically confirmed PTB patients in the first 2-4 weeks of treatment should spend as much time as possible outdoors, stay in a well-ventilated room, if possible, and spend as little time as possible in congregate settings. Children less than 5 years old should spend as little time as possible in the same living spaces as persons with bacteriologically confirmed PTB patients. Children contacts of MDR-TB patients should be followed up regularly with TB screening and if possible culture and DST.

 Home environment assessments should be conducted for TB-IPC adequacy to inform appropriateness of the home for TB care and to provide health education to families.  

Prevention and management of adverse drug reactions (FLDs) 

All health staff should be able to recognise and manage the common ADRs of first line anti-TB medicines. Tuberculosis patients should always be informed on starting treatment about the possibility of adverse reactions and what to do if they develop.

Patients at increased risk of ADRs 

There are certain groups of patients who are at increased risk of medicine adverse effects. These include:

• The elderly 

• Diabetics 

• The malnourished

• Patients with CKD

• Those who consume excessive amount of alcohol

• HIV infected individuals

• Pregnant and nursing mothers 

• Those with severe TB

• Persons with liver failure

• Patients with Anaemia 

• Persons with a family history of ADRs

• Atopic persons

• Patients on other medicines 

Carefully evaluate such patients before starting anti-TB treatment. Ensure that the medicine dosage is according to the weight of the patient in all cases. You may have to reduce the dose of the medicines in some cases, e.g. in renal failure and in the elderly. Inform the patient and relatives on the possibilities of ADRs and advise the patient to report to a clinician immediately when a ADRs is suspected. 

Adverse drug reactions induced by first line Anti-tuberculosis medicines 

Adverse drug reactions (ADRs) of anti-TB medicines can be classified into major and minor ones.

Symptom-based approach to identifying and managing ADRs due to FLDs ADR

Minor

Anorexia, nausea, abdominal pain Pyrazinamide Rifampicin- Continue anti-TB medicines, check medicine doses 

Even though the NTLP recommends DOT for all TB patients in Zimbabwe, patients experiencing these minor AEs should be advised to take the medicines at night preferably with family member DOT. Ranitidine, omeprazole, or an antacid may also be prescribed.

Joint pains Pyrazinamide Give nonsteroidal anti-inflammatory drugs (NSAIDS) e.g. Aspirin or Ibuprofen

Burning sensation in feet Isoniazid Give Pyridoxine 100 mg daily

Skin rash with mild itchiness, no mucous membrane involvement or blisters Rifampicin, Isoniazid & Pyrazinamide give Chlorpheniramine 4 mg tds or Promethazine 25-50 mg at night. Aqueous cream, Calamine skin lotion.

Peripheral neuropathy Isoniazid Pyridoxine 50 mg 1-3 times daily

Orange/red urine Rifampicin Reassure patient. Let patient know this at the beginning of treatment (before the first dose is taken).

Major Adverse Drug reactions

Stop responsible medicines. Refer patient to a medical officer and/or arrange admission to hospital. Itching of skin with rash, mucous membrane involvement, blistering (Rifampicin, Isoniazid & Pyrazinamide) Stop anti-TB drugs. Refer to the next level if you cannot manage. Wait until the rash has resolved and resume medication at a hospital as advised below.

Jaundice (other causes should be excluded) -Most anti-TB medicines (especially Pyrazinamide, Rifampicin and Isoniazid) Stop anti-TB drugs. Do liver function tests. Test for Hepatitis A, B and C 

Vomiting & confusion: suspect drug-induced acute liver failure -Most anti-TB medicines (especially Pyrazinamide, Rifampicin and Isoniazid) Refer to hospital for admission. Stop anti-TB medicines, do urgent liver function tests, Check for the presence of hepatitis viruses (A, B and C) and check the prothrombin time/International Normalized Ratio (INR) 

Hearing impairment (no wax on otoscopy) –(Streptomycin) Stop Streptomycin

Dizziness (vertigo and/or nystagmus) -Streptomycin Stop anti-TB drugs (Refer to Approach to management of adverse drug reactions section below)

Visual impairment (other causes excluded) (Ethambutol) Stop Ethambutol/ Refer to an eye specialist. 

Shock, purpura (bleeding under the skin), acute renal failure –(Rifampicin) Stop Rifampicin

The first step in managing a patient with ADRs is to evaluate the severity of the adverse reaction, i.e. determine whether it is a minor or a major ADR. A patient who develops minor adverse effects should continue the anti-TB treatment, usually at the same dose while the ADR is treated symptomatically e.g. with an anti-histamine for itching. If a patient experiences a major adverse event, treatment with the offending medicine should be stopped immediately. Further management depends on the nature of the adverse reaction and is shown in table 26 above. Patients with major adverse reactions should be managed in a hospital. Tuberculosis treatment should be withheld until the affected organ or system returns to normal, which usually takes 2-3 weeks. After the adverse reaction has resolved a cautious reintroduction of the treatment should be attempted. This may be done using a desensitisation approach.

Management of skin reactions

If a patient develops itching without a rash and there is no obvious cause (e.g. scabies), the recommended approach is to try symptomatic treatment with anti-histamines, continue anti-TB treatment and observe the patient closely. However, if a skin rash develops, then all anti-TB medicines must be stopped. Once the reaction has resolved, anti-TB medicines can be cautiously re-introduced (see below).  If a patient develops itching with a rash especially with a fever it is essential to stop all anti-TB medicines at once. Do not wait to see a widespread rash with peeling skin, blisters or raised red spots of a severe allergic reaction called Steven Johnson’s syndrome. The eyes and/or mucous membranes may also be affected. Patients with Steven Johnson’s syndrome are usually very ill with fever, hypotension and should be treated as a medical emergency. Such a patient may need intravenous fluids and high dose steroids (60 mg prednisolone a day). In view of the gravity of this severe ADR, all health workers should take the presence of a generalized itchy skin rash in a patient receiving anti-TB medicines seriously and stop all medicines as indicated above. Chloramphenicol eye ointment should be applied to the patient's eyes if they are involved, in addition to giving a course of antibiotics (e.g. amoxicillin plus clavulanic acid) if the blisters look infected. Anti-TB treatment is only restarted once the skin reaction has completely resolved, which usually takes up to 4 weeks or more depending on the severity of the reaction. 

Management of drug-induced hepatitis

Anti-TB medicines can damage the liver. Isoniazid, pyrazinamide and rifampicin are most commonly responsible. Ethambutol is rarely responsible. When a patient develops hepatitis during anti-TB treatment, it may be due to the anti-TB treatment or another cause. It is important to rule out other possible causes before deciding that the hepatitis is drug-induced. If the diagnosis is drug-induced hepatitis, then the anti-TB medicines should be stopped and the liver function tests checked regularly. After the hepatitis has resolved, the same regimen can often be re-introduced (see below).  If drug-induced hepatitis has been severe, then it is advisable to avoid pyrazinamide, rifampicin and isoniazid. Refer patient to a medical officer. A suggested regimen in such patients is a two-month initial phase of daily streptomycin, levofloxacin and ethambutol followed by a ten-month continuation phase of levofloxacin and ethambutol (2 [S + E + Lfx] / 10 [Lfx + E]). Note that this regimen’s effectiveness has not been assessed in any clinical trial. Therefore, it is important that patients are closely monitored for clinical and bacteriological improvement. Patients should also be monitored for relapse post treatment completion. 

Re-introduction of anti-TB medicines and desensitization

The reintroduction of treatment and desensitisation should not be attempted in patients who have developed severe toxic reactions. In such cases that are life threatening, a new regimen not including the implicated medicine in the reaction should be used. Do not also reintroduce treatment in HIV co-infected cases. 

The principles and steps for re-introduction of anti-TB medicines and desensitization following an adverse drug reaction are:

 1. Reintroduce the treatment, medicine by medicine (one medicine at a time), in progressively increasing dose.

 2. Start with the drug least likely to have caused the ADR. Add the other medicines from least to most likely to have caused the ADR.

 3. Start with low dose of the medicine, often a sixth of the total dose and gradually increase the dose, for example, double the dose each day until the full dose is reached. This usually takes up to 4-6 days for full reintroduction of each drug, a time too short for the selection of resistant strains to the particular medicine.

4. When the full dose of a particular medicine is introduced without any ADR, then an additional medicine should be reintroduced in the same way as the previous medicine. All reintroduction and desensitization must be done in a hospital setting under the care of an experienced medical officer. Before attempting to reintroduce treatment and desensitization, a plan should be established on how to proceed in the event of the adverse reaction reoccurring. Some recommend treating with prednisolone 40-60 mg for three days before re-introducing the medicine and continuing with the steroid for 2 weeks after reintroduction of anti-TB medicines. The medicine least likely to produce the side effect is started first and when its regular dose is achieved without any side effects the next less likely drug is introduced as

The standard approach to re-introduction of anti-TB medicines after an ADR Drug Day

 Day 1 INH 25mg

 Day 2 INH 50mg

 Day 3 INH 100mg

 Day 4 INH 300mg

 Day 5 INH 300mg + R 150mg

 Day 6 INH 300mg + R, 300mg

 Day 7 INH 300mg + R 450mg

 Day 8 INH 300mg +R 600mg (depends on weight)

 Day 9 INH 300mg + R 600mg + E 400mg

 Day 10 INH 300mg +R 600mg + E 800mg

 Day 11 INH 300mg +R 600mg + E 1.2g (depends on weight)

 Day 12 INH 300mg +R 600mg + E 1.2g + Z 400mg

 Day 13 INH 300mg + R 600mg + E 1.2g + Z 800g

 Day 14 INH 300mg + R 600mg + E 1.2g + Z 1.2g

 Day 15 INH 300mg + R 600mg + E 1.2g + Z 1.6g (depends on weight)

The last medicine to be re-introduced before the recurrence of a reaction is the cause of the reaction and that medicine should be replaced.  This may require a decision by a medical officer with extensive experience in management of TB. The patient may therefore have to be referred to the next level for further care.

Alternate regimens when first-line medicines cannot be used

It becomes extremely complicated when any of the first-line treatment medicines cannot be used. For this reason, it is advised that an experienced medical officer, be the one to care of patients in whom one or more of the first line medicines cannot be used. The principle is to use as many first-line medicines as possible in any treatment regimen. In the event that one first-line medicine cannot be used, due for example to severe drug adverse effects to one medicine, the recommended regimens are shown in table below:

 Alternate regimen when specific medicines cannot be used.

 Medicine that cannot be used (Pyrazinamide)

 Alternate Regimen 2HRE/7HR Isoniazid 2REZ/10RE Rifampicin 2HEZLfx/10HE Ethambutol 2HRZLfx/4HR

NOTE: 

1. None of the above regimens have been assessed in a clinical trial setting. Therefore, it is important that patients are closely monitored for clinical and bacteriological improvement. Patients should also be monitored for relapse post treatment completion.

2. The recommended regimen above for situations where Rifampicin cannot be used refers to a state where there is intolerance to Rifampicin. In the event of resistance to Rifampicin patient should be managed with the recommend regimen   

Managing ADRs when FDCs are used. 

Medicine AEs are not any more common when FDCs are used compared to single drug formulations. However, an ADR to one of the components in a FDC is suspected, there will be a need for single-drug formulations.  Limited stocks of single-drug formulations will be available in district/provincial/ referral hospitals where patients experiencing severe adverse event will be managed under supervision. 

 Isoniazid interacts with anticonvulsants, and may cause their concentration in the body to increase to toxic levels.  It is advisable to monitor serum concentration levels of anticonvulsant medicines, if possible. If this cannot be done, it may be necessary to reduce the dosage of anticonvulsant medicines during treatment with an isoniazid-containing regimen. The absorption of isoniazid is decreased by aluminium hydroxide. Medicines containing aluminium hydroxide should be taken at least 1 hour before or 2 hours after taking isoniazid containing treatment. Rifampicin induces several liver enzymes of the cytochrome P-450 system that metabolise medicines thereby reducing their blood levels. This results in faster elimination and lower blood concentrations of many medicines ranging from anti-coagulants and cardiac medications to hormones, anti-fungals, oral anti-diabetics and antiretroviral drugs. Treating patients with rifampicin and these other medicines at the same time would result in lower blood levels and therefore loss of efficacy of these medicines.

Rifampicin interactions with selected antiretroviral medicines ARV drug Effect of interaction with Rifampicin Recommendation if patient is on Rifampicin-containing regimen Nevirapine (NVP) NVP level decreases by 37%. Rifampicin levels remain unchanged. Avoid combined use of NVP and rifampicin, and therefore, switch patient to EFV if not contraindicated. If EFV is contraindicated consider switching patient to ATZ/r and switching from Rifampicin to Rifabutin (see Chapter 7) Efavirenz (EFV) The reduction of plasma concentration of EFV by rifampicin is not clinically significant.  If ART must be started whilst patient is still on a rifampicin containing anti-TB treatment, EFV 600mg should be used instead of EFV 400mg. ATZ/r Plasma concentration of ATZ/r is reduced by up to 90% by rifampicin. Use Rifabutin instead of Rifampicin for patients on second line ART LPV/r Plasma concentration of LPV/r is reduced by rifampicin. Use Rifabutin instead of Rifampicin for patients on second line ART. In the absence of Rifabutin, LPV/r can be used with either double dosing or super boosting (see chapter 7 on TB/HIV). 

Rifampicin and contraceptive methods 

The effects of rifampicin on contraceptives are summarized in table 30 below.  Dual protection should be recommended for all patients receiving rifampicin and hormonal contraceptives concurrently.   Rifampicin interactions with hormonal contraceptive methods Contraceptive method Interaction with Rifampicin Recommendation Oral contraceptives containing < 50 mcg of ethinylestradiol Efficacy reduced by rifampicin and pregnancy may occur Change to high-dose OC, Depo Provera or IUCD and use condoms correctly and consistently Progestin-only-pill Efficacy reduced by Change to high-dose OC, Depo rifampicin and pregnancy may occur Provera or IUCD and use condoms correctly and consistently.

Depo-medroxyprogesterone (Depo-Provera).

No known interaction DUAL PROTECTION necessary.

Hormonal implant

Efficacy reduced by rifampicin and pregnancy may occur Use IUCD concomitantly or use condoms correctly and consistently Intrauterine contraceptive device (hormone releasing or not).

No known interaction May increase transmission of HIV DUAL PROTECTION necessary.

Medicines that are ototoxic or nephrotoxic should not be administered to patients receiving streptomycin. These include other aminoglycoside antibiotics, amphotericin B, cephalosporins, etacrynic acid, cyclosporin, cisplatin, furosemide and vancomycin. Furthermore, streptomycin may potentiate the effect of neuromuscular blocking agents administered during anaesthesia.

Patient information about adverse drug reactions and interactions.

To ensure good compliance during treatment, it is essential for patients, treatment supporters and family members to know basic facts about anti-TB medicines, their side effects and what to do in case of the occurrence of an ADR. Because TB patients are seen daily for directly observed treatment, at least during the initial (intensive) phase of treatment, health staff are encouraged to use more than one consultation to explain the symptoms of side effects and check that patients have understood.  It is also important to ask and look for any possible signs of side effects. ‘Ready-made’ messages adapted for local situations should be used as much as possible. 

Example of health education messages

If you take all the anti-TB treatment with my (or the name of the treatment supporter) assistance and when I (s/he) can confirm that you have been able to swallow all the tablets, as instructed, and for the recommended period, you are going to get better.  You will stop coughing, you will feel less tired, regain your appetite and gain weight.  It is very important to continue taking all the medications, even when you start feeling very well for all TB germs to be killed and for you to be permanently cured. TB can be cured even if you are HIV-positive. Anti-TB medicines are powerful and they can also cause side effects. Common side effects include nausea, vomiting, abdominal pain and discomfort, joint pains, itching, skin rash, numbness, tingling or loss of sensation or burning sensation in feet and hands, yellow discolouration of eyes, diminished hearing or sight.  Contact me or the clinic without delay and tell the doctor or nurse if you develop any of these symptoms. Rifampicin colours all body fluids red or orange.  This is not dangerous.

Note to Health Care workers

• If your patient is female and has had secondary amenorrhoea in spite of not being pregnant, inform her that it is likely that her monthly periods will start again as she recovers from tuberculosis. • If your patient is female and is on modern contraception, find out what method she is using and discuss what additional method she should use during anti-TB treatment. Remember the importance of dual protection.

 • Talk with all female TB patients about their reproductive plans and advise them about the benefits of starting to use contraception if she is not planning a pregnancy.  This is particularly important if your patient is also HIV-positive

• If your patient is taking anti-epileptic drugs: check what medication she/he uses and explain that the effect of anti-epileptic medication may be decreased.  Suggest that the patient keeps a seizure diary, and she/he reports to you immediately if an increase in seizures is observed.

•  If your patient is HIV-positive and is also on antiretroviral treatment:  check what medication she/he uses and explain that added toxicities could occur and that it is important for the patient to contact you if nausea, vomiting, abdominal pain, skin rash or jaundice appears.  

There are multiple adverse events that can be seen in patients undergoing treatment for DR-TB.  Prompt identification and management of AEs is important in maintaining patient health and adherence. 

Adverse event Signs and Symptoms Average onset (in weeks)

Nausea and vomiting

Diarrhoea Loose stool > 3 times a day

Hepatitis/ liver abnormalities Nausea, vomiting, jaundice, anorexia

Hearing loss Buzzing in ears, loss of ability to hear sounds, pressure in the ears, leaning forward when listening

Renal failure Oedema, decreased urine output

Electrolyte imbalances Tremors, muscle cramps 

Seizure Loss of consciousness, tonic-clonic movements 

Psychosis Hallucinations, loss of touch with reality

Hypothyroidism Fatigue, decreased reflexes, constipation, dry skin

Rash Red skin or bumps over trunk, face or extremities Anytime Peripheral neuropathy Tingling or burning in hands or feet

Arthralgia Joint pain or swelling 

Adverse reactions are common and to be expected in most patients treated for DR-TB.  In order to ensure adherence, these should be quickly identified and managed with ancillary medicines provided free of charge to the patient.  Studies have shown that careful management of adverse reactions improves overall treatment outcomes.

It is important to educate patients about what to expect during treatment and to encourage the patient to continue taking the anti-TB medicines if the symptoms are mild. Many AEs resolve spontaneously but some may need to be treated with supplementary medicines.  Some adverse events are dose-dependent and can be managed by reducing the dosage. Significant dose reduction should be avoided (i.e. dose of the previous weight band), which can affect the efficacy of the medicine.  Algorithms for the identification and management of common adverse reactions are discussed in table 32 below. Of note, pyridoxine should be prescribed to all individuals taking Cycloserine to prevent neurological adverse events (50 mg for every 250 mg of CS).

Seizures

Most likely: Cycloserine (Cs), Less likely: Isoniazid (H), Fluoroquinolones (Fqs)

Suspend suspected agent pending resolution of seizures. Initiate anticonvulsant therapy (e.g. carbamazepine, phenobarbitone). Increase pyridoxine to maximum daily dose (200 mg per day). Restart suspected agent or reinitiate suspected agent at lower dose, if essential to the regimen. Discontinue suspected agent if this can be done without compromising regimen.

Anticonvulsant is generally continued until MDR-TB treatment is completed or suspected agent discontinued. History of previous seizure disorder is not a contraindication to the use of agents listed here if a patient's seizures are well controlled and/or the patient is receiving anticonvulsant therapy. Patients with history of previous seizures may be at increased risk for development of seizures during MDR-TB therapy. 

Peripheral neuropathy

 Most likely: Cycloserine (Cs), Isoniazid (H), Streptomycin (S), Kanamycin (Km), Amikacin (Am), 

 Less likely: Capreomycin (Cm), Ethionamide (Eto)/ Prothionamide (Pto), Fluoroquinolones (Fqs)

Increase pyridoxine to maximum daily dose (200 mg per day). Change injectable to capreomycin if patient has documented susceptibility to capreomycin. Initiate therapy with tricyclic antidepressants e.g. amitriptyline. Non-steroidal anti-inflammatory drugs or acetaminophen may help alleviate symptoms. Lower dose of suspected agent if this can be done without compromising regimen.

Patients with co-morbid disease (e.g. Diabetes, HIV, alcohol dependence) may be more likely to develop peripheral neuropathy, but these conditions are not contraindications to the use of the agents listed here. Neuropathy may be irreversible; however, some patients may experience improvement when offending agents are suspended.

Hearing loss and vestibular disturbances

Most likely:  Streptomycin (S), Kanamycin (Km), Amikacin (Am), Less likely:  Capreomycin (Cm), Clarithromycin (Clr)

Discontinue suspected agent if this can be done without compromising regimen. Document hearing loss and compare with baseline audiometry if available. Change parenteral treatment to capreomycin if patient has documented susceptibility to capreomycin. Decrease frequency and/or lower dose of suspected agent if this can be done without compromising the

Patients with previous exposure to aminoglycosides may have baseline hearing loss. In such patients, audiometry maybe helpful at the start of MDR-TB therapy. Hearing loss is generally not reversible. The risk of further hearing loss must be weighed against the risks of stopping the injectable in the treatment regimen. While the benefit of hearing aids is minimal to moderate in auditory toxicity, consider a trial use to determine if a patient with hearing loss can benefit from their use.

 Psychotic symptoms

Most likely: Cycloserine (Cs), Isoniazid (H), Less likely: Fluoroquinolones (Fqs), Ethionamide (Eto) / Prothionamide (Pto)

Stop suspected agent for a short period of time (1–4 weeks) while psychotic symptoms are brought under control. Initiate antipsychotic therapy. Lower dose of suspected agent if this can be done without compromising regimen. Discontinue suspected agent if this can be done without compromising regimen.

Some patients will need to continue antipsychotic treatment throughout MDR-TB therapy. Previous history of psychiatric disease is not a contra- indication to the use of agents listed here but may increase the likelihood of psychotic symptoms developing during treatment. Psychotic symptoms are generally reversible upon completion of MDR-TB treatment or cessation of the offending agent.

Depression

Most likely: Socio-economic circumstances, chronic disease, CS Less likely: FQs, H, Eto/Pto

Provide psycho-social support. Offer group or individual counselling. Initiate antidepressant therapy. Lower dose of suspected agent if this can be done without compromising the regimen. Discontinue suspected agent if this can be done without compromising regimen.

Socioeconomic conditions and chronic illness should not be underestimated as contributing factors to depression. Depressive symptoms may fluctuate during therapy and may improve as illness is successfully treated. History of previous depression is not a contraindication to the use of the agents listed but may increase the likelihood of depression developing during treatment.

 Gastritis

Most likely: P-aminosalicylic acid (PAS), Ethionamide (Eto) Prothionamide (Pto), 

Less likely: Clofazimine (CFZ)

Give antacids, H2-blockers (ranitidine) or proton-pump inhibitors (omeprazole) depending on duration and severity; Stop suspected agent(s) for short periods of time (e.g., one to seven days). Lower dose of suspected agent, if this can be done without compromising regimen. Discontinue

Severe gastritis, as manifested by hematemesis, melaena or haematochezia, is rare. Dosing of antacids should be carefully timed so as to not interfere with the absorption of anti-tuberculosis medicine (take 2 hours before or 3 hours after anti tuberculosis medications). Reversible upon discontinuation of suspected agent(s).

Rash

Most likely: PZA, AMOX-CLV Less likely: INH, RIF, Pto/Eto, PAS, CFZ Any drug can cause rash

Assess for mucous membrane involvement; if mucous membranes involved discontinue all drugs and start prednisone. If rash is mild, can treat with nicotinamide, topical steroids

If rash is severe or if drug rash is suspected, discontinue all agents and restart the agents least likely to cause rash first.  This can be done one at a time over short periods; alternatively, the three least likely agents can be started first followed by additional single agents.

 Hepatitis (transaminases > 5X the ULN)

Most likely: Pyrazinamide (Z), Isoniazid (H), 

Less likely:  P- amino salicylic acid (PAS), Rifampicin (R), Ethionamide (Eto) Prothionamide (Pto), Ethambutol, FQs

Stop all therapy pending resolution of hepatitis (to < 2 x the upper limit of normal for the transaminases. Investigate to rule-out other potential causes of hepatitis (malaria, ART, viral causes). Consider suspending most likely agent permanently. Reintroduce remaining drugs, one at a time with the least hepatotoxic agents first, while monitoring liver function. If single drug introduction being used, must introduce the agents over 714 days; could also introduce 3 less likely drugs at once then add back additional agents

History of previous hepatitis should be carefully analysed to determine most likely causative agent(s); these should be avoided in future regimens. Generally reversible upon discontinuation of suspected agent.  

Renal toxicity

Most likely: Streptomycin (S), Kanamycin (Km), Amikacin (Am), Less likely: Capreomycin (Cm),

Discontinue suspected agent. Consider using capreomycin if an aminoglycoside had been the prior injectable in regimen. Consider dosing 2–3 times a week if drug is essential to the regimen and patient can tolerate (close monitoring of creatinine). Adjust all anti-tuberculosis medications according to the creatinine clearance 

History of diabetes or renal disease is not a contraindication to the use of the agents listed here, although patients with these co-morbidities may be at increased risk for developing renal failure. Renal impairment may be permanent.

Electrolyte disturbances

Most likely: Streptomycin (S),

Check serum potassium level If potassium is low replace both

If severe hypokalaemia admit patient. Amiloride 5–10 mg QD or (hypokalaemia and hypomagnesaemia)

Kanamycin (Km), Amikacin (Am), Less likely Capreomycin (Cm), potassium and magnesium. Check other electrolytes (i.e. calcium) if no improvement:

Spironolactone 25 mg 6 hourly

May decrease potassium and magnesium wasting and is useful in refractory cases. Oral potassium replacements can cause significant nausea and vomiting. Oral magnesium may cause diarrhoea.

Optic neuritis

Most likely: Ethambutol Less likely: Eto, Pto, CFZ

Stop Ethambutol. Refer patient to   an ophthalmologist to assess for other causes

Usually reverses with cessation of Ethambutol. Rare case reports of optic neuritis have been attributed to streptomycin.

ECG changes Most likely: Bedaquiline (BDQ), Moxifloxacin, Levofloxacin Less likely: CFZ

Stop BDQ if there is worrying QT prolongation (>500ms), replete electrolytes, stop other medicines that affect the cardiac rhythm

Arthralgias

Most likely: Pyrazinamide (Z), Less likely: Fluoroquinolones (FQs)

Initiate therapy with non-steroidal anti-inflammatory drugs. Lower dose of suspected agent if this can be done without compromising regimen. Discontinue suspected agent if this can be done without compromising regimen.

Symptoms of arthralgia generally diminish over time, even without intervention. Uric acid levels may be elevated in patients on pyrazinamide. Allopurinol appears not to correct the uric acid levels in such cases.

Drug-drug interactions of ARVs and second line anti-TB medicines Fluoroquinolones and DDI: Reduced intestinal absorption of fluoroquinolones can be related to the concomitant administration of buffered DDI, which contains an aluminium/magnesium-based antacid. DDI is rarely used in the management of HIV except in extreme conditions. If the two must be used, this problem could be by-passed deferring the 2 administrations (DDI taken 6 hours before taking FQ or 2 hours later) or prescribing the enteric-coated formulation of DDI. Clarithromycin: It is an inhibitor of cytochrome P3A. Consequently, it could have several pharmacological interactions with PIs and NNRTIs. On this basis and on the evidence of its poor activity against DR-TB strains, it should not be used in patients on ART. 

Bedaquiline has not been extensively tested for use with ART. Dose adjustments are needed if it is used with EFV, as Bedaquiline has been shown to decrease the concentrations of EFV in the blood. Furthermore, due to limited information on the co-administration of BDQ and ART, therapeutic drug monitoring (TDM) is recommended where available. It is also recommended to closely monitor the effectiveness of ART through monthly viral load testing. 

Monitoring and reporting adverse events due to Second Line Anti-TB medicines

The World Health Organisation (WHO), recommends the use of active drug safety monitoring (aDSM) for the continuous monitoring and reporting of adverse events induced by second line TB medicines. The term ‘active TB drug-safety monitoring and management’ defines active and systematic clinical and laboratory assessment of patients while on treatment. Health programmes that systematically monitor patient safety are at an advantage to prevent and manage ADRs, as well as improve health-related quality of life and treatment outcomes. National tuberculosis programmes (NTPs) that actively pursue drug safety monitoring and management are also better prepared to introduce new tuberculosis (TB) drugs and novel regimens.

The primary difference with the spontaneous adverse event reporting system described earlier is that, with aDSM the health worker assesses meticulously for any perceived adverse events. 

Spontaneous ADR reporting is recommended for ADRs suspected to be caused by first line anti-TB medicines. In spontaneous ADR reporting, reporting is the initiative of health care workers (HCWs). HCWs are encouraged to report all severe adverse events and adverse events of clinical significance. 

How to report suspected ADRs and ADR reporting tools 

An ADR report should be submitted to the Medicine Control Authority of Zimbabwe (MCAZ), as soon as possible after the reaction. To report an ADR, the MCAZ e-ADR reporting platform http://www.mcaz.co.zw/index.php/2016-01-08-06-40-00/e-reporting can be used. Once submission is made on-line, the e-ADR form is received by the MCAZ.  A standard ADR reporting form can also be completed (Annex 11), and submitted to the MCAZ (see figure 19 below). All ADR reports once submitted, are treated in an anonymous manner i.e. information for both the patient and reporting health care worker are kept confidential.

Key Points to Note: At every contact with a TB patient, ask about symptoms, such as nausea, vomiting, abdominal pains and discomfort, itching, joint pains and numbness, tingling or burning sensation or loss of sensation in hands and feet. At every contact with a TB patient, look for skin rash, jaundice with continued nausea and vomiting. If an ADR occurs diagnose it promptly followed by appropriate management of the ADR.