XAVIER UNIVERSITY - DR. JOSE P.

RIZAL SCHOOL OF MEDICINE

ATENEO DE CAGAYAN

Draft Case Protocol

Department of Preventive and Community Medicine

Xavier University Community Health Care Center

Committee of German Doctors
Programmatic Management of Drug-resistant Tuberculosis

In partial fulfilment of the Requirements in Medicine Level IV

Submitted by:

Centino, Tizabelle G.
Lucman, Harissa M.
Pahilan, Ritzjeral Christer A
Papelleras, Ken Jeryl M.
Si, Roselyn L.
Ting, Stacy Yin M.
Veloso, Maria Kristina M.
 April 2018
ABSTRACT

This is a case of a 52 year old female, diabetic presenting with chronic cough. She is a college
graduate and is a retired accountant. Diabetes is the only heredofamilial disease known. She is
a non-smoker, non-alcoholic beverage drinker with no history of illicit drug use. She was
diagnosed with bacteriologically confirmed rifampicin resistant pulmonary tuberculosis last
2013, denying exposure to persons with the disease. She started treatment at a TB-DOTS
facility in Cotabato City but was lost to follow-up after complying less than 1 month of
treatment. Since then, she underwent several incomplete TB treatment regimens with different
private practitioners. 5 months ago, she was admitted due to shortness of breath with an
impression of pulmonary tuberculosis, bronchiectasis with pleural effusion. Persistence of
cough with associated dyspnea prompted her to seek consult with her private MD and was
subsequently referred to this institution. On physical examination, the patient appeared thin
and was awake, conscious, and coherent, per wheel chair, on O2 support at 2 liters per minute
via nasal cannula with normal vital signs. Pertinent chest and lung finding was decreased
breath sounds on right lower lung field.

Majority of PTB patients worldwide are infected with drug susceptible strains and they can
expect a relapse-free cure with a short course of first-line medication. On the other hand,
patients with rifampicin resistant TB (RR-TB) commonly combined with isoniazid resistance
(MDR-TB), require treatment regimens that are longer, less effective and less accessible than
first-line regimens, but more costly, toxic, and complicated to deliver. Most second-line
MDR-TB regimens in recent decades were designed to last for >=20 months. Hence, all those
factors present as a challenge to health service providers in ensuring treatment adherence and
increase in cure rates. All or some of these may have been the reason for our patient’s
nonadherence to her treatment regimen. Another challenge that was identified in the patient, is
her co-morbidity which is diabetes mellitus type 2. This condition may have predisposed her in
developing active TB as it can weaken the immune system. ​Each disease is thought to
exacerbate and worsen the outcome for the other. ​Drug-drug interactions can lead to
decreased efficacy and increase in side-effects which ultimately could lead to nonadherence,
treatment failure and disease progression.

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OBJECTIVES
1) To present a case of a 52 year old female with bacteriologically confirmed
Rifampicin-resistant pulmonary tuberculosis
2) To discuss the relationship between diabetes mellitus and pulmonary tuberculosis
3) To discuss the reasons for treatment noncompliance among PTB patients
4) To discuss the consequences of treatment noncompliance
5) To discuss strategies used to reinforce adherence to treatment in MDR-TB cases

GENERAL DATA
A case of N.D. 52 y/o Female, Married, Filipino, Islam from Bulua Cagayan de Oro City who
came in for the second time in this institution due to chronic cough.

SOURCE OF INFORMATION:
Patient herself with 90% reliability

CHIEF COMPLAINT:
Chronic cough

HISTORY OF PRESENT ILLNESS

5 years prior to consult, patient had onset of on and off productive cough associated with
whitish sputum without any febrile episodes, chest and back pains, and dyspnea. Patient
tolerated the condition with no consults done, nor any medications taken. Patient gradually
began to notice changes in her weight as evidenced by loosening of her clothes which was
now associated with body malaise and decreased appetite.

Persistence of above symptoms led her to seek consult on May 2013 at a private hospital in
manila where it was revealed she had an uncontrolled blood sugar level. Patient was advised
for admission wherein chest xray was done revealing presence of fungal balls along with
pulmonary tuberculosis. She underwent surgery and was subsequently treated for her
tuberculosis with Ethambutol HCl, Rifampicin, Isoniazid, and Pyrazinamide (Myrin P40) for 26
days. Sputum culture and drug susceptibility testing was done which revealed negative
findings.

3 months after discharge, patient went back home to Cagayan de Oro City and went for a
regular check-up with her private physician with a complaint of productive cough without
associated symptoms of dyspnea, night sweats, or chest and back pains. Chest xray was
ordered revealing presence of PTB and patient was then started on Moxifloxacin 400mg tablet,
and Ethambutol HCl, Rifampicin, Isoniazid, and Pyrazinamide (Myrin P40). Patient was
maintained on this regimen for 4 months after which she was then referred to XUCHCC for

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further treatment. Due to the nature of patient’s work, patient asked to receive treatment at
Cotobato TB-DOTS where she was currently working for as an accountant. She was started on
Pyrazinamide, Ethambutol,, Kanamycin, Moxifloxacin, Prothionamide, and Clofazimine. She
also received treatment at a private hospital in manila with a total duration of less than one
month of treatment. Patient claims that due to her busy schedule of frequent travelling, and
side effects of the drugs namely nausea and vomiting along with numbness and tingling
sensation of the lower extremities, patient was not compliant with her medications which led to
lost to follow-up.

During the interim, patient noticed gradual weight loss associated with body malaise. Cough
still persisted with the same characteristics, but still, patient did not seek consult nor take any
medications.

October of 2017, patient noted onset of difficulty of breathing even at rest which was
associated with easy fatigability. She sought consult at a private clinic where a chest xray was
ordered revealing presence of PTB along with fluid in the lungs. Patient was advised for
admission and was admitted at CUMC where she received treatment for her PTB with
Ethambutol HCl, Rifampicin, Isoniazid, and Pyrazinamide along with Ciprofloxacin 500mg.
Patient maintained this regimen for 4 months, but as patient claimed, she did not notice any
improvement of her symptoms as evidenced by persistence of shortness of breath. She thus
sought consult with her private physician and was then subsequently referred to our institution
hence this admission.

PAST MEDICAL HISTORY

In 2007, she was diagnosed with Diabetes Mellitus Type II. Highest blood sugar level of
400mg/dl. She is currently maintained on Pioglitazone, Xelevia, Pregabalin with usual capillary
blood glucose levels ranging from 120-140md/dL. She reports to have peripheral neuropathy
on both feet and occasional blurring of vision secondary to her DM.

In 2008, she underwent total abdominal hysterectomy due to profused uterine bleeding.

FAMILY HISTORY
Diabetes mellitus is present in the paternal side of the family. No other diseases are noted
such as hypertension, cardiovascular diseases, thyroid disease, or malignancy. No family
member is known to have pulmonary tuberculosis.

PERSONAL AND SOCIAL HISTORY

Patient is a college graduate and is currently a retired accountant. She has been married to her
husband for 35 years. She is a nonsmoker, non-alcoholic beverage drinker with no history of
illicit drug use.

ENVIRONMENTAL HISTORY

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Patient lives in a concrete house inside a subdivision which according to the patient is well
ventilated. The house is occupied by 6 adults all in all with no history of PTB. Her close
contacts have been screened for PTB.

GYNECOLOGIC HISTORY
Patient had her menarche at 14y/o with subsequent menses occurring at regular intervals
occurring 3-4 days in duration using 2-3 pads per day, fully soaked with associated symptoms
of dysmenorrhea. She had her coitarche at 17 y/o with only one sexual partner and had been
using oral contraceptives as a form of family planning.

OBSTETRICAL HISTORY
GRAVIDA YEAR TYPE OF DELIVERED AOG WHERE
DELIVERY BY DELIVERED
1 1983 NSD Physician Term Hospital
2 1990 NSD Physician Term Hospital
3 1991 NSD Physician Term Hospital
4 1993 NSD Physician Term Hospital
5 1995 NSD Physician Term Hospital

PHYSICAL EXAMINATION
General Survey
The patient appeared thin. She was awake, coherent, not in respiratory distress, per
wheelchair and on O2 support at 2lpm delivered via nasal cannula.

Vital Signs
BP: 90/60 mmHg Temperature: 36.8 C
PR: 90 beats per minute O2 Sat: 96% on O2 support at 1 lpm via nasal cannula
RR: 20 cycles per minute

Anthropometrics
Weight: 42.5 kg
Height: 156cm
BMI: 17.4 kg/m2

Skin:​ No rashes or jaundice. Extremities warm to touch with good skin turgor,

HEENT: ​Normocephalic. Anicteric Sclerae, Slightly pale palpebral conjunctivae, Non-sunken

eyeballs. Moist lips and oral mucosa. Tonsils are not swollen and nonhyperemic. Supple neck
with no lymphadenopathies.

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 Chest and Lungs: ​No deformities. No retractions or use of accessory muscles. Equal chest
expansion. Resonant on percussion. Tactile fremitus equal on both lung fields. Decreased
breath sounds on Right lower lung field.

Cardiovascular: ​Adynamic precordium. PMI: Left 5​th ICS, midclavicular line. Distinct S1 and
S2 heart sounds. Normal rate and regular rhythm. No murmurs.

Gastrointestinal: ​Flat, no visible pulsations and peristalsis, normoactive bowel sounds, soft,
no tenderness.

Genitourinary: ​No costovertebral angle tenderness

Musculoskeletal: ​Full range of motion on all joints, poor muscle bulk, no joint swelling

Neurologic exam:
l status
oriented to time, place and person

Cranial Nerves
I: unassessed
II: Pupils equally round and reactive to light
III, IV, VI: able to follow through 6 cardinal movements of gaze
V: intact touch sensation, able to chew
VII: able to raise brows, smile, puff out cheeks, no asymmetry noted
VIII: able to hear whispered words
IX, X: able to swallow, no hoarseness of voice
XI: able to shrug shoulders and turn head from side to side
XII: on protrusion, tongue is midline

Motor. Poor muscle bulk, good tone, strength of 5/5 throughout all extremities

Sensory: Intact light touch and pinprick sensation

Cerebellum: Rapid alternating movements (RAMs) intact. No tremors noted.

Reflexes: On both sides, triceps, patellar and achilles reflexes are 2+ and Babinski reflex is
negative.

SALIENT POINTS
HISTORY PHYSICAL EXAM

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 ✓ Cough of 4 years duration with greenish ✓ Weak-looking, thin, per wheel chair, on
sputum O2 support at 2 LPM delivered via nasal
✓ Shortness of breath when not on O2 cannula
support ✓ BMI=17.4kg/m2 (underweight)
✓ Unintentional weight loss ✓ Decreased breath sounds on Right lower
✓ Known diabetic lung field
✓ History of multiple incomplete PTB
treatment

DIFFERENTIAL DIAGNOSES

DISEASE POINTS FOR POINTS AGAINST

Lung cancer ✓ Chronic cough ✓ Non-smoker
✓ Shortness of breath at rest ✓ No family history
✓ Decreased breath sounds on
right lower lung field
✓ Unintentional weight loss
✓ History of pulmonary tuberculosis
infection (develop in scars)
Pulmonary abscess ✓ Chronic cough ✓ Non-alcoholic beverage
✓ History of pulmonary tuberculosis drinker
infection ✓ Greenish yet not
✓ Decreased breath sounds on foul-smelling sputum
right lower lung field
✓ Diabetic
Heart failure ✓ Chronic cough ✓ Productive cough
✓ Shortness of breath at rest ✓ Nonhypertensive
✓ Decreased breath sounds on ✓ No edema
right lower lung field
✓ Diabetic

PERTINENT DIAGNOSTICS

Diagnostic laboratories and imaging done to the patient were chest x-ray, ecg, alkaline
phosphatase, fasting blood sugar, serum uric acid, serum BUN, serum creatinine, sgpt, sgot,
complete blood count, direct sputum smear microscopy, gene xpert, and drug susceptibility
test.

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Chest x-ray result showed right apical pleural thickening, right lower lobe opacities with volume
loss, bronchiectatic changes, atelectasis and minimal right pleural effusion from post-infectious
process, stable thicked-wall lucencies in the right lung, likely pulmonary cavitary lesions and
thoracic dextroscoliosis.

ECG showed sinus rhythm with sinus tachycardia with baseline QT interval of 0.28 seconds
and corrected QT interval of 348msec.

Aklaline Phosphatase showed 63 U/L which is within nomal range. Fasting blood sugar was
140.91mg/dl which is above normal.

Serum uric acid, BUN, creatinine, sgpt and sgot were all within normal range​, ​4.70mg/dl, 7.14
mg/dl, 0.50 mg/dl, 10.50 U/L and 13.90 U/L respectively.

CBC results were the following: hematocrit 31.3%, hemoglobin 9.96, RBC 3.8, WBC
8,000/mm3, segmenters 80%, lymphocytes 11%, monocytes 6%, eosinophils 3%, platelet
count 395,000. Direct sputum smear microscopy showed positive.

Gene xpert showed MTB detected with rifamipicin resistance detected.

Drug susceptibility test showed resistance to fluoroquinolones and aminoglycosides not

detected.

TREATMENT PLAN
1. Monitoring Plan
Monitor for occurrence of clinical problems during treatment.

Daily: Manage adverse events and drug reactions and document in the PPRF.

Monthly:
● Perform sputum smear, culture and DST in identifying response to treatment.
● Clinical assessment (physical exam to include Visual acuity, Ishihara test, weber and
rinne)
● Blood chemistry (Crea, AST, ALT, FBS, HBA1c)
● ECG
● Audiometry

2. Therapeutics
Definitive

ration units/day

8
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mycin g

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onamide g ets

mizine g et

b) Supportive
ration units/day

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PROGRESS NOTES
On our first day of observation, patient complained of having shortness of breath when not
hooked to oxygen for about 1 hour. She also complained of hyper salivation whenever she
drinks medicine. She stated of feeling of numbness on the injection site. No other complaints
noted. Patient was seen awake, conscious, coherent, in respiratory distress, per wheelchair
and hooked to oxygen via nasal cannula. Vital signs were as follows: BP 90/60 mmHg, pulse
rate 104 bpm, respiratory rate 24 cycles per minute, temperature 36.9 C, and Oxygen
saturation of 97 % at 2 lpm. Patient was noted to be slightly tachycardic. Patient has no
retractions with clear breath sounds and equal chest expansion. For the treatment, patient had
1.5 tabs of Isoniazid 300mg, 3 tabs of Pyrazinamide 500mg, 2 tabs of Ethambutol 400 mg, 1.5
tabs Moxifloxacin 400mg, 2 tabs Prothionamide 250mg,1 tab of Clofazimine 100mg, and
675mg of Kanamicin.

On the second day, patient had the same subjective complaints. Patient can only tolerate
about 1 hour off the oxygen. No other complaints noted. Patient was seen awake, conscious,
coherent, in respiratory distress, per wheelchair and hooked to oxygen via nasal cannula. Vital
signs were as follows: BP 90/60 mmHg, pulse rate 102 bpm, respiratory rate 26 cpm,
temperature 36.8 C and oxygen saturation of 98% at 1 l-2 lpm. Patient was noted to be slightly
tachycardic and tachypneic. Patient has no retractions with clear breath sounds and equal
chest expansion. No clinical improvement was noted from the first day. For the treatment,
patient had 1.5 tabs of Isoniazid 300mg, 3 tabs of Pyrazinamide 500mg, 2 tabs of Ethambutol

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400 mg, 1.5 tabs Moxifloxacin 400mg, 2 tabs Prothionamide 250mg,1 tab of Clofazimine
100mg, and 675mg of Kanamicin.

On the third day, patient still had the same subjective complaints except that at this time,
patient noted to have tolerated 1-2 hours off the oxygen. No other complaints noted. Patient
was seen awake, conscious, coherent, in respiratory distress, per wheel chair and hooked to
oxygen via nasal cannula. Vital signs were as follows: BP 100/60 mmHg, pulse rate 104bpm,
respiratory rate 23 cpm, temperature 36.9 C and oxygen saturation of 98% at 1 lpm. Patient
has no retractions with clear breath sounds, and equal chest expansion. Patient was noted to
have slight improvement clinically. Patient’s medications were the same from the previous
days. She was able to take and tolerate all of them.

On the fourth day, patient noted to have tolerated more than 2 hours off the oxygen. She still
has hyper salivation before drinking medicines and still feels numbness on the injections site.
Patient was seen awake, conscious, coherent, in respiratory distress, per wheel chair and
hooked to oxygen via nasal cannula. Vital signs were as follows: BP 90/60 mmHg, pulse rate
104bpm, respiratory rate 21 cpm, temperature 37.1 C and oxygen saturation of 98% at 1 lpm.
Patient has no retractions with clear breath sounds, and equal chest expansion. Patient was
noted to have improvement clinically. Patient’s medications were the same from the previous
days. She was again able to take and tolerate all of them.

CASE DISCUSSION

1. Drug-Resistant Tuberculosis (DR-TB)

Tuberculosis (TB) is caused by a bacterium called Mycobacterium tuberculosis which is

transmitted through coughing, sneezing and talking. It is a major public health problem in the
Philippines and is the 8th leading cause of mortality and morbidity among Filipinos.

DR-TB refers to resistance of the TB bacilli to one or more anti-TB drugs. Rifampicin resistant
TB (RR-TB) is resistance to rifampicin with or without resistance to other drugs. Multidrug
resistant TB (MDR-TB) is resistance to at least both isoniazid and rifampicin. While, extensively
drug resistant TB (XDR-TB) refers to MDR-TB plus resistance to any fluoroquinolone and at
least one 2​nd​ line injectable drug (Kanamycin, Amikacin and Capreomycin).

Persons at high risk of developing DR-TB include all for retreatment. As for the new cases,
those who are contacts of DR-TB cases, those who remain smear positive at the end of the 3​rd
month of treatment, and the immunocompromised such as people living with HIV with radiologic
findings or any of the following symptoms: cough, fever, weight loss, night sweats, those with
chronic diseases such as diabetes and those at the extremes of age.

There are two principal pathways leading to the development of active drug-resistant -
primary or acquired (secondary) resistance. Primary drug resistance results when a person

10
has been infected with a drug-resistant TB strain. Often facilitated by overcrowding, poor
ventilation, poor infection control and congregate settings. Acquired (secondary) drug resistance
results from inadequate, incomplete or poor treatment quality that allows the selection of
mutant resistant strains.

Conventional (phenotypic) drug susceptibility testing (DST) on culture isolates remains the
reference standard for the diagnosis of drug resistant tuberculosis. However, its long turnaround
time, cumbersome procedures and complex quality assurance requirements limits availability to
the general population. In 2013, the WHO updated their relationship for the use of Xpert®
MTB/Rif as an initial test for presumptive DR-TB in adults before initiating any form of TB
treatment. Currently, the WHO-endorsed available diagnostic tests in the country are Xpert
MTB/RIF that detects rifampicin resistance and Line Probe Assay (LPA) for first and second line
anti-TB drugs. TB culture and DST for FLD and SLD shall be done when rifampicin resistance is
detected.

Detection of RR-TB strain suffices to start the patient on MDR-TB regimen. First, they are
assessed for eligibility for the shorter MDR-TB regimen (SSTR). If the patient has none of the
following then he/she may continue with the SSTR:
a. Confirmed or suspected resistance to second line injectable agent and/or fluoroquinolone
b. Exposure to > 1 second line drugs in the shorcourse of treatment for RR-/MDR-TB
lasting 9-12 months, which is largely standardised.ter MDR-TB regimen for > 1 month
c. Intolerance to > 1 drugs in the shorter MDR-TB regimen or risk of toxicity (e.g.
drug-drug interactions)
d. Pregnancy
e. TB Meningitis, Osteoarticular TB, Disseminated TB
f. At least one medicine in the shorter MDR-TB regimen not available in the program.

The standard Short Treatment Regimen (SSTR) course of treatment for RR-/MDR-TB
lasting 9-11 months is largely standardised and consists of:
4-6 MfxKmPtoCfzZEHh/5MfxCfzZE
Those who do not qualify for SSRT will be enrolled at the Conventional Treatment Regimen
(CTR). The treatment regimen for the patient should consist of at least four (4) effective anti-TB
drugs that have not been used before and/or are susceptible by DST, taking into account DST
reliability and cross-resistance. Total duration of therapy is 20-24 months with intensive phase
of 8 months and continuation phase of 12-16 months. The anti-TB drugs are classified into four
(4) groups.

Table 1 - Anti-TB Drugs Recommended for Treatment of Rifampicin-Resistant and

Multi-Drug Resistant TB

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Monitoring for response to medication and occurrence of clinical problems during treatment
should be done. Adverse events and drug reactions are monitored daily and should be
documented in the PPRF. On a monthly basis, clinical assessment then sputum smear and
culture are done to identify response to treatment or early failure.

The outcome of patients is decided based on completion of treatment regimen, sputum

follow-up results and clinical improvement or lack of clinical deterioration. The treatment
outcomes for MDR-TB are: Cured, Treatment completed, Treatment failed, died and lost to
follow-up. After successful completion of the regimen, patients are advised for post-treatment
follow-up every 6 months for 2 years. On each visit, clinical assessment, sputum collection for
DSSM, TB culture, and DST (if positive TB culture) and Chest x – ray are done.

2. Relationship between diabetes mellitus type 2 and pulmonary tuberculosis

South Asia is known as the diabetes capital and the tuberculosis capital of the world. It is
worthwhile to mention that both these diseases may simulate the symptoms of the other. Such
symptoms that are common to both include lethargy, fatigue, weight loss, fever and loss of
appetite. It is not unheard of for people with diabetes to present to the doctor with complaints of
worsening of blood glucose control only to find out later that they have TB.

The two diseases interact with each other at multiple levels – each exacerbating and worsen the
outcome for the other. ​There is growing evidence that diabetes mellitus is an important risk
factor for tuberculosis. . ​Diabetes is associated with a decrease in cellular immunity. There are
fewer T lymphocytes and a decreased neutrophil count in diabetics. Th1 cytokines are vital in
the control and inhibition of mycobacterium tuberculosis bacilli. This decrease in T lymphocyte

12
 number and function is primarily responsible for the susceptibility of diabetics to TB.
Macrophage function is also inhibited in individuals with diabetes, with an impairment of the
production of reactive oxygen species, and phagocytic and chemotactic function. Hyperglycemia
has a direct depressive effect on the respiratory burst. A combination of these dysfunctional
processes contributes to an increased risk of TB in diabetes. ​On the other hand, tuberculosis
might induce glucose intolerance and worsen glycaemic control in people with diabetes.
Infections are known to worsen diabetic control, and tuberculosis is no exception.

Management of patients with concomitant TB and diabetes differs from that of either disease alone.
Treatment of DM in TB should be aggressive. An optimal glycemic control results in a better
patient outcome; therefore vigorous efforts should be made to achieve such control. Insulin
therapy should be initiated at the outset, using basal bolus regime or premixed insulin. Insulin
requirements are high to begin with but fall after a few weeks once glucotoxicity is corrected and
infection is controlled. In patients with co-existing peripheral neuropathy due to diabetes, it is
mandatory to give the patient pyridoxine if isoniazid is to be used.

Oral hypoglycemic agents are contraindicated in severe tuberculosis but may be used with
caution once the disease has settled. Rifampicin is a potent hepatic enzyme-inducer. It
accelerates the metabolism of several oral hypoglycemic agents, especially sulphonylureas and
biguanides, and lowers their plasma levels. Therefore it may cause hyperglycemia in diabetic
patients using these drugs. Isoniazid, in contrast to rifampicin, inhibits the metabolism of oral
hypoglycaemic agents and may lead to an increase in the plasma levels of these drugs. Its main
interaction is with sulphonylureas, the action of which it antagonizes and worsens the glycemic
control of diabetics on this medication. It also impairs the release and action of insulin leading to
hyperglycemia even in non-diabetics. Therefore the dosage of insulin should be adjusted while
adding and removing these drugs from the patients’ prescriptions. Dipetidyl protease inhibitors
(the gliptins), a comparatively newer class of hypoglycemic agents, have a theoretical possibility
of reducing immunocompetence because of their mechanism of action. This effect could
possibly worsen the outcome of patients with TB.

Diabetes might alter the pharmacokinetics of antituberculosis drugs. DM may multiply the
adverse effects of anti-TB drugs, especially renal dysfunction and peripheral neuropathy.
Monitor creatinine and potassium concentrations more frequently than usual, preferably weekly
during the first month of treatment and at least every three months thereafter depending on the
clinical status of the patient and based on physician’s discretion. Patients should have regular
monitoring of blood glucose level and other important parameters for diabetes management.
Oral hypoglycemic agents can be used during DR-TB treatment but may require dose
adjustment due to drug-drug interaction. Some experts recommend the use of insulin for tight
blood glucose control. Ethionamide or Prothionamide may make it more difficult to control
insulin levels. In one study in Indonesia, diabetic patients with tuberculosis had rifampicin serum
concentrations that were 53% lower than in non-diabetic patients with tuberculosis, and there
was an indirect relation between fasting glucose and rifampicin concentrations. Given that low

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concentrations of anti-tuberculosis drugs have been linked to treatment failure or resistance, this
finding is of particular concern. Diabetes can also cause changes in oral absorption, decreased
protein binding of drugs, and renal insufficiency or fatty liver with impaired drug clearance. Its
effect on tuberculosis drug concentrations has not been formally studied; in cases of poor
response to treatment in diabetic patients with tuberculosis, therapeutic drug monitoring might
be considered.

3. Reasons for treatment noncompliance to PTB regimens

Non-adherence to anti tuberculosis treatment is one of the crucial challenges in improving

tuberculosis cure-rates and reducing further healthcare costs. Treatment after lost to follow-up
(TALF) are TB “patients who did not start treatment or whose treatment was interrupted for two
consecutive months or more.” These patients were previously referred to as “defaulters.”
Patients who were TALF are more at risk to develop relapse, and even at risk of developing
multi-drug resistant tuberculosis (MDR-TB). (Wohlleben et al. BMC Infectious Diseases (2017))

In the Philippines, there has been a rise of total number of lost to follow-up from 21% in
2007 to 39% in 2013 despite advances in diagnostics. Also, the rate of success in treatment had
decreased in that same timeline from 63%-44% (Tropical Disease Foundation, 2016). Despite
this data, there has only been few studies regarding the reasons why TB patients become lost
to follow up.

In a study conducted in India by Heemanshu, A. et. al. in 2016, they have found out that
age, gender, total number of family members in household and eductation were not risk factors
of non-compliance. In contrast to this, marital status, occupation, smoking, alcoholism and poor
socio-economic status were determined as risk factors.

Medication side effects or fear of side effects was the most commonly reported primary
reason for lost to follow-up according to the results of the study conducted by Tupasi, T et. al.
(2017) in the Philippines. The same study also reported that the patient’s knowledge regarding
TB was significantly lower among those patients who were lost to follow-up.

Specifically, patients who had higher rating of severity in their adverse drug reactions were
more likely to quit treatment (Tupasi, T. et. al., 2017). Among these symptoms were vomiting,
dizziness and fatigue.

Among various studies on determinants and/risk factors associated with lost to follow-up,
alcohol abuse has been consistently found out to be one contributing factor. In a study
conducted by Heemanshu, A et. al. (2016), alcohol abuse during treatment period can lead to
non-compliance. Alcohol abuse is common among those in the lower socio-economic class, a
risk factor in itself. Hence, being poor multiplies ones risk for non-compliance.

Aside from alcohol abuse, poverty was linked to non-compliance due to costly transport
expenses (Heemanshu, A et. al. 2016). This is not only observed in India. This barrier to

14
treatment was also relevant to the Philippines. Hence, assistance for TB patients i.e. covering
for transportation, food and housing was found out to be a protective factor (Tupasi, T. et. al.,
2017).

Levels of trust in, rapport with, and support from physicians, nursing staff, and other
caregivers in the treatment facility were significantly lower among those patients who were lost
to follow-up (Tupasi, T. et. al., 2017).

Marital status was not found out to be a risk factor for lost to follow up among TB patients.
However, in few journals conducted in India, it was found out that singles, especially women,
are more likely to quit treatment and become lost to follow up compared to those married
individuals. This can be linked to good support system.

Another risk factor that was not reported in the Philippines but were reported in other
countries was migration. In a qualitative study in Tajikstan conducted by Whollenben, J. et. al.
(2017), migration abroad or even within the country increases the risk of lost to follow up.
Hence, a proper referral system must be develop among health care providers to alleviate this
barrier.

Another barrier to compliance were stigma, family problems and patient refusing to
treatment. In a study conducted in India, social stigma and discrimination is a barrier to
treatment. Some patients in their study refused counselors to enter their house due to
embarrassment (Deshmukh, R. et. al., 2015). Some patients wouldn’t want health care
providers enter inside their houses.

A study abroad also revealed that being employed, especially employed and breadwinner,
was associated with higher risk of lost to follow up (Deshmukh, R. et. al., 2015). Many patients
who are already working would rather earn something for a living for their family than continue
and finish treatment.

In conclusion, factors leading to lost to follow up among TB patients in general can be

grouped into 1. medication related, 2. Service provider related, 3. Socio-economic factors
related and 4. patient related. Hence, programs to reduce TALF rate were implemented and
were focused on these factors.

4. Outcome of treatment noncompliance among tuberculosis patients

According to Bam et al. (2006), non-compliance with TB treatment is one of the major barriers in
achieving global TB control targets in most parts of the world regardless of strategies put in
place globally to control TB (Bam et al., 2006; Newell et al., 2006; WHO, 2011).

Compliance requires patients to take their TB treatment in a regular and consistent way in order
to reduce the risk of treatment failure, relapse and development of drug resistant strains. The

15
WHO requires a TB treatment compliance of greater than 90% in facilitating cure and achieving
treatment success. Compliance has been defined and measured differently in different settings,
but most of the studies have adopted the WHO recommendation.

According to Afns & Ji (2010), interruptions that occur especially in the early stages of treatment
can cause an increase in the TB transmission rate. This is because the initial stage of treatment
is regarded as the most infectious stage with many TB bacilli. This is also the stage where
resistant bacilli survive if not properly treated, therefore it requires correct and consistent
administration of medication in order to ensure that the majority of TB bacilli are killed and
resistant bacilli have no chance of surviving. To prevent the increase in TB cases and the
emergence of drug resistant TB, patients need to be encouraged to comply with their TB
medication (Adane et al., 2013; Brust et al., 2010). According to blah, majority of the studies
reported the time of treatment interruption or lost to follow up occurred during continuation
phase.

Noncompliance with therapy also has adverse consequences for the community through
transmission of tuberculosis to contacts during periods of noncompliance. In a DNA
fingerprinting study in San Francisco, the apparent index cases of the three largest clusters,
which together accounted for 14% of the cases of tuberculosis during the 2-year study, were
noncompliant and remained sputum culture positive for prolonged periods of time. 20 We
previously reported that the apparent index case of the largest DNA fingerprint cluster in Denver
was a patient who had been noncompliant. Therefore, noncompliance with therapy has adverse
consequences for the community, as well as for the noncompliant patients.

5. Strategies to improve adherence to PTB treatment regimens

In order to prevent lost to follow-up among patients who were diagnosed as DRTB, the following
strategies were emphasized in PMDT Implementing Guidelines:

a. Health care provider shall give enough time to clearly explain to the patient the contents
of the Paunawa form. Involve the family and significant others as well. Provide IEC
material.

b. Promptly inform patient through various means once the result of Xpert examination has
been received. If patient does not arrive in the facility a day after he/she was informed
about the result, this should serve as a signal to the health care provider to immediately
contact the patient and document the reason why he/she did not come to the facility for
initiation of treatment. If patient is not enrolled within 2 days, this should serve as an alert
to the health care provider. A home visit shall be conducted by the PMDT treatment
facility staff or by the nearest DOTS facility staff. If patient is not enrolled after 2 days,
this should serve as an alarm to the health care provider. Coordination with RHUs, and
LGUs shall be done to convince the patient and provide support. If patient still is not
enrolled after 3 days, this shall be elevated to ROs for further action.

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 c. If patient could not come due to financial and geographical constraints, health care
provider shall reiterate to patient the options for treatment locations (facility or home
based) or provide enablers.

d. If patient prefers to be treated by another facility, prepare all necessary documents and
coordinate with the receiving health facility.

e. If the patient still refuses to be treated despite all efforts, document reason/s of refusal
and action/s taken (infection control, palliative care).

REFERENCES

1. 2016. Clinical practice guidelines for the diagnosis, treatment, prevention and control of
tuberculosis in adult filipinos 2016 update.
https://www.pcp.org.ph/documents/PSBIM/2017/CPG%20TB%202016%20E-copy.pdf

2. 2016. National tuberculosis control program manual of procedures 5​th​ edition.

https://www.philhealth.gov.ph/partners/providers/pdf/NTCP_MoP2014.pdf

3. Dooley, K. and Cahison, R. 2009. Tuberculosis and diabetes mellitus: convergence of two
epidemics. ​https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2945809/

4. Adane A, Alene KA, Koye DN, Zeleke BM. 2013. Nonadherence to anti-tuberculosis
treatment and determinant factors among patients in northwest Ethiopia.
https://www.ncbi.nlm.nih.gov/pubmed/24244364

5. Programmatic Manmagement of drug-resistant tuberculosis (PMDT) Implementing guidelines.

6. Diabetes and tuberculosis: a review of the role of optimal glycemic control.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3598170/

7. Wohlleben, J, et. al. (2017). Risk factors associated with loss to followup from tuberculosis
treatment in Tajikistan: a case-control study. BMC

8. Deshmukh, R, etl. al. 2015. Patient and Provider Reported Reasons for Lost to Follow Up in
MDRTB Treatment: A Qualitative Study from a Drug Resistant TB Centre in India. PLOS One
Journal. India

9. Heemanshu, A. et. al. 2016. Determinants of lost to follow up during treatment among
tuberculosis patients in delhi. International Journal of Medical Research & Health Sciences

10. Tupasi, T. et. al. 2017. Factors Associated with Loss to Follow-up during Treatment for

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Multidrug-Resistant Tuberculosis, the Philippines, 2012–2014. Emerging Infectious Diseases.
www.cdc.gov/eid

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