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Update on scrofuloderma

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Bali Dermatology and Venereology Journal (BDV) 2019, Volume 2, Number 2, 34-41
P-ISSN.2089-1180, E-ISSN.2302-2914

Update on scrofuloderma

Marianto1*, Hartono Kosim2, Pande Agung Mahariski3, Paulus Mario Christopher2

ABSTRACT

Tuberculosis is one of the most significant diseases which causes improperly due to its similarity with abscess. In addition, there were
death worldwide. TB infection is assumed to infect the lungs only still no national and international guidelines for scrofuloderma.
from a general perspective. In fact, TB infection also causes lesions This review to give insights and review about an update in the basic
on the skin. Scrofuloderma, as one of the most common types principle of scrofuloderma and management.
of cutaneous tuberculosis, often misdiagnosed and managed

Keywords: Scrofuloderma, cutaneous, tuberculosis, management

Cite this Article: Marianto., Kosim. H., Mahariski, P.A., Christopher, P.M. 2019. Update on scrofuloderma. Bali Dermatology and Venereology
Journal 2(2): 34-41. DOI: 10.15562/bdv.v2i2.20

1
Faculty of Medicine, Universitas INTRODUCTION and international guidelines for handling standards
Sumatera Utara, Indonesia have been established. Meanwhile, there is still no
2
Faculty of Medicine, Universitas Tuberculosis (TB) is one of the ten most significant such recommendation in cutaneous tuberculosis
Pelita Harapan, Tangerang, diseases which causes death worldwide.1 Around cases.7 Thus, it is essential to review and update the
Indonesia 45% out of a total of 10.4 million of tuberculosis
3
Faculty of Medicine, Universitas principle of scrofuloderma.
infections cases are located in Southeast Asia.2
Udayana, Bali, Indonesia
Indonesia, along with India, China, Philippines,
and Pakistan accounted for the most contributor
ETIOPATHOGENESIS
in these cases (56%).2 Based on the Ministry of Cutaneous tuberculosis is classified based on
Health’s data in 2018, the number of tuberculosis morphology, route of spread, and immunity status
cases had reached 845,000 cases in Indonesia.2 Even of patients.8 This disease has six infection routes:6,9,10
Indonesia ranked as third highest TB burden in a. Direct transmission to the skin from organs
2018.3 under the skin
TB infection is assumed to infect the lungs only b. Direct inoculation of the skin around the
from a general perspective. In fact, TB infection genital orifice
also causes lesions on the skin. Although the c. Hematogenous transmission
involvement of skin only occurs in 1-2% of people d. Direct transmission of lymphokines mucosa
with tuberculosis, tuberculosis skin infection e. Germs that enter the skin directly
(cutaneous tuberculosis) was still one of the most
notable infection in certain patients, especially Cutaneous tuberculosis also had several clinical
immunocompromised patients.4 Scrofuloderma, forms, such as tuberculosis verrucosa cutis,
as one of the most common types of cutaneous tuberculous chancre, lupus vulgaris, scrofuloderma,
tuberculosis, was found at Cipto Mangunkusumo orificial tuberculosis, metastatic tuberculosis
*Corresponding author:
Marianto; Faculty of Medicine,
Hospital (84%)4 and mostly infected the children.5 abscess, and miliary tuberculosis.11 Scrofuloderma,
Universitas Sumatera Utara, Due to the similarity of scrofuloderma with or often called colliquative cutis, results from the
Indonesia; cold abscess infection, misdiagnosis, and treatment direct spread of tuberculosis lesions from infected
[email protected] delay often occurs. These challenges often arise in organs.12 The neck, axilla, groin folds with lymph
Indonesia and other developing countries even after node involvement are the most common sites for
several laboratory tests have been developed to aid scrofuloderma.10,13,14 Factors related to disease
the diagnosis of latent or suspected TB.6 Therefore, progression can be assessed in host interactions,
the condition really needs medical professionals infectious agents, and the environment detailed
Received: 2019-09-20
Accepted:  2019-11-10 to be more cautious in the management of below:15
Published: 2019-12-01 scrofuloderma. In pulmonary TB cases, national a. State of host immunity:

34 Published by DiscoverSys | BDV

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2019;
access:
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34-41 | doi: 10.15562/bdv.v2i2.20
 ORIGINAL ARTICLE

• Only 5-10% of infected patients will cause immature immunity in children. In adults,
tuberculosis infection.16 This is due to the immunocompromised factors are still the
host’s ability to deal with infections. Another main cause of cutaneous tuberculosis, in
proposed mechanism is the variations in the addition to malnutrition, alcoholism, silicosis,
apoptotic ability of infected macrophages diabetes mellitus, gastrectomy, and other
when eliminating mycobacterium is no longer immunosuppressive conditions.15
possible.17 b. Route of infection
• Some autoimmune conditions, such as SLE and • The infection route initiated by having close
RA, have a higher risk of infection. Apart from contact with patients, coupled with a person’s
defects in the natural and acquired immune immune response will affect clinical symptoms.
systems, the use of immunosuppressant drugs The type of cutaneous tuberculosis depends
will also affect the host’s immune system. greatly on the route of infection described
• Host unmodifiable risk factors for the previously. Until now, there has been no further
occurrence of scrofuloderma, such as explanation about what causes different types

Table 1. Classification of cutaneous tuberculosis10

Types of
Bacterial History of
No cutaneous Infection route Symptoms
count sensitization
tuberculosis
1 Veruccal Exogenous Paucibacillary ++ Verruccal lesions on:
tuberculosis cutis inoculation • Dorsal manus or digital, ankle or buttocks
2 Primary Exogenous Multibacillary - Nodular lesions at:
tuberculosis inoculation • Face or upper or lower extremities associated with
lymphadenopathy
3 Scrofuloderma Spread directly Multibacillary + More often on:
• Children, youth and the elderly; predilection in the neck
region; can be co-infected with pulmonary TB
4 Lupus vulgaris Hematogenous Paucibacillary ++ Most commonly:
or direct • Women and manifests as burning nodules, annular
distribution plaques, or vegetative or hypertrophic lesions; the initial
lesion begins with a collection of reddish papules that unite
to form plaque with the edge of verrucose or serpiginous
with the middle part of atrophy and heal.
5 Tuberculosis Direct spread Multibacillary - Most often in:
orificial cutis • Unhealed ulcers in the mouth, mouth, or skin or
anogenital mucosa in patients with TB, lung, digestive or
genital infections.
6 Acute miliary Hematogenous Multibacillary - Often occurs in:
tuberculosis • Immunocompromised patients with solitary or multiple
subcutaneous nodules that have the potential to become
ulcers or sinuses without regional adenopathy.
7 Tuberculosis Hematogenous Multibacillary - Skin lesions appear on:
abscess • Can manifest as umbilication and crusty cellulitis
metastases or purplish papules. Usually in people with severe
immunosuppression (AIDS, malnutrition)
8 Tuberculids Hypersensitivity Negative +++ Indications erythema Bazin (more common in women) and
reactions to M. culture manifests as
Tuberculosis • Painful granulomatous lobular panniculitis, usually of the
infection lower extremities
• Papulonecrotic tuberculids (more often in children
and young adults) may look like lupus vulgaris and
scrofuloderma, appearing with dark red or purplish papules
that become pustules or necrotic tissue.
• Fever and constitutional symptoms can occur;
• Lichen scrofulosorum (more common in children and
young adults) with pulmonary or lymphatic TB (this
condition is often associated with BCG vaccination and
with intracellular M. avium infection)

Published by DiscoverSys | BDV 2019; 2(2): 34-41 | doi: 10.15562/bdv.v2i2.20 35

 ORIGINAL ARTICLE

of cutaneous tuberculosis.14 plaque verrucose, or other types of lesions.23

c. Virulence, survival, and mycobacteria Scrofuloderma can also resemble bacterial
resistance abscesses or malignancies.24
• Macrophage produces NO and RNI, which • Initial scrofuloderma lesion will appear as a
are potent bactericidal compounds against dense, brownish-red, and painless subcutaneous
mycobacterium. However, the mycobacterium, nodule.10 This nodule then splits into ulcers
through series of enzymatic processes, such as and sinuses, which secrete purulent fluid. These
peroxiredoxin alkyl hydroperoxide reductase lesions would be encountered with epidermal
C subunit (AhpC), dihydrolipoamide hyperplasia, and solid infiltrates in the dermis
dehydrogenase (Lpd) dihydrolipoamide composed of neutrophils, lymphocytes, and
succinyltransferase (SucB), or thioredoxin-like plasma cells.10,25 Over time, inflammatory cells
AhpD forming a complex compound called and granulomatous inflammation will replace
nicotinamide-adenotoxidoxidase reductase neutrophils with caseous necrosis, which varies
which acts antioxidant defenses against RNI.18,19 in degree. Basil can be found in the initial lesion,
• The ability of mycobacteria to inhibit MHC but it will be difficult to find after granulomas
class II process and presentation also enables have formed.23
the bacteria’s survival. All this contributes to • Scrofuloderma can heal spontaneously into
the defense of mycobacteria in macrophages.19 keloids, retractions, and atrophy.25 A proper
• Bacilli resistance is also one of the most critical diagnosis of scrofuloderma is often delayed
factors for the emergence of drug-resistant because cutaneous tuberculosis is not routinely
Mycobacteria. Initially, due to environmental considered in the differential diagnosis due
factors, bacteria would reduce metabolism rate, to varied clinical manifestations.4 Whereas
replication rate, and at the same time, tolerate in the case of pulmonary TB, national
small doses of antibiotics. This tolerance is and international guidelines for treatment
reversible in the initial phase if the treatment have been made, but there are no specific
is delivered in appropriate periods and doses. recommendations that are similar for cases of
However, when the presence of inadequate cutaneous tuberculosis. Therefore, it is essential
doses persists and the ability of bacteria to to consider the type of examination based on
replicate decreases in poor conditions causing evidence.7
spontaneous mutations and resistance to a • Finding bacilli in cutaneous TB lesions is still
type of drug.20 This continued until bacteria a challenge. Overall, all diagnostic methods
emerged with resistance to several types of have lower sensitivity and specificity for
drugs, called multidrug-resistant (MDR) and cutaneous TB compared to pulmonary TB.
extensively drug-resistant (XDR).21 This is worsened by uncommon rash and
d. Environmental factor histopathological, which may not have a clear
• Weather and geographic location determine result. Clinicians should use every possible test.
differences in the prevalence of cutaneous Hence, the supporting results can sum up to
tuberculosis. This is supported by establish the diagnosis. This is also indeed an
epidemiological data where locations such as effort to reduce empirical treatment.7
scrofuloderma are commonly found in Brazil,
and lupus vulgaris is more frequent in Asia and LABORATORY EXAMINATION
Europe.22
• Tuberculin test (TST)
Tuberculin tests are used to identify individuals
DIAGNOSIS who have been sensitized by Mtb bacteria and
Several data should be obtained from history and will be positive within 2 to 10 weeks after
physical examination, such as: infection. False-negative results can occur in
• Symptoms caused by scrofuloderma vary children under two months, pregnant women,
greatly. A patient can become infected with diabetes, kidney failure, or disorders of cellular
pulmonary TB with cutaneous TB, which may immunity. The history of recent vaccines,
have constitutional symptoms of pulmonary children over one year, and atypical mycobacteria
TB. Symptoms caused depend on the infected co-infection can cause false positives.7 The
organ. From the patient’s history, there may be tuberculin test has a sensitivity of 33-95% and
signs of other causes of immunodeficiency.23 a specificity of 62.5% when using a cutoff value
• On physical examination, various types of skin of 10 mm. In unvaccinated populations, the
lesions can be found in cutaneous tuberculosis, sensitivity of the tuberculin test is higher.26,27
ranging from papules, nodules, pustules, ulcers, In miliary tuberculosis cases, original TB, it

36 Published by DiscoverSys | BDV 2019; 2(2): 34-41 | doi: 10.15562/bdv.v2i2.20

 ORIGINAL ARTICLE

Table 2. Differential diagnoses of cutaneous tuberculosis4 will also give a negative result. However, results
Classification Cutaneous TB Comparative Diagnosis can be positive on scrofuloderma and lupus
Sporotrichosis, atypical mycobacteriosis, vulgaris and vary depending on types of other
Tuberculosis chancre cutaneous tuberculosis, especially the type of
syphilis, cat scratch disease, tularemia
Paracoccidioidomycosis, leishmaniasis, paucibacillary. In addition to TST and chest
Exogenous sporotrichosis, verrucose tuberculosis X-ray on all patients, it is very important to
Cutaneous TB Tuberkulosis and chromomycosis, lobomycosis, do a histopathological examination, detection
verrucosa kutis atypical mycobacteriosis, hypertrophic of acid-resistant bacillus through culture, and
lichen planus, verrucose carcinoma, amplification of Mycobacterium tuberculosis
vulgaris verrucose, pyoderma vegetans
(Mtb) DNA with (PCR) both in tissue samples
Tertiary syphilis, and in blood.7
Paracoccidioidomycosis, actinomycosis,
• Acid-fast bacilli (AFB) staining
Scrofuloderma lymphogranuloma venereum, bacterial
abscess, metastatic tumor, histiocytosis, The microscopic examination with the Ziehl-
and hidradenitis Neelsen (ZN) staining method is still an
Bullous disease, trauma, fungal disease, effective diagnostic tool for early detection of
Endogenous Orificial tuberculosis syphilis, sarcoidosis, or squamous cell TB. The ZN is a common, inexpensive, and
CutaneousTB carcinoma high specificity technique for detecting AFB in
Basal cell carcinoma, sarcoidosis, discoid sputum. However, studies reported quite low
Lupus vulgaris
lupus, leprosy, severe fungal infection sensitivity (20-60%).7
Leishmania, sporotrichosis, nocardiosis, • Culture
Tuberculous gumma mycobacteria apical, pyogenic infection, Culture is the standard diagnostic method for
and fungal infection TB. In addition to a confirmative or definitive
Acute miliary TB Metastatic carcinoma diagnosis, it also plays an important role in
Pityriasis lichenoides et varioliformis Mycobacterium tuberculosis’s sensitivity test to
Papulonecrotic acuta (PLEVA), leukocytoclastic the anti-tuberculosis drug. Culture also could
tuberkulid necrotizing vasculitis, pruritus, and
be used in monitoring and detecting cases of
secondary syphilis
MDR.7,28 The principle of culture is multiplying
Lichen planus, lichen nitidus, syphilid
and growing bacteria in order to overcome the
Lichen lichenoides, eczematid, keratosis piliaris,
Tuberculids scrofulosorum pityriasis rubra pilaris, and micropapular challenge in diagnosing HIV co-infection with
sarcoidosis TB cases, which are often found with smear-
Erythema nodosum, cutaneous negative. With slow bacterial growth, it takes
polyarteritis, pancreatic panniculitis, more than three weeks to have the results. At
Erythema induratum
lupus profundus, subcutaneous this time, more accurate and sensitive culture
of Bazin
sarcoidosis, and cutaneous T-cell methods have been developed, both liquid
lymphoma. and solid culture media, called the BACTEC
system and Mycobacteria Growth Indicator
Tube (MGIT). An accurate and straightforward
Table 3. Tuberculosis treatment in adult
method is still being developed at a low cost.29
Regiment Composition Bodyweight Dose
Liquid media in the form of blood are expected
Intensive phase (R) Rifampicin – 150 mg >50 kg 4 tablets
to be similar to in vivo conditions in lung
(2 months) (H) Isoniazid – 75 mg 36 – 50 kg 3 tablets parenchymal tissue, which are also rich in iron
(Z) Pyrazinamide – 400 mg 20 – 35 kg 2 tablets
(E) Ethambutol – 275 mg and albumin and other nutrients. Therefore,
by using the biphasic media blood jelly, it
Available combination can promote the growth of Mycobacterium
(tablet): tuberculosis optimally so it will be easily
R(150 mg) + H(75 mg) + identified. Establishing a TB diagnosis helps
Z(400mg) + E(275 mg) to determine the proper treatment, thereby
Maintenance (R) Rifampicin – 300 or 150 >50 kg 2 tablets or accelerating the recovery of TB, in results,
phase mg capsule A stopping the chain of transmission.29,30
(4 months) (H) Isoniazid – 200 or 100 36 – 50 kg 1 tablet or • PCR
mg capsule A or Detection of Mycobacterium tuberculosis
1 tablet or
in sputum can be done by Polymerase Chain
capsule B
Available combination Reaction (PCR) technique, microscopic
20 – 35 kg 1 tablet or
(capsule or tablet): capsule A examination, and bacterial culture. Microscopic
A: R(300 mg) + H(200 mg) examination of Mycobacterium tuberculosis
B: R(150 mg) + H(100 mg) requires a certain number of germs (about

Published by DiscoverSys | BDV 2019; 2(2): 34-41 | doi: 10.15562/bdv.v2i2.20 37

 CASE REPORT

5,000 germs/ml of sputum). Meanwhile, TREATMENT

growing bacteria via culture needs a minimum
of 50-100 germs/ml of sputum. TB detection Recently the principle of cutaneous tuberculosis
by PCR technique has a very high sensitivity. treatment is the same as for pulmonary
Mycobacterium tuberculosis in vitro can be tuberculosis. In addition to In TB treatment, at least
used specifically for DNA amplification for two bactericidal drugs must be included. The drug
the PCR test. This process requires a double- of choice should be personalized and consider the
stranded DNA template containing the target economic condition, the severity of the disease, and
DNA, a DNA polymerase enzyme, a nucleotide whether there are any contraindications.1,3,7,28,32
triphosphate, and a pair of primers.7,28 In the treatment of tuberculosis, there are two
stages, an initial or intensive 2 month-treatment
phase followed by a continuation phase.31 During
the initial or intensive phase, which included
Table 4. Tuberculosis treatment in the child four types of drugs, there should be a reduction
Regiment Composition Bodyweight Dose in the number of germs accompanied by clinical
Intensive phase (R) Rifampicin – 75 mg 16 – 24 4 tablets improvement. Infected patients become no
(2 months) (H) Isoniazid – 50 mg 12 – 15 3 tablets longer infectious within two weeks. During the
(Z) Pyrazinamide – 150 mg 8 – 11 2 tablets continuation phase, fewer drugs are needed, but
4–7 1 tablet over a longer period of time. The latter phase is
Available combination:
R(75 mg) + H(50 mg) + Z(150mg) sterilization activities to kill slow-growing germs.
Maintenance (R) Rifampicin – 75 mg 16 – 24 4 tablets The sterilizing effect of these drugs was to clean
phase (H) Isoniazid – 50 mg up germs remnants and prevent a recurrence. In
12 – 15 3 tablets
(4 months) patients with smear-positive sputum, there is a risk
8 – 11 2 tablets
of selective resistance. The use of 4 drugs (3 drugs in
Available combination 4–7 1 tablet
the child) during the intensive phase and two drugs
A: R(75 mg) + H(50 mg) during the continuation phase will reduce the risk
A child with 25kg of body weight or more recommended using an adult dose of selective resistance. In patients with negative
smear sputum or extrapulmonary TB, there is no

Table 5. Daily dose recommendation in adult and child

Adult Child
Drug of choice Dose and range Maximum Dose and range Maximum dose
(mg/kg bobdy weight) dose (mg) (mg/kg bobdy weight) (mg)
(R) Rifampicin 10 (8 – 12) 600 15 (10 – 20) 600
(H) Isoniazid 5 (4 – 6) 300 10 (7 – 15) 300
(Z) Pyrazinamide 25 (20 – 30) - 35 (30 – 40) -
(E) Ethambutol 15 (12 – 18) - 20 (15 – 25) -
(S) Streptomycin 15 (12 – 18) - Not recommended as first-line

Table 6. The medical approach to major adverse reaction of tuberculosis treatment

Causative drug(s)
Major adverse reaction Medical consideration
probability
Isoniazid Itchy or non-itchy skin rash Tuberculosis medication discontinuation. Reintroduce medication
Streptomycin with time interval after skin improvement. Recurrent skin rash should
Pyrazinamide consider avoiding causative agent on continuation tuberculosis
Rifampicin treatment
Streptomycin Nystagmus and vertigo Streptomycin discontinuation. Reinitiate without streptomycin
Rifampicin Acute kidney failure, purpura, shock Rifampicin discontinuation. Reinitiate without rifampicin
Streptomycin Hearing loss Streptomycin discontinuation. Reinitiate without streptomycin
Ethambutol Visual problems Ethambutol discontinuation. Reinitiate without ethambutol
Rifampicin Hepatotoxicity (hepatitis or jaundice) Tuberculosis medication discontinuation. Reintroduce medication
Isoniazid with time interval separately after transaminase improvement
Pyrazinamide
Streptomycin Low urine production Streptomycin discontinuation. Reinitiate without streptomycin
Isoniazid Seizure, coma, psychosis or toxic Isoniazid discontinuation. Reinitiate without isoniazid
encephalopathy

38 Published by DiscoverSys | BDV 2019; 2(2): 34-41 | doi: 10.15562/bdv.v2i2.20

 ORIGINAL ARTICLE

Table 7. The medical approach to minor adverse reaction of tuberculosis treatment

Causative drug(s)
Minor adverse reaction Medical consideration
probability
Isoniazid Neuropathy (burning, tingling, numbness Vitamin B6 prescription (50-75mg) daily
Ethambutol in the feet or hand)
Pyrazinamide Arthralgia Analgesic, non-steroidal anti-inflammatory drugs
Rifampicin Red or orange urine, sweating Encourage and comfort patient about common side effect and
continue medication
Pyrazinamide Nausea, vomit, stomach ache, anorexia Symptomatic medication, tuberculosis medication reschedule (with
Isoniazid breakfast or two hours after breakfast), transaminase evaluation
Ethambutol
Rifampicin
Isoniazid Anxiety, cephalgia, sleep disturbance, Encourage and comfort patient about common side effect and
euphoria continue medication
Isoniazid Mild rash or itchy Anti-histamine prescription
Rifampicin
Isoniazid Fever Encourage and comfort patient about common side effect and
Rifampicin continue medication

risk of selective resistance because the number of the initial phase and three drugs for the advanced
bacteria in the lesion is relatively small. Initial phase phase. During the initial phase, at least 2 of the
treatment with three drugs and advanced phase drugs given must be selective. Standard treatment
with two drugs are usually sufficient. 1,3,7,28,32 First- with isoniazid, rifampicin, pyrazinamide, and
line drug of choice based on available fixed drug streptomycin is recommended. First-line re-
combination (FCD) (Table 3 and Table 4) have been treatment with 2RHZES/1RHZES/5RHE if a low
provided.7,28,32-35 However, the specific guideline for or medium case of TB MDR (multidrug resistance)
cutaneous tuberculosis is not available yet. reported or data not available in that country.32-36
Several conditions should be treated as The surgical approach, such as excision, is the
special considerations such as renal insufficiency, treatment of choice in lupus vulgaris, tuberculosis
pregnancy, elderly, and hepatic insufficiency. verrucosa, including scrofuloderma. If an ulcer is
Streptomycin and ethambutol have a teratogenic found, it should be covered with a wet soak and
effect and contraindicated in pregnancy.7,28,33 In added 1:5000 potassium permanganate to the
elderly patients, daily dose reduction recommended solution. Patients with cutaneous tuberculosis
increasing drug tolerance. The standard dose should have improved if the therapy was administered
be administrated if creatinine clearance more than accordingly.7,28
30 ml/minute. Drug administration should be
adjusted on the condition which creatinine clearance CONCLUSION
less than 30 ml/minute.7 Isoniazid, rifampicin, and
pyrazinamide increasing liver damage (hepatotoxic) Scrofuloderma is the most common type of
and required special consideration. Elevated up to cutaneous tuberculosis. Misdiagnosed and
three times of transaminase upper normal limit can managed improperly due to its similarity with
be given with standard treatment. Transaminase other skin infection often occurs. National or
elevation more than three times normal upper international guidelines for scrofuloderma was not
limit should consider to suspend pyrazinamide, available. Thus, this review is expected to provide
keep using ethambutol, streptomycin, and another an appropriate description and management of
drug of choice (ofloxacin, rifampicin, isoniazid) scrofuloderma.
addition. Transaminase should be evaluated every
month.7,28,32-36 Patient management on major AUTHORS CONTRIBUTION
adverse event need special medical consideration All authors contributed to this review.
(Table 6). Discontinuation specific medication
often needed to achieve the treatment goal. Side CONFLICT OF INTEREST
effect control without discontinuation anti-TB drug
applied on minor adverse reaction (Table 7).7,32-37 None.
In re-infected patients who have been treated
previously, there is a risk of resistance will happen. FUNDING
The re-medication guide consists of 5 drugs for
None.

Published by DiscoverSys | BDV 2019; 2(2): 34-41 | doi: 10.15562/bdv.v2i2.20 39

 ORIGINAL ARTICLE

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