TUBERCULOSIS AND ITS TREATMENT

Přemysl Mladěnka

TUBERCULOSIS ................................................................................................................................................. 2

DEFINITION AND SIGNS ............................................................................................................................................. 2

CAUSE ................................................................................................................................................................... 2

EPIDEMIOLOGY........................................................................................................................................................ 2

PATOPHYSIOLOGY .................................................................................................................................................... 3

TBC PREVENTION – ACTIVE IMMUNISATION .................................................................................................................. 4

TBC TREATMENT TACTICS .......................................................................................................................................... 4

CHARACTERISTICS OF ANTITUBERCULOSIS DRUGS ............................................................................................................ 5

FIRST-LINE DRUGS .................................................................................................................................................... 5

SECOND-LINE DRUGS ................................................................................................................................................ 9

NEW DRUGS FOR MULTIRESISTANT TUBERCULOSIS .......................................................................................................... 9

LEPROSY ......................................................................................................................................................... 10

REFERENCES ................................................................................................................................................... 10

Figure 1. Schematic depiction of a mycobacterium showing outer parts of the cell wall. The cytoplasmic
membrane is shown in green, cell wall in orange and its outer part containing lipids and also carbohydrates in light
blue. The presence of mycolic acids (shown as light blue small mallets in the magnified cut-out), polysaccharide
chain is shown in dark blue.

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TUBERCULOSIS
Definition and signs
 Tuberculosis is a specific disease caused by Mycobacterium tuberculosis, or more preciselly
by Mycobacterium tuberculosis complex
 I affects lungs in most cases, but can be present in other tissues
 Typical clinical signs are
 General signs: fatigue, weekness, fever, night sweating, weight loss → greek term
phthysis (consumption)
 Functional signs in the lung form: cough, breathlessness, pain

Cause
 Mycobacteria are specific (Figure 1)
 aerobic G+ bakteria
 They have lipids, polysaccharides and proteins in the outer part of the cell wall
 Characteristic is the presence of so-called mycolic acids1
 Very slow growth
 Some of them are obligatory parasites of human, mentioned M.tuberculosis and e.g. M.
bovis
 Some of them are potentially pathogenic (M. avium-intracelulare, M. kansasii) →
mycobacteriosis → clinically resembling tuberculosis
 M. leprae is causing leprosy

Figure 2. Incidence a mortality on tubeculosis in the Czech republic and Czechoslovakia

Epidemiology
 In the ČR: M.tuberculosis is almost exclusivelly the cause, M. bovis was eradicated,
nontuberculous mycobacteria only rarely
 Thanks to vaccination, the incidence and mortality is low in the ČR (Figure 2)
 about 500 cases each year, about 1/5 of them are immigrants
 about 1/3 of world population is infected and aproximatelly 3 millions are dying every year 2

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slow staining and the dye cannot be washed out in acidic conditions → acidoresistant bacteria
2
95% in developping countries
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Patophysiology
 The bacteria are spread from person to person in tiny microscopic droplets – airways are
primarily affected
 slow growth of bacteria in lungs → long incubation period, minimally 4 weeks
 primary infection – mycobacteria are fagocyted and a characteristic inflammatory tubecle is
formed (Figure 3)
 Primary infection is taking place in the childhood, but thanks to vaccination is
incommon in the ČR.
 commonly asymptomatic
 Bacteria could be fully eliminated or remain as dormant forms.
 Delayed hypersensitivity (tuberculine reaction) is a sign of acquired immunity.
 Memory T-cells are responsible for it.
 dissemination of the infection in various organs in 5% of cases
 postprimary (secondary) infection – reactivation of the primary infection after a long period
or exceptionally new exogenous infection. It is taking place in 5-10% cases after primary
infection.
 Destruction of lungs or other tissues, including erosion of small (→ hemoptoe)
 The cause of degeneration is exagerated reaction of the immune system
 The functional status of immune system is the key factor for the defence capacity of an
individual
 The causes of reactivation are not fully known, but higher probability is accociated with
following risk factors:
 age
 exposition to new mycobacteria
 drugs
 co-corbidities, e.g.
 viral infection, particularly AIDS
 diabetes mellitus
 alcoholism, malnutrition, liver disease

Figure 3. Lung tuberculosis – a tubercle. So called Ghon complex formed from central caseous necrosis and
epitheloid and giant cells containing mycobacteria. Figure from Damjanov, 2000.

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TBC prevention – active immunisation
 tzv. kalmetizace
 it protects against TBC appearance in most humans
 attenuated M.bovis, so-called bacillus Calmette-Guerin (BCG) vaccine (currently VACCINE SSI
inj)
 In the ČR, the vaccination was obligatory from 1953 to 2010, currently only in risk groups
 acquired immunity is associated with more intense and rapid reaction u většiny lidí zabrání
vzniku tuberkulózy

TBC treatment tactics

 Long-term treatment, commonly 6-9(12) months
 At the beginning (initial or intensive phase) – a combination of 4 drug is used (isoniazid +
rifampicin + ethambutol + pyrazinamide, or even 5-drugs-regimen (+streptomycin) for 2
months 1x daily or 3x in a week
 → these drugs are first-line drugs3
 then (continuous phase) – mostly ISO + RIF for 4 months
 alternativelly other drugs according to the mycobacterial sensitivity
 In risk cases ISO + RIF + ETM
 Resistance as the problem in TBC treatment is increasing
 multiresistance – insensitivity to 2 most efficient drugs (isoniazid+rifampicin)
 incidence 3-5% of cases, in some states even higher
 4-drugs-regimen is used, therapy is longer
 treatment succcesfulness 60-80%
 extensive multiresistance - multiresistance + resistance on one from i.v. antituberculotic
second-line drugs and one fluoroquinolone
 about 10-20% of multiresistances
 treatment succesfulness up 40 %
 other drugs can be used for the treatment of multiresistance
 ethionamide
 aminoglykosides and analogous antibiotics (capreomycin)
 fluoroquinolones of 3. generation
 p-aminosalicylic acid is very rarely used at the moment
 In the prophylactic regimen, isoniazid in monotherapy for 6 months is preferred in both
primary and secondary prevention
 Infection of M.avium-intracellulare is cured by clarihtromycin or azitromycin + ethambutol
With or without rifampicin, profylacticaly one of the mentioned macrolides

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Streptomycin is generally ranged in Europe to second-line drugs, but in US as the first-line drug
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Figure 4. Mechanisms of action of 4 antituberculotic drugs of first-line drugs. A: isoniazid, B: rifampicin,
C: ethambutol, D: pyrazinamide.

Characteristics of antituberculosis drugs

First-line drugs
isoniazid (oral: Nidrazid®)

MA
 blockade of mycolic acid synthesis (Figure 5Chyba! Nenalezen zdroj odkazů.)
 it is a prodrug which is converted by mycobacterial enzyme catalase/peroxidase into the
reactive product → which forms a complex with NAD+ → strong inhibitor of NADH-
dependent enoyl-ACP reduktase → the prolongation of chain of mycolic acids is blocked

Spectrum and resistance

 Mycobacteria including potentially pathogenic forms
 Mycobactericidal effect
 Resistance can develop rapidly with exception of prophylactic regimen
PK
 oral administration, F ↓ with food
 Metabolized by acetylation (Figure 6) → marked differences between slow and rapid
metabolizers → t1/2el from 1 to 6 hours

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 H S NH2
O N NH2
NAD+ NAD+
INH-NAD ETH-NAD
a b

N
N CO S ACP
A R B

enoyl acyl carrier protein (ACP)

reductase

COOH
R

Figure 5. Probable mechanism of isoniazid (INH, A) and ethionamide (ETH, B) activity. a:

catalase/peroxidase of mycobacteria responsible for activation of isoniazid and b: monooxygenase EthA
analogously activating ethionamide. The ffigure is a simplification of Catherine et al. Antimicrob Agents
Chemother 2005

Figure 6. Metabolism of isoniazid. The figure is from Sotsuka et al., In vivo 2011

Adverse reactions
 in general, the drug is well tolerated
 higher risk of adverse reactions is in the case of slow acetylators
 Periferal neuropathy, convulsions and psychotic reaction → due to interference with the
function of vitamin B6 → suplementation with vitamin B6
 hepatotoxicity – an increase in tranaminases in 10-15% cases → symptomatic hepatitis 0.1-
0.15% cases. The patient should be monitored.
 Cancerogenesis was not observed in human → suitable drug for TBC in pregnancy

Interaction
 + alcohol → potentiation of hepatotoxicity + ↓ antituberculosis effect
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rifampicin (Figure 4B, in US rifampin, oral Benemicin®)

MA, spectrum, resistance and therapeutic use

 Blockade of bacterial DNA-dependent RNA-polymerase
 A broad-spectrum, bactericidal, mainly G+ but as well a row of other bacteria
 Treament of TBC but also in a combination regimen for severe staphylococcal infections
 used as well for leprosy
 Cannot be used in the monotherapy because the risk of resistence is high

PK
 oral administration, food ↓ absorption
 an important inducer of CYP but also of P-glycoprotein
 t1/2el = 2-5 hours at the first dose, but 2-3 hours by repeated doses

Adverse reaction
 in general, the drugs is well tolerated
 mild skin reactions and a flu-like syndrom
 hepatotoxicity but lower than isoniazid
 some risk of pseudomembranous colitis
 innocent coloration of body fluid in orange-red (pay attention to contact lenses)
 it appears that does not increase the risk of malformations, but there is a risk of bleeding in
mother and fetus

Interaction
 the effects of many drugs can be decreased by induction of metabolism and of P-glycoprotein,
e.g. oral contraception, vastatins, Ca-channel blockers and digoxin

pyrazinamide (oral Pyrazinamid Krka®)

MA and spectrum
 effective only on M.tuberculosis
 almost inactive at neutral pH, but bactericial effect on mycobacteria inside macrophages →
suitable for initial phases of tuberculosis (inflammation)

PK
 food has negligible impact on absorption
 t1/2el = 9-10 hours
 metabolized by xanthinoxidase (Figure 7) → interactions

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 Figure 7. Metabolism of pyrazinamide.

Adverse reactions
 hepatotoxicity is the most serious, it is dose- and lenght of the treatment-dependent, incidence
bellow 3%
 hyperuricemia
 data on its use in the pregnancy are not sufficient, but it can be used

Interaction
 alopurinol blocks its metabolism → paradoxical deterioration in hyperuricemia

ethambutol (Figure 4C, oral Sural®)

MA
 Inhibition of polymeration of arabnose into arabinan → interference with the synthesis of
carbohydrate part of the cell wall → derangement in cell wall synthesis

Spectrum
 Considered as a bactriostatic antibiotic but it increasis bactericidal potential in combinations
 Both M. tuberculosis and nontuberculosis mycobacteria are sensitive

PK
 low impact of food on absorption
 t1/2el = 3-4 hours

Adverse reactions
 the most afraided is retrobulbar neuritis – mostly reversible
 hyperuricemia
 it is not hepatotoxic

streptomycin see aminoglycosides

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 second-line drugs
 Used when there is resistence on first-line drugs

capreomycin (inj: Capastat®)

 cyclic peptide antibiotic with analogous mechanism of action and side effects as
aminoglycosides

cykloserine (oral Cycloserine®) – blocks the synthesis of cell wall, the problem is frequent
neurotoxicity

ethionamide (nereg.)

 mechanism of action is similar to isoniazid (Figure 5).

 adverse reaction can be bothering and the patient frequently does not tolerate the drug
 it has teratogenic potential in animals

p-aminosalicylic acid (not registered)

 formerly, largerly used, today only minimally

 it interferes with folic acid metabolism

kanamycin and amikacin are used from aminoglycosides, ciprofloxacin, ofloxacin and
pefloxacin from fluoroquinolones

new drugs for multiresistant tuberculosis

bedaquiline (Sirturo tbl®) – FDA 2012, inhibition of mycobacterial ATP synthase

deladamid (Deltyba tbl®) – EMA 2013, inhibition of mycolic acid synthesis

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LEPROSY
 The disease is not occuring neither in the Europe nor in the North America
 But in the whole World, about 10 millions patients are infected
 The cause is Mycobacterium leprae
 The incubation period is long

There are 2 major forms

 Tuberculoid type – slow progression and healing, it is not contagious, a relativelly

benign form
 Lepromatous type – a deforming disease
Treatment
 dapsone with rifampicin on tuberculoid form for 6 months
 dapsone + rifampicin + clofazimine on lepromatous form for 2 years

References
Brayfield A et al. Martindale The complete drug reference. 38th edition. Pharmaceutical press: London,
2014
Brunton L, Chabner B & Knollman B. Goodman & Gilman's The Pharmacological Basis of Therapeutics,
12th edition. Mc Graw-Hill: New York, 2011.
Catherine V, Weisbrod TR, Chen B et al. Altered NADH/NAD+ Ratio Mediates Coresistance to Isoniazid
and Ethionamide in Mycobacteria. Antimicrob Agents Chemother 2005; 49(2):708-720
Chen J & Raymond K. Roles of rifampicin in drug-drug interactions: underlying molecular mechanisms
involving the nuclear pregnane X receptor. Ann Clin Microbiol Antimicrob. 2006;5:3.
Damjanov I. Pathology for the Health-Related Professions, 2nd ed.. WB Saunders: Philadelphia, 2000.
D'Ambrosio L, Centis R, Sotgiu G, Pontali E, Spanevello A, Migliori GB. New anti-tuberculosis drugs and
regimens: 2015 update. ERJ Open Res. 2015 May 6;1(1):1-15
Griffith DE, Aksamit T, Brown-Elliott BA et al. An official ATS/IDSA statement: diagnosis, treatment, and
prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med. 2007;175(4):367-416.
Homolka J & Votava V. [Tuberkulosis]. Karolinum: Praha, 2012 book in Czech
Potrepčiaková S a Skřičková J. Tuberkulóza. Practicus 2008;4:24-9.
Sotsuka T, Sasaki Y, Hirai S, Yamagishi F, Ueno K. Association of isoniazid-metabolizing enzyme genotypes
and isoniazid-induced hepatotoxicity in tuberculosis patients. In vivo. 2011;25(5):803-12
Tuberculosis and respiratory diseases 2013. Institute of Health Information and Statistics of the Czech
Republic
Wang F, Jain P, Gulten G et al. Mycobacterium tuberculosis dihydrofolate reductase is not a target relevant
to the antitubercular activity of isoniazid. Antimicrob Agents Chemother. 2010;54(9):3776-82

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