Mycobacteria: Exploring the Intriguing World of Sluggish-Rising Microorganisms with Distinctive Pathogenic and Therapeutic Implications
Mycobacteria are cardio, acid-fast bacilli (rods) (Determine 21–1).
They’re neither gram-positive nor gram-negative (i.e., they
are stained poorly by the dyes utilized in Gram stain). They’re
nearly the one micro organism which can be acid-fast. (One exception is
Nocardia asteroides, the most important reason behind nocardiosis, which is
additionally acid-fast.) The time period acid-fast refers to an organism’s skill
to retain the carbol fuchsin stain regardless of subsequent therapy
with an ethanol–hydrochloric acid combination. The excessive lipid con-
tent (roughly 60%) of their cell wall makes mycobacteria
The main pathogens are Mycobacterium tuberculosis, the
reason behind tuberculosis, and Mycobacterium leprae, the trigger
of leprosy. Atypical mycobacteria, reminiscent of Mycobacterium
avium-intracellulare complicated and Mycobacterium kansasii,
may cause tuberculosis-like illness however are much less frequent
pathogens. Quickly rising mycobacteria, reminiscent of Mycobacterium
chelonae, often trigger human illness in immunocompro-
mised sufferers or these in whom prosthetic units have been
implanted (Desk 21–1). The medical options of three necessary
mycobacteria are described in Desk 21–2.
Extra info relating to the medical elements of
infections attributable to the organisms on this chapter is offered
in Half IX entitled Infectious Ailments starting on web page 589.
This organism causes tuberculosis. Worldwide, M. tuberculosis
causes extra deaths than some other single microbial agent.
Roughly one-third of the world’s inhabitants is contaminated
with this organism. Annually, it’s estimated that 1.7 million
individuals die of tuberculosis and that 9 million new instances happen.
An estimated 500,000 individuals are contaminated with a multidrug-
resistant pressure of M. tuberculosis.
Mycobacterium tuberculosis grows slowly (i.e., it has a doubling
time of 18 hours, in distinction to most micro organism, which may double
in quantity in 1 hour or much less). As a result of development is so sluggish, cultures
of medical specimens should be held for six to eight weeks earlier than being
recorded as unfavorable. Mycobacterium tuberculosis will be cul-
tured on bacteriologic media, whereas M. leprae can’t. Media
used for its development (e.g., Löwenstein-Jensen medium) comprise
complicated vitamins (e.g., egg yolk) and dyes (e.g., malachite
inexperienced). The dyes inhibit the undesirable regular flora current in
Mycobacterium tuberculosis is an obligate aerobe; this
explains its predilection for inflicting illness in extremely oxygen-
ated tissues such because the higher lobe of the lung and the kidney.
The acid-fast property of M. tuberculosis (and different mycobac-
teria) is attributed to long-chain (C78–C90) fatty acids referred to as
mycolic acids within the cell wall.
Twine issue (trehalose dimycolate) is correlated with viru-
lence of the organism. Virulent strains develop in a attribute
“serpentine” cordlike sample, whereas avirulent strains don’t.
The organism additionally incorporates a number of proteins, which, when com-
bined with waxes, elicit delayed hypersensitivity. These proteins
are the antigens within the purified protein by-product (PPD) pores and skin
take a look at (also called the tuberculin pores and skin take a look at). A lipid situated
within the bacterial cell wall referred to as phthiocerol dimycocerosate is
required for pathogenesis within the lung.
Mycobacterium tuberculosis is comparatively immune to acids
and alkalis. NaOH is used to pay attention medical specimens; it
destroys undesirable micro organism, human cells, and mucus however not
the organism. M. tuberculosis is immune to dehydration and
due to this fact survives in dried expectorated sputum; this property
could also be necessary in its transmission by aerosol.
Strains of M. tuberculosis immune to the primary antimycobac-
terial drug, isoniazid (isonicotinic acid hydrazide, INH), as
effectively as strains immune to a number of antibiotics (referred to as multidrug-
resistant or MDR strains), have turn out to be a worldwide downside.
This resistance is attributed to a number of chromosomal muta-
tions, as a result of no plasmids have been discovered on this organism.
One in every of these mutations is in a gene for mycolic acid synthesis,
and one other is in a gene for catalase-peroxidase, an enzyme
required to activate INH inside the bacterium.
Transmission & Epidemiology
Mycobacterium tuberculosis is transmitted from particular person to per-
son by respiratory aerosols produced by coughing. The supply
of the organism is a cavity within the lung that has eroded right into a
bronchus. The portal of entry is the respiratory tract, and the
preliminary website of an infection is the lung. In tissue, it resides mainly
inside reticuloendothelial cells (e.g., macrophages). Macro-
phages kill most, however not all, of the infecting organisms. The
ones that survive can proceed to contaminate different adjoining cells or
can disseminate to different organs.
People are the pure reservoir of M. tuberculosis.
Though some animals, reminiscent of cattle, will be contaminated, they’re
not the primary reservoir for human an infection. Most transmission
happens by aerosols generated by the coughing of “smear-positive”
individuals (i.e., these whose sputum incorporates detectable bacilli within the
acid-fast stain). Nevertheless, about 20% of individuals are contaminated by
aerosols produced by the coughing of “smear-negative” individuals.
In the USA, tuberculosis is sort of completely a
human illness. In creating nations, Mycobacterium bovis
additionally causes tuberculosis in people. Mycobacterium bovis is
present in cow’s milk, which, except pasteurized, may cause gas-
trointestinal tuberculosis in people.
The illness tuberculosis happens in solely a small variety of
contaminated people. In the USA, most instances of tuber-
culosis are related to reactivation in aged, malnourished
males. The chance of an infection and illness is highest amongst socio-
economically deprived individuals, who’ve poor housing
and poor vitamin. These elements, moderately than genetic ones,
most likely account for the excessive fee of an infection amongst Native
People, African People, and Native Alaskans.
In the USA, there are roughly 15 million
individuals with latent tuberculosis and 10,000 instances of energetic
illness. Most instances of energetic illness in the USA are
attributable to reactivation of latent an infection. The chance elements for
an infection and reactivation (development) to illness are listed
in Desk 21–3.
An total scheme of pathogenesis by M. tuberculosis is proven
in Determine 21–2. It describes main tuberculosis, which typi-
cally ends in a Ghon focus within the decrease lung. Main tuber-
culosis can heal by fibrosis, can result in progressive lung illness,
may cause bacteremia and miliary tuberculosis, or may cause
hematogenous dissemination leading to no fast illness
however with the chance of reactivation in later life.
If the first an infection heals with out inflicting illness, it’s
referred to as a latent an infection. Of these uncovered to M. tuberculosis,
roughly 90% develop latent an infection and roughly
10% develop illness. Of those that have latent an infection,
roughly 10% progress to energetic illness (reactivation) at a
later time, whereas 90% stay latent.
Determine 21–2 additionally describes secondary tuberculosis with
a cavity within the higher lobes. This could trigger illness immediately
or lead to reactivation illness in later life with central ner-
vous system lesions, vertebral osteomyelitis (Pott’s illness), or
involvement of different organs.
Mycobacterium tuberculosis produces no well-recognized
exotoxins and doesn’t comprise endotoxin in its cell wall.
Nevertheless, M. tuberculosis produces two proteins that seem
to play a task in pathogenesis. One is tuberculosis necrotizing
toxin (TNT), which cleaves nicotinamide adenine dinucleotide
(NAD) inside macrophages leading to dying of the contaminated
macrophage. The opposite is early secreted antigen-6 (ESAT-6), a
protein that reduces the innate immune response by lowering
gamma interferon manufacturing, thereby enhancing the virulence
of the organism. The exact position of those proteins in pathogen-
esis stays to be decided.
The organism preferentially infects macrophages and different
reticuloendothelial cells. Mycobacterium tuberculosis survives
and multiplies inside a mobile vacuole referred to as a phagosome.
The organism produces a protein referred to as exported repetitive
protein that forestalls the phagosome from fusing with the lyso-
some, thereby permitting the organism to flee the degradative
enzymes within the lysosome.
Lesions are depending on the presence of the organism and
the host response. There are two forms of lesions:
(1) Exudative lesions, which include an acute inflamma-
tory response and happen mainly within the lungs on the preliminary website of
(2) Granulomatous lesions, which include a central space
of big cells containing tubercle bacilli surrounded by a zone of
epithelioid cells. These big cells, referred to as Langhans’ big cells,
are an necessary pathologic discovering in tuberculous lesions. A
tubercle is a granuloma surrounded by fibrous tissue that has
undergone central caseation necrosis. Tubercles heal by fibro-
sis and calcification.
The first lesion of tuberculosis normally happens within the
lungs. The parenchymal exudative lesion and the draining lymph
nodes collectively are referred to as a Ghon complicated. Main lesions
normally happen within the decrease lobes, whereas reactivation lesions
normally happen within the apices. Reactivation lesions additionally happen in
different well-oxygenated websites such because the kidneys, mind, and
bone. Reactivation is seen primarily in immunocompromised
or debilitated sufferers.
Unfold of the organism inside the physique happens by two
(1) A tubercle can erode right into a bronchus, empty its caseous
contents, and thereby unfold the organism to different components of the
lungs, to the gastrointestinal tract if swallowed, and to different
individuals if expectorated.
(2) It might probably disseminate through the bloodstream to many inner
organs. Dissemination can happen at an early stage if cell-mediated
immunity fails to comprise the preliminary an infection or at a late stage if
an individual turns into immunocompromised.
Immunity & Hypersensitivity
After restoration from the first an infection, resistance to the
organism is mediated by mobile immunity (i.e., by CD4-
optimistic T cells and macrophages). The CD4-positive T cells are
Th-1 helper T cells (see Chapter 58).
Circulating antibodies additionally kind, however they play no position in
resistance and aren’t used for diagnostic functions. Sufferers
poor in mobile immunity, reminiscent of sufferers with acquired
immunodeficiency syndrome (AIDS), are at a lot greater danger
for disseminated, life-threatening tuberculosis. Mutations in
the interferon-γ receptor gene are one other reason behind faulty
mobile immunity that predisposes to extreme tuberculosis. This
emphasizes the significance of activation of macrophages by
interferon-γ within the host protection towards M. tuberculosis.
Prior an infection will be detected by a optimistic tuberculin pores and skin
take a look at consequence, which is because of a delayed hypersensitivity response.
PPD is used because the antigen within the tuberculin pores and skin take a look at. The
intermediate-strength preparation of PPD, which incorporates 5
tuberculin items, is normally used. The pores and skin take a look at is evaluated by
measuring the diameter of the induration surrounding the pores and skin
take a look at website (Determine 21–3). Be aware that induration (thickening), not
merely erythema (reddening), should be noticed.
The diameter required to guage the take a look at as optimistic varies
relying on the standing of the person being examined. Indu-
ration of 15 mm or extra is optimistic in an individual who has no
recognized danger elements. Induration of 10 mm or extra is optimistic in
an individual with high-risk elements, reminiscent of a homeless particular person, an
intravenous drug person, or a nursing residence resident. Induration
of 5 mm or extra is optimistic in an individual who has poor cell-
mediated immunity (e.g., AIDS sufferers) or has been in shut
contact with an individual with energetic tuberculosis.
A optimistic pores and skin take a look at consequence signifies earlier an infection by
the organism however not essentially energetic illness. The tuberculin
take a look at turns into optimistic 4 to six weeks after an infection. Immunization
with bacillus Calmette-Guérin (BCG) vaccine (see web page 182)
may cause a optimistic take a look at, however the reactions are normally solely 5 to
10 mm and have a tendency to lower with time. Folks with PPD reac-
tions of 15 mm or extra are assumed to be contaminated with
M. tuberculosis even when they’ve obtained the BCG vaccine.
A optimistic pores and skin take a look at reverts to unfavorable in about 5% to 10% of
individuals. Reversion to unfavorable is extra widespread in the USA
now than a few years in the past as a result of now an individual is much less prone to
be uncovered to the organism and due to this fact much less prone to obtain a
increase to the immune system.
The pores and skin take a look at itself doesn’t induce a optimistic response in
an individual who has not been uncovered to the organism. It might probably,
nevertheless, “increase” a weak or unfavorable response in an individual who
has been uncovered to provide a optimistic response. The medical
implications of this “booster impact” are past the scope of
Tuberculin reactivity is mediated by the mobile arm of the
immune system; it may be transferred by CD4-positive T cells
however not by serum. An infection with measles virus can suppress
cell-mediated immunity, leading to a lack of tuberculin pores and skin
take a look at reactivity and, in some cases, reactivation of dormant
organisms and medical illness.
A gene referred to as Nramp determines pure resistance to tuber-
culosis. Individuals who have mutations within the Nramp gene have
a a lot greater fee of medical tuberculosis than these with a
regular allele. The NRAMP protein is situated within the membrane
of the phagosome in macrophages and performs an necessary position
in killing the organism inside the phagosome.
The medical findings are various, and plenty of organs will be
concerned, however the lungs are the primary website of an infection. Constitu-
tional signs reminiscent of fever, fatigue, night time sweats, and weight
loss are widespread.
In pulmonary tuberculosis, the primary findings are cough
and hemoptysis. The chest X-ray findings in reactivation tuber-
culosis of the lung embrace an infiltrate within the higher lobe with
or and not using a cavity.
Scrofula is mycobacterial cervical lymphadenitis that pres-
ents as swollen, nontender lymph nodes, normally unilaterally.
Mycobacterium tuberculosis causes most instances of scrofula, however
nontuberculous mycobacteria, reminiscent of Mycobacterium scrofulaceum,
also can trigger scrofula. Lymphadenitis is the commonest
extrapulmonary manifestation of tuberculosis. Sufferers contaminated
with human immunodeficiency virus (HIV) usually tend to
have multifocal lymphadenitis than these not contaminated with HIV.
Erythema nodosum, characterised by tender nodules alongside
the extensor surfaces of the tibia and ulna, is a manifestation
of main an infection seen in sufferers who’re controlling the
an infection with a potent cell-mediated response (Determine 21–4).
Miliary tuberculosis is characterised by a number of disseminated
lesions that resemble millet seeds. Tuberculous meningitis and
tuberculous osteomyelitis, particularly vertebral osteomyelitis
(Pott’s illness), are necessary disseminated varieties.
Gastrointestinal tuberculosis is characterised by belly
ache and diarrhea accompanied by extra generalized signs
of fever and weight reduction. Intestinal obstruction or hemorrhage
could happen. The ileocecal area is the positioning most frequently concerned.
Tuberculosis of the gastrointestinal tract will be attributable to both
M. tuberculosis when it’s swallowed after being coughed up
from a lung lesion or by M. bovis when it’s ingested in unpas-
teurized milk merchandise. Oropharyngeal tuberculosis usually
presents as a painless ulcer accompanied by native adenopathy.
In renal tuberculosis, dysuria, hematuria, and flank ache
happen. “Sterile pyuria” is a attribute discovering. The urine
incorporates white blood cells, however cultures for the widespread urinary
tract bacterial pathogens present no development. Nevertheless, mycobacte-
rial cultures are sometimes optimistic.
Be aware that the majority (roughly 90%) infections with M.
tuberculosis are asymptomatic. Asymptomatic infections, additionally
often known as latent infections, can reactivate and trigger symp-
tomatic tuberculosis. Crucial determinant of
whether or not overt illness happens is the adequacy of the host’s
cell-mediated immune (CMI) response. For instance, AIDS
sufferers have a really excessive fee of reactivation of prior asymp-
tomatic an infection and of fast development of the illness. In
these sufferers, untreated illness attributable to M. tuberculosis has a
50% mortality fee. Moreover, administration of infliximab
(Remicade), a monoclonal antibody that neutralizes tumor
necrosis issue (TNF), has activated latent tuberculosis in some
sufferers. Remicade is used within the therapy of rheumatoid
arthritis (see Chapter 66). Diabetics are additionally predisposed to
reactivation and development of illness.
In some sufferers with AIDS who’re contaminated with M.
tuberculosis, treating the affected person with extremely energetic antiretroviral
remedy (HAART) causes an exacerbation of signs. This
phenomenon is named immune reconstitution inflammatory
syndrome (IRIS). The reason of the exacerbation of symp-
toms is that HAART will increase the variety of CD4 cells, which
will increase the inflammatory response. To stop this, sufferers
needs to be handled for the underlying an infection earlier than beginning
Asymptomatic adults who’re at excessive danger of getting a latent
an infection needs to be screened utilizing both the PPD pores and skin take a look at or
the interferon-γ launch assay (IGRA) take a look at. Examples of adults at
excessive danger are those that have lived in nations with elevated
prevalence of tuberculosis and those that are homeless. If discovered
to be optimistic, these sufferers needs to be handled for latent infec-
tion. Screening assessments and the therapy of latent infections are
described later on this chapter.
Acid-fast staining of sputum or different specimens is the same old
preliminary take a look at (see Determine 21–1). Both the Kinyoun model of
the acid-fast stain or the older Ziehl-Neelsen model will be
used. The acid-fast stain has low sensitivity, as evidenced by the
discovering that roughly 50% of “smear-negative” samples
are “culture-positive.” For fast screening functions, auramine
stain, which will be visualized by fluorescence microscopy, is
Along with performing an acid-fast stain, the specimen
needs to be cultured. After digestion of the specimen by therapy
with NaOH and focus by centrifugation, the fabric is
cultured on particular media, reminiscent of Löwenstein-Jensen agar or
Middlebrook agar, for as much as 8 weeks. It won’t develop on a blood
agar plate. In liquid BACTEC medium, radioactive metabolites
are current, and development will be detected by the manufacturing of
radioactive carbon dioxide in about 2 weeks. A liquid medium
is most popular for isolation as a result of the organism grows extra rap-
idly and reliably than it does on agar. If development within the tradition
happens, the organism will be recognized by biochemical assessments. For
instance, M. tuberculosis produces niacin, whereas virtually no
different mycobacteria do. It additionally produces catalase.
Nucleic acid amplification assessments (NAATs) can be utilized
to detect the presence of M. tuberculosis immediately in medical
specimens reminiscent of sputum. NAATs can be found that detect
both the ribosomal RNA or the DNA of the organism. These
assessments are extremely particular, however their sensitivity varies. In sputum
specimens which can be acid-fast stain optimistic, the sensitivity is excessive,
however in “smear-negative” sputums, the sensitivity is considerably
decrease. These assessments are fairly helpful in deciding whether or not to provoke
remedy previous to acquiring the tradition outcomes.
As a result of drug resistance, particularly to isoniazid (see later), is
an issue, susceptibility assessments needs to be carried out. Nevertheless,
the organism grows very slowly, and susceptibility assessments normally
take a number of weeks, which is just too lengthy to information the preliminary selection of
medication. To deal with this downside, molecular assessments can be found that
detect mutations within the chromosomal genes that encode both
the catalase gene, which mediates resistance to isoniazid, or the
RNA polymerase gene, which mediates resistance to rifampin.
The luciferase assay, which may detect drug-resistant organ-
isms in just a few days, can be used. Luciferase is an enzyme remoted
from fireflies that produces flashes of sunshine within the presence of
adenosine triphosphate (ATP). If the organism remoted from the
affected person is resistant, it won’t be broken by the drug (i.e., it should
make a standard quantity of ATP), and the luciferase will produce
the conventional quantity of sunshine. If the organism is delicate to the
drug, much less ATP shall be made and fewer gentle produced.
There are two approaches to the prognosis of latent infec-
tions. One is the PPD pores and skin take a look at as described within the “Immunity &
Hypersensitivity” part earlier on this chapter. As a result of there
are issues each within the interpretation of the PPD take a look at and with
the particular person returning for the pores and skin take a look at to be learn, a quantifiable
laboratory-based take a look at is efficacious.
This laboratory take a look at is an interferon-γ launch assay (IGRA),
and there are two variations out there: QuantiFERON-TB Gold
and T-SPOT.TB. Within the IGRA assay, blood cells from the affected person
are uncovered to antigens from M. tuberculosis, and the quantity
of interferon-γ launched from the cells is measured. The sen-
sitivity and specificity of the IGRA are nearly as good as these of the
PPD pores and skin take a look at. As a result of the antigens used within the take a look at are particular
for M. tuberculosis and aren’t current in BCG, the take a look at isn’t
influenced by whether or not an individual has been beforehand immunized
with the BCG vaccine.
Be aware that the IGRA and PPD assessments are optimistic in each latent
illness and in energetic tuberculosis, so any particular person with a posi-
tive take a look at should be evaluated for the presence of energetic illness by
acquiring a chest X-ray and a sputum pattern.
Remedy & Resistance
Multidrug remedy is used to forestall the emergence of drug-
resistant mutants throughout the lengthy (6- to 9-month) period of
therapy. (Organisms that turn out to be resistant to 1 drug will
be inhibited by the opposite.) Isoniazid (INH), a bactericidal drug,
is the mainstay of therapy. Remedy for many sufferers with
pulmonary tuberculosis is with three medication: INH, rifampin,
and pyrazinamide. INH and rifampin are given for six months,
however pyrazinamide therapy is stopped after 2 months. A
considerably totally different routine will also be used. A handy
approach to do not forget that routine is to provide 4 medication (isoniazid,
rifampin, pyrazinamide, and ethambutol) for two months and
two medication (isoniazid and rifampin) for 4 months. In sufferers
who’re immunocompromised (e.g., AIDS sufferers), who’ve
disseminated illness, or who’re prone to have INH-resistant
organisms, a fourth drug, ethambutol, is added, and all 4
medication are given for 9 to 12 months.
Though remedy is normally given for months, the affected person’s
sputum turns into noninfectious inside 2 to three weeks. The neces-
sity for protracted remedy is attributed to (1) the intracellular
location of the organism; (2) caseous materials, which blocks
penetration by the drug; (3) the sluggish development of the organism;
and (4) metabolically inactive “persisters” inside the lesion.
As a result of metabolically inactive organisms will not be killed by
antitubercular medication, therapy could not eradicate the an infection,
and reactivation of the illness could happen sooner or later.
Lymphadenitis, together with cervical lymphadenitis (scrofula)
attributable to M. tuberculosis, needs to be handled with the drug
regimens described earlier for disseminated illness. Scrofula
attributable to M. scrofulaceum will be handled by surgical excision of
the one cervical lymph node, however various approaches exist.
A whole dialogue of those is past the scope of this e-book.
Remedy of latent (asymptomatic) infections consists
of INH taken for six to 9 months or INH plus rifapentine for
3 months. This method is most frequently utilized in asymptomatic
sufferers whose PPD pores and skin take a look at or IGRA take a look at not too long ago transformed to
optimistic. The chance of symptomatic an infection is biggest inside the
first 2 years after an infection, so INH is especially indicated for
these “latest converters.” INH can be utilized in kids uncovered
to sufferers with symptomatic tuberculosis. Sufferers who obtain
INH needs to be evaluated for drug-induced hepatitis, particularly
these over the age of 35 years. Rifampin can be utilized in these
uncovered to INH-resistant strains. A mixture of rifampin
and pyrazinamide shouldn’t be used as a result of it causes a excessive
fee of extreme liver harm.
Resistance to INH and different antituberculosis medication is being
seen with rising frequency in the USA, particularly
in immigrants from Southeast Asia and Latin America. Strains
of M. tuberculosis immune to a number of medication (MDR strains)
have emerged, primarily in AIDS sufferers. The commonest
sample is resistance to each INH and rifampin, however some iso-
lates are resistant to 3 or extra medication. The therapy of MDR
organisms normally includes the usage of 4 or 5 medication, includ-
ing ciprofloxacin, amikacin, ethionamide, and cycloserine. The
exact suggestions rely on the resistance sample of
the isolate and are past the scope of this e-book.
In 2013, bedaquiline was accredited for the therapy of MDR
strains. It needs to be utilized in mixture with different medication, not
as monotherapy. It’s a diarylquinoline that inhibits an ATP
synthase distinctive to M. tuberculosis.
Earlier therapy for tuberculosis predisposes to the selec-
tion of those MDR organisms. Noncompliance (i.e., the failure
of sufferers to finish the total course of remedy) is a significant fac-
tor in permitting the resistant organisms to outlive. One method
to the issue of noncompliance is immediately noticed remedy
(DOT), wherein health-care staff observe the affected person taking
The strains of M. tuberculosis immune to INH, rifampin,
a fluoroquinolone, and no less than one further drug are referred to as
extensively drug-resistant (XDR) strains. XDR strains emerged
in 2005 amongst HIV-infected sufferers in South Africa.
Be aware that M. tuberculosis produces β-lactamase, rendering
the organism immune to many penicillins and cephalosporins.
Trials utilizing amoxicillin-clavulanate to deal with energetic tuberculosis
had been unsuccessful.
The incidence of tuberculosis started to lower markedly even
earlier than the appearance of drug remedy within the Nineteen Forties. That is attrib-
uted to higher housing and vitamin, which have improved host
resistance. At current, prevention of the unfold of the organism
relies upon largely on the immediate identification and ample
therapy of sufferers who’re coughing up the organism. The
use of masks and different respiratory isolation procedures to
stop unfold to medical personnel can be necessary. Contact
tracing of people uncovered to sufferers with energetic pulmo-
nary illness who’re coughing needs to be finished.
An necessary element of prevention is the usage of the PPD
pores and skin take a look at to detect latest converters and to institute therapy
for latent infections as described earlier. Teams that ought to
be screened with the PPD pores and skin take a look at embrace individuals with HIV
an infection, shut contacts of sufferers with energetic tuberculosis,
low-income populations, alcoholics and intravenous drug customers,
jail inmates, and foreign-born people from nations
with a excessive incidence of tuberculosis.
As a result of there are some issues related to PPD pores and skin
assessments, such because the measurement and the interpretation of outcomes
and the inconvenience of the affected person having to return for the
pores and skin take a look at to be learn, a laboratory take a look at to detect latent infec-
tions was developed. This take a look at, referred to as QuantiFERON-TB Gold
(QFT-G), measures the quantity of interferon-γ launched from
the affected person’s lymphocytes after publicity to antigens from M.
tuberculosis in cell tradition. QFT-G requires solely a single blood
specimen and determines the quantity of interferon-γ by an
enzyme-linked immunosorbent assay (ELISA) take a look at.
BCG vaccine can be utilized to induce partial resistance to
tuberculosis. The vaccine incorporates a pressure of dwell, attenuated M.
bovis referred to as bacillus Calmette-Guérin. The vaccine is efficient in
stopping the looks of tuberculosis as a medical illness,
particularly in kids, though it doesn’t stop an infection by
M. tuberculosis. Nevertheless, a significant downside with the vaccine is
its variable effectiveness, which may vary from 0% to 70%. It’s
used primarily in areas of the world the place the incidence of the
illness is excessive. It isn’t normally utilized in the USA as a result of
of its variable effectiveness and since the incidence of the
illness is low sufficient that it isn’t cost-effective.
The pores and skin take a look at reactivity induced by the vaccine given to chil-
dren wanes with time, and the interpretation of the pores and skin take a look at
response in adults isn’t altered by the vaccine. For instance, pores and skin
take a look at reactions of 10 mm or extra shouldn’t be attributed to the
vaccine except it was administered not too long ago. In the USA,
use of the vaccine is proscribed to younger kids who’re in shut
contact with people with energetic tuberculosis and to navy
personnel. BCG vaccine shouldn’t be given to immunocom-
promised individuals as a result of the dwell BCG organisms may cause dis-
BCG vaccine can be used to deal with bladder most cancers. The vac-
cine is instilled into the bladder and serves to nonspecifically
stimulate cell-mediated immunity, which may inhibit the expansion
of the carcinoma cells.
Pasteurization of milk and destruction of contaminated cattle are
necessary in stopping intestinal tuberculosis.
A number of species of mycobacteria are characterised as atypical,
as a result of they differ in sure elements from the prototype, M.
tuberculosis. For instance, atypical mycobacteria are widespread
within the atmosphere and aren’t pathogenic for guinea pigs,
whereas M. tuberculosis is discovered solely in people and is extremely
pathogenic for guinea pigs. The atypical mycobacteria are some-
instances referred to as mycobacteria aside from tuberculosis (MOTTs) or
nontuberculous mycobacteria (NTM).
The atypical mycobacteria are labeled into 4 teams
based on their fee of development and whether or not they produce
pigment underneath sure circumstances (Desk 21–4). The atypi-
cal mycobacteria in teams I, II, and III develop slowly, at a fee
just like that of M. tuberculosis, whereas these in group IV are
“fast growers,” producing colonies in fewer than 7 days. Group
I organisms produce a yellow-orange–pigmented colony solely
when uncovered to gentle (photochromogens), whereas group II
organisms produce the pigment mainly at nighttime (scotochro-
mogens). Group III mycobacteria produce little or no yellow-
orange pigment, no matter the presence or absence of sunshine
Group I (Photochromogens)
Mycobacterium kansasii causes lung illness clinically resembling
tuberculosis. As a result of it’s antigenically just like M. tuberculosis,
sufferers are ceaselessly tuberculin pores and skin take a look at optimistic. Its habitat
TABLE 21–4 Runyon’s Classification of Atypical
Mild Darkish Typical Species
I Sluggish + – M. kansasii, M. marinum
II Sluggish + + M. scrofulaceum
III Sluggish – – M. avium-intracellulare
IV Speedy – – M. fortuitum-chelonae
within the atmosphere is unknown, however infections by this organism
are localized to the midwestern states and Texas. It’s vulnerable
to the usual antituberculosis medication.
Mycobacterium marinum causes “swimming pool granu-
loma,” also called “fish tank granuloma.” These granuloma-
tous, ulcerating lesions happen within the pores and skin on the website of abrasions
incurred at swimming swimming pools and aquariums. The pure habitat
of the organism is each recent and salt water. Remedy with a
tetracycline reminiscent of minocycline is efficient.
Group II (Scotochromogens)
Mycobacterium scrofulaceum causes scrofula, a granulomatous
cervical adenitis, normally in kids. (M. tuberculosis additionally
causes scrofula.) The organism enters by the oropharynx
and infects the draining lymph nodes. Its pure habitat is
environmental water sources, nevertheless it has additionally been remoted as a
saprophyte from the human respiratory tract. Scrofula can typically
be cured by surgical excision of the affected lymph nodes.
Group III (Nonchromogens)
Mycobacterium avium-intracellulare complicated (MAI, MAC) is
composed of two species, M. avium and M. intracellulare, that
are very tough to tell apart from one another by commonplace lab-
oratory assessments. They trigger pulmonary illness clinically indistin-
guishable from tuberculosis, primarily in immunocompromised
sufferers reminiscent of these with AIDS who’ve CD4 cell counts
of lower than 200/μL. MAI is the commonest bacterial trigger
of illness in AIDS sufferers. The organisms are widespread
within the atmosphere, together with water and soil, notably in
the southeastern United States. They’re extremely immune to
antituberculosis medication, and as many as six medication in combina-
tion are ceaselessly required for ample therapy. Present
medication of selection are azithromycin or clarithromycin plus one or
extra of the next: ethambutol, rifabutin, or ciprofloxacin.
Azithromycin is presently really helpful for stopping illness
in AIDS sufferers.
Group IV (Quickly Rising Mycobacteria)
Mycobacterium fortuitum-chelonae complicated consists of two
related species, M. fortuitum and M. chelonae. They’re sapro-
phytes, discovered mainly in soil and water, and barely trigger human
illness. Infections happen mainly in two populations: (1) immu-
nocompromised sufferers and (2) people with prosthetic hip
joints and indwelling catheters. Pores and skin and delicate tissue infections
happen on the website of puncture wounds (e.g., at tattoo websites). They
are sometimes immune to antituberculosis remedy, and remedy with
a number of medication together plus surgical excision could also be
required for efficient therapy. Present medication of selection are
amikacin plus doxycycline.
Mycobacterium abscessus is one other quickly rising myco-
micro organism acquired from the atmosphere. It causes power
lung infections, particularly in cystic fibrosis sufferers, in addition to
infections of the pores and skin, bone, and joints. It’s extremely antibiotic-
resistant. Present medication of selection are amikacin plus imipenem
or cefoxitin plus clarithromycin.
Mycobacterium smegmatis is a quickly rising mycobacte-
rium that isn’t related to human illness. It’s a part of the
regular flora of smegma, the fabric that collects underneath the
foreskin of the penis.
This organism causes leprosy (Hansen’s illness).
Mycobacterium leprae has not been grown within the laboratory,
both on synthetic media or in cell tradition. It may be grown in
experimental animals, reminiscent of mice and armadillos. People are
the pure hosts, though the armadillo seems to be a reservoir
for human an infection within the Mississippi Delta area the place these
animals are widespread. In view of this, leprosy will be considered
as a zoonotic illness, no less than in sure southern states, reminiscent of
Louisiana and Texas.
The optimum temperature for development (30°C) is decrease than
physique temperature; due to this fact, M. leprae grows preferentially in
the pores and skin and superficial nerves. It grows very slowly, with a dou-
bling time of 14 days. This makes it the slowest-growing human
bacterial pathogen. One consequence of that is that antibiotic
remedy should be continued for a very long time, normally a number of years.
Lepromatous leprosy in people can be attributable to Mycobac-
terium lepromatosis, a bacterium discovered primarily in Mexico and
the Caribbean area. This organism additionally causes lepromatous
pores and skin lesions in crimson squirrels within the British Isles, indicating the
possible zoonotic origin of this bacterium.
An infection is acquired by extended contact with sufferers with
lepromatous leprosy, who discharge M. leprae in giant numbers
in nasal secretions and from pores and skin lesions. In the USA,
leprosy happens primarily in Texas, Louisiana, California, and
Hawaii. Most instances are present in immigrants from Mexico, the
Philippines, Southeast Asia, and India. The illness happens world-
vast, with most instances within the tropical areas of Asia and Africa. The
armadillo is unlikely to be an necessary reservoir as a result of it isn’t
discovered in lots of areas of the world the place leprosy is endemic.
The organism replicates intracellularly, usually inside pores and skin his-
tiocytes, endothelial cells, and the Schwann cells of nerves. The
nerve harm in leprosy is the results of two processes: harm
attributable to direct contact with the bacterium and harm triggered
by CMI assault on the nerves.
There are two distinct types of leprosy—tuberculoid and
lepromatous—with a number of intermediate varieties between the
two extremes (Desk 21–5).
(1) In tuberculoid (also called paucibacillary) leprosy,
the CMI response to the organism limits its development, only a few
acid-fast bacilli are seen, and granulomas containing big
cells kind. The nerve harm appears prone to be attributable to cell-
mediated immunity as there are few organisms and the CMI
response is powerful.
The CMI response consists primarily of CD4-positive
cells and a Th-1 profile of cytokines, specifically, interferon-γ,
interleukin-2, and interleukin-12. It’s the CMI response that
causes the nerve harm seen in tuberculoid leprosy.
The lepromin pores and skin take a look at result’s optimistic. The lepromin pores and skin
take a look at is just like the tuberculin take a look at (see earlier). An extract of
M. leprae is injected intradermally, and induration is noticed
48 hours later in these in whom a CMI response towards the
(2) In lepromatous (also called multibacillary) leprosy,
the cell-mediated response to the organism is poor, the pores and skin
and mucous membrane lesions comprise giant numbers of organ-
isms, foamy histiocytes moderately than granulomas are discovered, and
the lepromin pores and skin take a look at result’s unfavorable. The nerve harm
appears prone to be attributable to direct contact as there are lots of
organisms and the CMI response is poor.
There’s proof that folks with lepromatous leprosy pro-
duce interferon-β (antiviral interferon) in response to M. leprae
an infection, whereas individuals with tuberculoid leprosy produce
interferon-γ. Interferon-β inhibits the synthesis of interferon-γ,
thereby lowering the CMI response wanted to comprise the
Be aware that in lepromatous leprosy, solely the cell-mediated
response to M. leprae is flawed (i.e., the affected person is anergic
to M. leprae). The cell-mediated response to different organ-
isms is unaffected, and the humoral response to M. leprae is
intact. Nevertheless, these antibodies aren’t protecting. The T-cell
response consists primarily of Th-2 cells.
The incubation interval averages a number of years, and the onset of
the illness is gradual. In tuberculoid leprosy, hypopigmented
macular or plaquelike pores and skin lesions, thickened superficial nerves,
and important anesthesia of the pores and skin lesions happen (Determine 21–5).
The disfiguring look of the illness outcomes from sev-
eral elements: (1) the pores and skin anesthesia ends in burns and different
traumas, which regularly turn out to be contaminated; (2) resorption of bone
results in lack of options such because the nostril and fingertips; and
(3) infiltration of the pores and skin and nerves results in thickening and
folding of the pores and skin. In most sufferers with a single pores and skin lesion,
the illness resolves spontaneously. Sufferers with types of the
illness intermediate between tuberculoid and lepromatous can
progress to both excessive.
In lepromatous leprosy, the bacilli are simply demonstrated by
performing an acid-fast stain of pores and skin lesions or nasal scrapings.
Lipid-laden macrophages referred to as “foam cells” containing many
acid-fast bacilli are seen within the pores and skin. Within the tuberculoid kind,
only a few organisms are seen, and the looks of typical
granulomas is adequate for prognosis. Cultures are unfavorable
as a result of the organism doesn’t develop on synthetic media.
A serologic take a look at for IgM towards phenolic glycolipid-1 is use-
ful within the prognosis of lepromatous leprosy however isn’t helpful in
the prognosis of tuberculoid leprosy. The prognosis of leproma-
tous leprosy will be confirmed by utilizing the polymerase chain
response (PCR) take a look at on a pores and skin pattern. False-positive ends in
the nonspecific serologic assessments for syphilis, such because the Venereal
Illness Analysis Laboratory (VDRL) and fast plasma reagin
(RPR) assessments, happen ceaselessly in sufferers with lepromatous
The mainstay of remedy is dapsone (diaminodiphenylsulfone),
however as a result of adequate resistance to the drug has emerged,
mixture remedy is now really helpful. For tuberculoid
(paucibacillary) leprosy, dapsone and rifampin are given for six to
12 months, whereas for lepromatous (multibacillary) leprosy, a
mixture of dapsone, rifampin, and clofazimine is given for
12 to 24 months. A mixture of ofloxacin plus clarithromy-
cin is an alternate routine. Thalidomide is the therapy of
selection for extreme ENL reactions.
Isolation of all lepromatous sufferers, coupled with chemopro-
phylaxis with dapsone for uncovered kids, is required. There
isn’t any vaccine.
1. Your affected person is a 25-year-old homeless man who complains of a
cough for the previous month. The cough is now productive of a number of
tablespoons of blood-streaked sputum per day. The sputum isn’t
foul-smelling. He has misplaced 10 kilos however says that he doesn’t eat
repeatedly. On bodily examination, temperature is 38°C, and coarse rales
are heard within the apex of the left lung. An acid-fast stain of the
sputum reveals acid-fast rods. Tradition of the sputum reveals no
development at 7 days, however buff-colored colonies are seen at 21 days.