Mycobacteria: Exploring the Intriguing World of Sluggish-Rising Microorganisms with Distinctive Pathogenic and Therapeutic Implications

Mycobacteria: Exploring the Intriguing World of Sluggish-Rising Microorganisms with Distinctive Pathogenic and Therapeutic Implications

 

INTRODUCTION

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

acid-fast.

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.

MYCOBACTERIUM TUBERCULOSIS

Illness

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.

Essential Properties

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

sputum samples

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.

Pathogenesis

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

an infection.

(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

mechanisms:

(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

this e-book.

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.

Scientific Findings

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

HAART.

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.

Laboratory Prognosis

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

used.

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 remedy.

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.

Prevention

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-

seminated illness.

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.

ATYPICAL MYCOBACTERIA

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

(nonchromogens).

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

Mycobacteria

Group

Development

Price

Pigment Formation

Mild Darkish Typical Species

I Sluggish + – M. kansasii, M. marinum

II Sluggish + + M. scrofulaceum

III Sluggish – – M. avium-intracellulare

complicated

IV Speedy – – M. fortuitum-chelonae

complicated

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.

MYCOBACTERIUM LEPRAE

Illness

This organism causes leprosy (Hansen’s illness).

Essential Properties

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.

Transmission

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.

Pathogenesis

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

organism exists.

(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

an infection.

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.

Scientific Findings

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.

Laboratory Prognosis

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

leprosy.

Remedy

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.

Prevention

Isolation of all lepromatous sufferers, coupled with chemopro-

phylaxis with dapsone for uncovered kids, is required. There

isn’t any vaccine.

SELF-ASSESSMENT QUESTIONS

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.