J Thorsurg 2018 09 002
J Thorsurg 2018 09 002
J Thorsurg 2018 09 002
Tub e rc u l o s i s
A. Thomas Pezzella, MD
KEYWORDS
Mycobacterium tuberculosis complex (MTBC) TB- Tubercle bacillus Sanatorium
Collapse surgery Thoracoplasty Lung resection Drug resistance DOTS
KEY POINTS
TB parallels human evolution and development.
TB is preventive and curative with proper treatment and patient compliance.
TB continues to be a major challenge in low-middle income countries and emerging economies.
Expanded thoracic surgery role in TB treatment.
serious threat in low-middle income countries colleagues16 have suggested a fifth stage that
(LMICs) and emerging economies (EEs), sees a rising epidemic with globally increasing
noncommunicable disease that includes obesity, is transmitted by inhaling the infected droplets
diabetes, and hypertension. that are airborne with sneezing, coughing,
Svizzero and Tisdell17 elaborated nicely on the speaking, or spiting.
Adam Smith theories of a sequential model age From the lungs, TB can spread to other parts of
of human evolution. These stages included the 4 the body (extrapulmonary disease) via the hema-
ages of hunters and gatherers, shepherds (pasto- togenous, lymphatic, or direct extension path-
ralism), agriculture, and commerce. The current ways. Infection occurs in the lung with alveolar
age of commerce has created more socialization contact, then spreads distally with an inflamma-
and human interaction, along with urbanization tory reaction and formation of a Ghon focus that
and the increased population growth and crowd- can be seen on radiographs, then can spread to
ing, thus increasing the risk for disease transmis- regional nodes (Ghon complex), followed by the
sion, especially for TB. TB has been involved in formation of a tuberculoma that can progress to
all the stages, either in a dormant or latent form, an open or closed cavity with a fibrous rim around
or an active form throughout the ages, yet has a pool of inner acellular liquefaction, caseous ne-
been more active and apparent during the periods crosis, and finally lung fibrosis, destruction.
of industrialization, migration, famine, poverty, and Further resultant sequelae includes hemoptysis,
in areas of increased population density. cavities with aspergillomas, and empyema. Datta
Globally, TB remains the ninth leading cause of and colleagues,25 in 2016, studied the oxygen
global deaths, and the leading cause from a sin- transport of pulmonary TB granulomas to confirm
gle infectious agent. In addition, in 2016, there that low oxygen levels in the granuloma can impair
were an additional 374,000 deaths among HIV- the host immune response, whereas the tubular
positive people. An estimated 10.4 million people bacillus can adapt and continue to persist in a hyp-
fell ill with TB in 2016, and 56% of the total were oxic environment.
living in 5 countries: India, Indonesia, China, The activation of latent bacterial infection in
Philippines, and Pakistan. Associated TB with 10% of the infected patients is slow, and it can
HIV, as well as TB drug resistance remains a remain dormant for many years. A suppressed
continuing threat and challenge. There were host immune system from stress or other illnesses,
600,000 new cases with resistance to rifampicin especially HIV, can activate and accelerate the
(RRTB), the most effective first-line drug, of which infective process. This is important because it
490,000 were multidrug-resistant TB (MDR-TB), may explain the long-term ability of TB to survive
and almost half of these cases were in India, in the human host.
China, and Russia.18–21 Despite increased availability of medical treat-
Globally, the TB mortality rate is now falling at a ment, new challenges have developed with the
3% per year rate. TB incidence is also decreasing growing incidences of drug-resistant tuberculosis
at a rate of 2% per year. Between 2005 and 2015 that include DR-TB (drug resistant), MDR-TB
the total TB mortality rate decreased by (multidrug resistant), XDR-TB (extensively drug
17.4%.The global goal by 2020 is to improve to resistant), XXDR-TB (extremely drug resistant),
4% to 5% per year and 10%, respectively.19,20 and TDR-TB (totally drug resistant). Social issues
The disability-adjusted life year (DALY) is a mea- that enhance TB include poverty, poor education,
sure of overall disease burden, expressed as the migration, and urbanization with resultant crowd-
number of years lost due to ill-health, disability, ing, pollution, and poor sanitation. No age group,
or early death.21 In the communicable disease country, or geographic location has been spared
group TB DALYs ranked 13th as the leading cause exposure to TB. Presently, with proper identifica-
of DALYs in 1990, 15th in 2005, and 18th in 2015. tion and management, TB is diagnosable, prevent-
able, controllable, and curative.
TUBERCULOSIS PRIMER
EARLY HISTORY
TB is an obligate aerobic infectious bacterial
organism (Mycobacterium tuberculosis or The origin and history of TB follows 4 time lines
MTB).22,23 The tubercle bacillus is a resistant in- that include the following: (1) the early or ancient
fectious organism, in that it has a thick waxed archeological findings, along with modern scienti-
cell wall that gives protection against external fic DNA methodology testing; (2) documentation
and host forces. Roy and Milton24 stress that TB from the medical and nonmedical literature and
may be the only communicable disease that is events; (3) the discovery of the causation of TB;
initiated only through aerosols deposited in the and (4) the subsequent treatment modalities of
distal lung. Pulmonary tuberculosis is the major TB. The latter time lines can be further divided
target organ involved in 85% of the victims, as it into 5 parts: folk care and medicinal offerings,
History of Pulmonary Tuberculosis 3
sanatoriums, thoracic surgery, medical drugs, and approximately 10,000 years ago, MTBC under-
emerging strategies for combined medical and went changes or lineages, along with the develop-
adjuvant surgical approaches.26–35 ment of agriculture and domestication, and the
The earlier aspects and evolution of TB have resultant changes or adjustments in the host hu-
been well studied and recorded. Archeological man mDNA. This has been supported by molecu-
and paleontological discoveries and evidence of lar aDNA and mDNA testing.32–34 Gagneux,30 in
decayed human or animal teeth or bones, espe- 2016, confirmed that MTBC is an ancient disease
cially the vertebral bones (Pott disease) in Egyptian that evolved with humanity and not animals in
mummy structures, have traditionally been the East Africa, with humans as the primary host. It
major source of TB identification.5 This has been developed the ability to remain dormant and ree-
supported and supplemented by modern scientific merge many years later. TB diversity increased
molecular genotyping (ancient DNA [aDNA], mod- as the human population increased during the
ern DNA [mDNA]), DNA sequencing with single migratory phase out of East Africa. At the same
nucleotide polymorphisms, and polymerase chain time, Gagneux30 postulated that humans may
reaction testing (Box 1).26–29 Presently, there are have developed increased immunity to TB. This
refined genotyping methods to study the M tuber- makes a case for host-pathogen coevolution.
culosis strains.30–35 The path of TB from East Af- This is defined as “reciprocal, adaptive genetic
rica accompanied the migration of Homo sapiens changes in interacting host and pathogen spe-
to the rest of the world, especially along the estab- cies.”30 Box 1 highlights several historical global
lished trade routes with increased mingling and fossils, in humans or animals. Namouchi and col-
crowding of populations (Fig. 1).30 leagues35 support the theory that TB is a success-
An accurate or definitive history of the origin, ful pathogen that emerged from the bottleneck
evolution, and spread of the M tuberculosis with the ability to diversify by recombination and
complex (MTBC) genus/species that includes M natural selection.
tuberculosis, Mycobacterium bovis, Mycobacte-
rium microti, Mycobacterium africanum, Mycobac- FOLK LORE, FOLK REMEDIES, MYTHS, AND
terium pinnipedii, Mycobacterium caprae, and SCIENCE
Mycobacterium canetti species, remain and
continue to evolve. There is a paucity of credible documented scienti-
As noted, TB has been known to mankind since fic literature sources regarding the discovery and
ancient times. It has been postulated that TB has description of TB during the ancient period, Middle
existed for at least 150 million years.5 Gutierrez Ages, and Renaissance that has given factual
and colleagues,31 in 2005, postulated that MTBC insight into the causation or natural history of
was the clonal progeny of a single progenitor TB.4–13 Fear and acceptance dominated this time
ancestor (Mycobacterium prototuberculosis) that frame. The recorded literature concentrated on
dated back more than 3 million years, and started the bizarre and lethal occurrences that affected
in East Africa where early hominids were located. all levels of society.36 The time line of activity is
This progeny occurred from an evolutionary divided into the BC and AD periods.37
bottleneck that occurred 20,000 to 35,000 years Boxes 2 and 338–40 highlight the documented
ago. With migration out of East Africa starting sources of those time periods. Once the existence
of TB was suspected, discovered, or appreciated,
then a series of medical and nonmedical writings,
Box 1 terms, observations, and theories evolved during
Ancient time line human and animal the latter ancient period, and extended through
tuberculosis (TB) identification the Middle Ages, the Renaissance, and the mod-
ern period. Most of these iterations were stroked
United States: Bison: 17,000 years ago:
by the fears, misery, and romanticizing of this
ancient DNA (aDNA)26
strange and lethal phenomenon, along with a
Israel: Alit-Yam: Neolithic period: 9000 years plethora of ineffective therapeutic remedies, and
ago: woman and child aDNA27 futile attempts to explore, define, or understand
Germany: 5450 to 4780 BC: aDNA28 the TB causation.
Egypt: Mummies: 2400 BC: Pott’s lesions with Many lingering disagreements and debates
degenerative tubercular lesions on the centered around hereditary and acquired conta-
thoracic spine gion causation. Prevailing medical evaluation and
Peru: Paracas-Caverna women, 1001 to 1300 treatment cures were still influenced by the Hippo-
AD: aDNA29 crates and Galen humors theories.39 Both believed
that TB (phthisis) was the most widespread of all
4 Pezzella
Fig. 1. Out-of-and-back-to-Africa. The evolutionary history of the out and back of TB to East Africa. MTBC orig-
inated in East Africa and some lineages accompanied the out and back Africa migrations of modern humans. The
evolutionary modern MTBC lineages spread, and expanded with increases in human populations throughout the
global regions (each dark gray dot corresponds to 1 million people) via exploration, trade, and conquest. In (A)
the 3 colors represent the three evolutionary lineages. (From Hershberg R, Lipatov M, Small PM, et al. High func-
tional diversity in Mycobacterium tuberculosis driven by genetic drift and human demography. PLoS Biol
2008;6(12):e311; with permission.)
the diseases of that time. Hippocrates believed member was visiting the house at night as a
that tuberculosis was hereditary, whereas Galen vampire and slowly sucking their lives away.
believed the disease was essentially contagious.39 Because tuberculosis patients were slowly be-
Aretaeus of Cappadocia40 defined the cause of ing “consumed” by the disease, it was assumed
the disease in which phthisis was a pulmonary ab- that vampires were feeding off of their blood.42
scess that produced cough, fever, increased
expectoration, and emaciation. Another example of folk theory was advanced in
A number of terms reflected the effects of TB. 1530 by Paracelsus. He believed that tuberculosis
Consumption was the translation of a Sanskrit was caused by a failure of an internal organ to
word (1000 BC) for a wasting disease. Hippocrates accomplish its alchemical duties. When this
coined the word phthisis (decaying) to describe the occurred in the lungs, stony precipitates would
disease. Scars from TB cervical lymph nodes were develop causing tuberculosis in what he called
called scrofula (Fig. 2). They were called “Kings the tartaric process.43
Evil” by the king, and it was widely believed that Folk remedies were widespread. Galen recom-
the kings of England and France could cure scrofula mended fresh air, human breast milk, wolf livers,
by touching those affected, as well as relieving and phlebotomy, as well as diet, exercise for chil-
symptoms like hacking cough, bloody cough, mi- dren, rest for adults, and sunlight (ultraviolet light
asmas, and fatigue. A number of other terms have or heliotherapy).
been recorded that defined or characterized the A bevy of preventive methods with plausible ef-
TB atm during those turbulent times (Box 4).41 fects included the following: no spitting, the use of
A mystical culture, along with folklore also sur- spittoons (pinger was the sound of wet tobacco
rounded TB. A notable example was vampirism: when it hit the spittoon); house cleaning with anti-
septic carbolic acid; avoiding women’s trailing
When people died from consumption and other skirts; and not sweeping dry floors, thus avoiding
members of their household soon sickened as contaminated dust inhalation. Other preventive
well, it was believed that the dead family or palliative measures without proven efficacy
History of Pulmonary Tuberculosis 5
Box 3
AD time line sources
Once isoniazid became available, attention turned to the drugs needed in combination to avoid the
development of resistance. Triple therapy of isoniazid, streptomycin, and PAS became the standard
triple therapy until the availability of rifampin in 1966.
1995: The World Health Organization launches DOTS (Directly Observed Treatment, Short-Course)
program as a control strategy for tuberculosis.
Data from Refs.4–13
from TB patients. This established M tuberculosis had developed. However, because the pictures
bacteria (tubercle bacillus) as the etiology and did not distinguish between healed and dormant
cause of the clinical disease (Fig. 3). The Ziehl- lesions, a bacterial test was needed to supplement
Neelsen microscopic acid-fast stain was and confirm the diagnosis.48 This was resolved in
described by the bacteriologist Franz Ziehl 1908 when a tuberculin sensitivity screening skin
(1859–1926) and the pathologist Friedrich Neelsen test was developed (PPD or purified protein deriv-
(1854–1898). Using the microscope, Koch showed ative or Mantoux test) by Mendel and Mantoux.49
that the thick cover of the organism’s protein made In addition, bedside clinical teaching was initi-
it difficult to visualize unless a specific spot of ox- ated by Pierre-Joseph Desault in the late eigh-
ide of the Zeihl-Neelson oxide stain was removed. teenth century. Joseph Leopold Auenbrugger
The bacteria were termed the Koch bacillus and introduced chest percussion in the early nine-
because it took red acid dye, the red rods were teenth century, along with Dr Rene Laennec’s in-
called acid-fast bacilli or red snappers. Later in- vention of the stethoscope.50
vestigations proved that air and secretions These events heralded a major turning point or
expelled from consumptive lungs contained live paradigm shift in the understanding and approach
bacteria. These were the defining moments in the to TB diagnosis and treatment. This now provided
history of TB. Koch was awarded the Nobel Prize a more complete pathway to accurately complete
in 1905 for this seminal accomplishment.46 the assessment and diagnosis of the unfortunate
The Koch Postulates demonstrated the relation- TB victims.
ship between agent and disease47. Koch also
developed a glycerine extract of the tubercle bacilli TREATMENT EVOLUTION
as a remedy for tuberculosis in 1890, calling it “tu- Sanatorium
berculin,” yet it was not effective, especially for
children, and was terminated. It was clear that the lists of treatments during the
In 1895, Wilhelm Konrad Roentgen developed previous centuries were of questionable effect, in
the radiograph, which advanced the diagnoses terms of specific prevention or cure.13 As noted,
of TB. The chest radiograph became a standard
diagnostic tool that revealed the tubercular pulmo- Box 4
nary lesions, even before any clinical symptoms Examples of descriptive phrases for TB
they were treated in a sanatorium or treated at cavity with filtered air to a goal of zero pressure in
home.57 the created space. This allowed the diseased lung
Daniel5 noted a report from 1923 in which the re- to rest, because the lung could not heal under the
sults of 4000 patients with 5-year follow-up constant irritation of inflation and deflation.66This
were studied. Fourteen percent of sanatorium technique required “multiple refills” over several
sputum-negative patients died, whereas 38% of years. In addition, incomplete collapse, secondary
home-treated patients died. For sputum-positive to residual adhesions, restricted total collapse.56
patients, the split was 61% and 81% mortality. Jacobaeus, in 1912, introduced the thorascopic
In summary, the sanatorium experience was a closed intrapleural pneumolysis procedure utiliz-
mixed physical and psychological experience for ing a galvanocautery.64,67,68 This was the
most, and unlike the spiritual malaise as experi- early forerunner of the current video-assisted thor-
enced by Hans Castorp in The Magic Mountain acoscopic surgery procedure that decreased the
novel by Thomas Mann.58 blind finger method. This approach was well
received because it was less invasive and more
Thoracic Tuberculin Surgery effective in patients in whom adhesions prevented
a satisfactory result by the open technique.
Stop at the pleura As noted, artificial pneumothorax was used pri-
—Ernest Dieffenback59 marily in patients with TB cavitary disease. It was
postulated that collapse would limit disease
The history of TB surgery has been well spread by inducing fibrosis and encapsulation
reviewed.59–64 of the infected area. More likely, by impairing
Thoracic surgery advanced with the discovery ventilation to the treated lung, and collapsing
of the radiograph in 1895. This allowed an the cavity within, it reduced oxygen levels and
anatomic view of the TB pathology within the chest inhibited growth of the oxygen-dependent tuber-
cavity. Then the development, and severity of TB cle bacillus.
could be objectively evaluated. However, thoracic Because air injected during pneumothorax ther-
surgery at the end of the nineteenth century was apy was resorbed after 1 to 2 weeks, recurrent
somewhat limited because surgical entry to the injections were required (usually repeated over
chest cavity beyond the chest pleura was not 1–2 years). The risk of pleuritis often prevented
advised or advocated for fear that opening the maintenance of the collapse. Other complications
pleura would compromise the patient’s negative included infection and bleeding into the pleural
lung pressure. This changed with the advances space.
in anesthesia and positive airway control and Further advances with collapse therapy
management. continued, as these early approaches were not
The time line for TB surgery is summarized in very effective over the long term, especially with
(Box 6). It is ironic that the goal changed lower lung and bilateral cavities. For lower-lobe
from external fresh air to the lungs in the sanato- cavities, other less invasive methods were per-
rium era to relaxing the lung and suppressing oxy- formed. Pneumoperitoneum, in which air was
gen entry with surgical collapse and resection injected into the abdominal cavity, resulting in dia-
techniques. Both the sanatorium and surgery phragmatic elevation or, with phrenic nerve crush,
approach complemented each other in the early where the diaphragm it innervated was temporarily
stages, because many sanatorium patients went paralyzed, were both marginally effective, but not
on to have surgery with increasing successful difficult to perform, and often used together.69
outcomes. Thoracoplasty was a major advance in TB sur-
In 1821, the concept of collapse was originally gery.60–62 In 1885, Edouard Bernard de Cerenville
advanced by Dr James Carson. There was a long introduced the thoracoplasty procedure for apical
lapse before the collapse concept was further cavitary disease. In 1922, Ludolf Brauer and Paul
developed. Collapse surgery with the artificial Friedrich developed a more radical thoracoplasty
pneumothorax procedure, using a pneumothorax involving 2 to 9 ribs. These procedures were per-
apparatus, was initiated by Carlo Forlanini in formed under local anesthesia with high mortality.
1882.65 The rationale was that the affected lung In 1912, Ernst Sauerbruch and Max Wilms devel-
would collapse, thus allowing the lung to “rest” oped a less radical thoracoplasty that involved pri-
and heal. However, the pneumothorax was limited marily the extrapleural paravertebral ribs and the
to the upper lung TB cavities, yet it remained pop- transverse processes.
ular for many years.56 Thoracoplasty was developed to induce long-
The procedure involved inserting a long needle term collapse, but it was an extensive and
between the patient’s ribs and pumping the chest mutilating procedure. This operation carried
10 Pezzella
Box 6
Timeline of TB surgery
Giorgio Baglivi: 1696: improvement of TB patient following pneumothorax injury from chest sword
wound
F.H. Ramge:1834: successful therapeutic pneumothorax
James Carson: 1819: initiated the concept of collapse
Carlo Forlanini: 1882: artificial pneumothorax65
J. Hastings and R. Storks: 1844: cavernostomy
Crawford Long: 1842: Ether gas applied anesthesia
William Morton: 1846: discovery of anesthesia
John Collins Warren: first operation with anesthesia at the Ether dome in Massachusetts General Hospi-
tal, Boston, Massachusetts
Edouard Bernard de Cerenville: 1885: Costal resection (2–4 ribs)
Anesthesia: 1882: open drop method with either or chloroform and spontaneous negative breathing
Carl Spengler: 1890: successful apicolysis with extrapleural plombage procedure
Theodore Tuffier: 1891: first partial lung resection (apicolysis): the forerunner of the extrapleural plom-
bage; 1896: with cuffed endotracheal tube
Joseph O’Dwyer/George Fell: 1888: invented the respirator apparatus
E. Delorme: 1894: decortication
Rudolph Matas:1898: performed chest wall surgery with Fell device
Wilhelm Conrad Roentgen: 1895: invention of radiograph
Brauer/Friedrich: 1929: thoracoplasty with first rib left intact
Hans Christian Jacobaeus: 1912: thorascopic closed intrapleural pneumolysis of pleural adhesions
Ernst Sauerbruch/Wilm: 1912: paravertebral thoracoplasty; inventor of the negative-pressure chamber
Samuel Meltzer and John Auer: 1904: anesthesia via endotracheal access and positive-pressure
ventilation
H. Schlange: 1907: extrapleural plombage
A. Stuertz: 1912: phrenicectomy
A. Bernou: 1922: plombage with oleothorax (vegetable and mineral oil) (see Fig. 5)
Leo Eloesser: 1924: division of adhesions extrapleurally to avoid lung tears; developed open drainage
technique79 (see Fig. 6)
Harold Brunn: 1929: 1-stage lobectomy with individual ligation of hilar vessels and suture of bronchial
stump
Heidenhain Lilienthal: 1933: first successful pneumonectomy for TB mass hilar ligation
Samuel Freedlander: 1934: successfully excised the right upper lobe of a patient with a tuberculous cav-
ity who had failed collapse therapy
Carl Semb: 1935: apicolysis via subperiosteal approach
John Alexander: 1934: major thoracoplasty pioneer; also performed thoracic muscle plombage (Alex-
ander J. Supraperiosteal and subcostal pneumolysis with filling of pectoral muscle. Arch Surg
1934;28:538–547)
Vincent Monaldi: 1939: cavernostomy (2-stage intracavitary aspiration)
Churchill/Klopstock: 1943: lobectomy with individual vessel ligation technique
considerable morbidity and mortality. As a conse- involved disarticulation of the ribs with preserva-
quence, it was often performed in 2 or 3 stages at tion of the costal periosteum, so that with time
2-week to 3-week intervals to allow gradual the rib would regenerate into a position inducing
realignment of the mediastinum. The operation permanent pulmonary collapse. The ultimate goal
History of Pulmonary Tuberculosis 11
observe and learn the new techniques and ap- infected milk. Pasteurization, started in 1906, elim-
proaches. The learning curve was very steep, given inated that as a cause of infection, especially in
the high early mortality and morbidity rates in the children.85
early years. Naef63 pointed out that the early oper- Adequate treatment of TB required a reliable
ations were performed by nonsurgical physicians, correct diagnosis, as noted with a positive skin
yet emerging experienced thoracic surgeons grad- test (PPD), positive sputum acid-fast stain (Ziehl-
ually took over. In addition, many of the operations Neelsen) test (number of red snappers per HPF),
were performed at the sanatoriums, given the fear or the auramine fluorescein stain, and a positive
of performing operations in their own hospital. Lowenstein-Jenson medium culture.51 Other cur-
The development and reporting of thoracic sur- rent diagnostic tests included IGRAS-Quanti
gical procedures were difficult to evaluate. The FERON TB Gold test, and T-Spot TB test.86
chronology was available, but the caseloads, de- Following the principles of Louis Pasteur, in
gree of complexity, timing of the surgery, and se- 1880, with attenuating the virulence of a living
lection of a particular procedure were not well microbe, a vaccine produced with Mycobacteria
recorded or evaluated. There existed an atmo- bovis was developed in 1908 by Albert Calmette
sphere of individual preferences, and a paucity of and Camilo Guerin.87 They grew the Koch bacillus
consensus. There was a high learning curve, yet in several media to decrease its virulence and to
the overall results improved with time. increase immunity. The Bacille Calmette Guerin
The early major complications included (BCG) vaccine was first used in humans in 1921,
bronchopleural fistula, sepsis, pulmonary lung and became widely used primarily for children.87
dysfunction, and recurrent disease secondary to Currently, there remains no universal totally effec-
incomplete lung resection. tive vaccine for TB.
Casadevall,88 in 2017, discussed the role of vac-
cines in cell-mediated responses to TB. He postu-
Medical Treatment
lated that latent TB is more effective in protection
The major therapeutic modality in the early to mid- and inhibition of the growth of M tuberculosis
dle twentieth century continued to be the sanato- in vitro than active TB. This implies that newer vac-
rium and surgical treatment. Thereafter, with the cines that promote latency may be more beneficial
development of antibiotics, between 1944 and in infection control.
the early 1950s, surgery declined, as well as the The timeline for the antibiotic development for
sanatoriums.83,84 TB started in 1935 when Gerhard Domagk pub-
As noted, most previous medical efforts were lished a report on the use of "Prontosil," an
not effective. One exception was with bovine organic compound containing sulfur (sulfanil-
tuberculosis that was passed to humans through amide), yet it was deemed too toxic for humans.
In 1944, a major advance occurred with the dis-
covery of streptomycin (Streptomyces griseous)
by Schatz, Bugie, and Waksman. It was limited
by the early development of resistance. In
1945, para-aminosalicylic acid (PAS) was
discovered. When combined with streptomycin,
it decreased drug resistance. Following strepto-
mycin, isoniazid (1952), pyrazinamide (1954),
ethambutol (1962), and rifampin (rifampicin)
(1963) were introduced.83,84,89–91
Treatment strategies beyond the drugs
depended on prevention, education, social as-
pects, and compliance, along with access to
care, availability, and surveillance. Developed by
Karel Styblo with the International Union Against
Tuberculosis and Lung Disease in the 1970s, the
directly observed treatment, short-course (DOTS)
strategy was recommended by the World Health
Organization (WHO). In 1995, the WHO adopted
Fig. 6. Status post TB pneumonectomy with empyema the DOTS that focused on cure rates, and limiting
and BPF requiring Eloesser flap open drainage. BPF, the spread of drug resistance. Subsequent
bronchopleural fistula. (Courtesy of A. Thomas Pez- trials found significant differences in cure
zella, MD, Boca Raton, FL.) rates or treatment completion between DOTS
14 Pezzella
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