Drug-resistant tuberculosis is not a new phenomenon:
resistance to antituberculosis drugs has been noted
since the drugs were first introduced, and occasionally
outbreaks of drug-resistant tuberculosis have been
reported. But recent outbreaks of multidrug-resistant
tuberculosis have differed considerably from the
previous outbreaks. This article will review the
causes, the treatment, and the control of drug-resistant
tuberculosis and describe the recent outbreaks of
Tuberculosis has afflicted humans since ancient
times. Tuberculous lesions have been found in Egyptian
mummies, and the disease was well described by Hippocrates.
During the Industrial Revolution, substantial increases
in tuberculosis accompanied urban crowding and malnutrition.
In the 19th century, an estimated one quarter of
the adult population of Europe died of tuberculosis.
In the United States, approximately
20% of deaths in the early 1800s were attributed
to tuberculosis; this figure had decreased to 11%
by midcentury. Mortality declined throughout the
century probably because of improvements in living
conditions and nutrition. The realization in the
late 1800s that tuberculosis was infectious eventually
led to the isolation of tuberculosis patients in
treatment centers, or sanatoria. Treatment in sanatoria
consisted of bed rest, enhanced nutrition, and various
surgical procedures aimed at closing lung cavities.
The discovery of antituberculosis medications in
the mid20th century further reduced tuberculosis
incidence and mortality and rendered surgical resection
Soon after antituberculosis medications
were introduced, researchers recognized that tuberculosis
was unique with respect to the frequency and importance
of the emergence of drug resistance during therapy.
They discovered that drug-resistant mutants existed
in wild strains of Mycobacterium tuberculosis,
that selection of these mutants could occur under
certain treatment conditions, and that drug-resistant
tuberculosis was more difficult to cure. Once additional
drugs were available, controlled trials were conducted
and demonstrated that combined regimens were more
efficient than single-drug regimens in treating
tuberculosis and preventing the emergence of drug
Transmission and Pathogenesis of
Drug-resistant and drug-susceptible tuberculosis
are transmitted in the same way. For many years,
drug-resistant tuberculosis was believed to be less
infectious than drug-susceptible tuberculosis. This
belief was largely based on animal studies that
showed that isoniazid-resistant bacilli were less
virulent than isoniazid-susceptible bacilli. Reports
of outbreaks of drug-resistant tuberculosis in the
1970s and 1980s did not completely dispel this notion.
In 1985 Snider and colleagues compared the risk
of infection among persons exposed to drug-resistant
bacilli with the risk among persons exposed to drug-susceptible
bacilli (1). They
found no evidence that drug-resistant bacilli were
less infectious than drug-susceptible bacilli. In
fact, contacts of previously untreated patients
had a similar risk of infection, regardless of whether
the bacilli were drug-resistant or drug-susceptible.
They did find, however, an increased risk of infection
in contacts of patients with drug-resistant tuberculosis
who had been previously treated. They suggested
that the increased risk resulted from prolonged
exposure rather than increased infectiousness of
the drug-resistant bacilli. Patients with drug-resistant
tuberculosis who have a history of prior treatment
are more likely to have been nonadherent to therapy
and infectious for longer periods of time than patients
with drug-susceptible tuberculosis. The recent outbreaks
of multidrug-resistant tuberculosis support these
findings that drug-resistant tuberculosis is no
less infectious than drug-susceptible tuberculosis
and that, in fact, prolonged periods of infectiousness
may facilitate transmission.
Drug-resistant tuberculosis occurs when drug-resistant
bacilli outgrow drug-susceptible bacilli. The drug-resistant
organisms are produced by random mutations in the
bacterial chromosome which occur spontaneously in
wild-type strains even before the strains come in
contact with an antituberculosis drug (2).
Mutations can produce bacilli resistant to any of
the antituberculosis drugs, although they occur
more frequently for some drugs than others. The
average mutation rate in M. tuberculosis
for resistance to isoniazid is 2.56 x 10-8
mutations per bacterium per generation; for rifampin,
2.25 x 10-10; for ethambutol, 1.0 x 10-7;
and for streptomycin, 2.95 x 10-8. The
mutation rate for resistance to more than one drug
is calculated by multiplying the rates for the individual
drugs. For example, the mutation rate for resistance
to both isoniazid and rifampin is approximately
2.56 x 10-8 times 2.25 x 10-10,
or 5.76 x 10-18. The expected ratio of
resistant bacilli to susceptible bacilli in an unselected
population of M. tuberculosis is about 1:106
each for isoniazid and streptomycin and 1:108
for rifampin. Mutants resistant to both isoniazid
and rifampin should occur less than once in a population
of 1014 bacilli. Pulmonary cavities contain
about 107 to 109 bacilli;
thus, they are likely to contain a small number
of bacilli resistant to each of the antituberculosis
drugs but unlikely to contain bacilli resistant
to two drugs simultaneously (3).
Drug-resistant mutants are selected
when therapy is inadequate, for example, when a
single drug is used to treat a large population
of bacilli. The treatment of a wild-type strain
of M. tuberculosis with a single drug kills
the majority of the bacilli in the population, but
the small number of mutants resistant to the drug
continue to multiply (Figure
1). After 2 weeks to several months of treatment
with the single drug, the resistant bacilli will
outgrow the susceptible bacilli, causing clinical
drug resistance. Furthermore, in a large population
of resistant mutants, additional mutations can occur
resulting in doubly-resistant mutants (Figure
Figures 1 and 2. Empty circles represent
tubercle bacilli susceptible to all antituberculosis
drugs. A circle with a letter in it represents
a tubercle bacillus with resistance to the drug
indicated by the letter: I = isoniazid resistance;
R = rifampin resistance; P = pyrazinamide resistance.
Adapted with permission from Reichman LB: A looming
public health nightmare. Lungs at Work
1992. Copyright © 1992 American Lung Association.
In contrast, the emergence of drug
resistance is far less likely in most types of extrapulmonary
tuberculosis, in which the bacillary population
is much smaller. The bacillary population is even
smaller in latent tuberculosis infection, so the
chances that drug resistance will emerge during
preventive therapy are negligible.
Drug resistance is divided into two
types: primary resistance and secondary (or acquired)
resistance. Primary resistance occurs in persons
who do not have a history of previous treatment;
these persons are initially infected with resistant
organisms. Secondary resistance occurs during therapy
for tuberculosis, either because the patient was
treated with an inadequate regimen or because the
patient did not take the prescribed regimen appropriately.
Treatment with two or more drugs in combination
can prevent the emergence of drug resistance, if
the regimen includes at least two drugs to which
the organisms demonstrate in vitro susceptibility.
Multidrug resistance is defined as
in vitro resistance of a strain of M.
tuberculosis to two or more of the antituberculosis
drugs. Clinically, the most important pattern of
multidrug resistance is resistance to both isoniazid
and rifampin. This combination has been associated
with an overall cure rate of less than 60% in some
reports, similar to the rate of cure before the
discovery of antituberculosis drugs (4,5).
The two main causes of drug resistance
are nonadherence to therapy and the use of inadequate
treatment regimens. When medications are not taken
as prescribed, the infecting bacilli may be exposed
to a single drug for long periods of time, which
allows drug-resistant organisms to emerge (Figure
In addition, some regimens may contain
multiple drugs but only one drug to which the infecting
bacilli are susceptible. This can happen when primary
drug resistance is not suspected or when a single
drug is added to a failing regimen (Figure
4). These regimens are equivalent to single-drug
therapy, and they can select multidrug-resistant
organisms. Acquired multidrug resistance usually
results from a combination of nonadherence and inappropriate
Tuberculosis in the United States
Since nationwide reporting first began, the
number of reported tuberculosis cases declined by
an average of 5.6% per year, from more than 84,000
cases in 1953 to 22,255 cases in 1984. In 1985 this
decline ended abruptly; from 1985 through 1993,
the number of cases increased by 14%. It is estimated
that 64,000 more cases have occurred since 1985
than would have been expected had the trend of 1980
to 1984 continued (Figure
5) (6). The
excess cases have been attributed to a number of
factors including the human immunodeficiency virus
(HIV) epidemic, tuberculosis occurring in foreign-born
persons from countries with a high prevalence of
tuberculosis, the transmission of tuberculosis in
congregate settings (e.g., health care facilities,
correctional facilities, drug treatment facilities,
and shelters for the homeless), and a deterioration
of the public health care infrastructure.
Drug-resistant tuberculosis in
the United States
Until recently, the national surveillance system
for tuberculosis has not included the reporting
of drug susceptibility. Therefore, information about
trends in drug-resistant tuberculosis is limited.
Several regional surveys and some larger national
surveys provide some information, but methodological
differences make comparing the surveys difficult.
The Centers for Disease Control and Prevention (CDC)
has conducted several surveys of primary drug resistance.
The first survey examined drug susceptibility results
among tuberculosis patients hospitalized between
1961 and 1968. Resistance to at least one drug was
found in 3.5% of the 9350 strains tested, and resistance
to two or more drugs was found in 1% of the strains
In a second survey of city and state
laboratories that was conducted between 1975 and
1982, 6.9% of the cases involved resistance to one
or more drugs, and 2.3% of cases involved resistance
to two or more drugs (9-11).
The third survey, conducted between 1982 and 1986,
found that 9% of strains isolated in 31 health department
laboratories were resistant to one or more drugs
The difference in primary resistance
rates in the three surveys may be due to methodological
differences; however, each survey showed a rate
of primary drug resistance that was relatively low
and that was stable or decreasing during the study
period. Drug resistance did not appear to be an
increasing problem, and the surveys were discontinued.
Prompted by outbreaks of multidrug-resistant
tuberculosis, CDC conducted an additional survey
of drug resistance among tuberculosis cases reported
from January through March 1991 (13).
CDC then conducted a second survey of cases reported
in the first quarter of 1992, and compared the findings
from that survey with the findings from the 1991
survey (CDC, unpublished data, 1995). The proportion
of culture-positive patients with drug susceptibility
test results increased from 81.8% in 1991 to 84.1%
in 1992. In 1991 resistance to at least one drug
was found in 13.4% of new cases, 26.6% of recurrent
cases, and 14.2% of cases overall; in comparison,
in 1992 resistance to at least one drug was found
in 12.8% of new cases, 19.4% of recurrent cases,
and 13.1% of all cases. Resistance to both isoniazid
and rifampin was reported in 3.2% of new cases,
6.9% of recurrent cases, and 3.5% of all cases in
1991, and was reported in 3.4% of new cases, 3.7%
of recurrent cases, and 3.3% of all cases in 1992.
The findings of these two surveys
may not be comparable to the findings of the previous
surveys because of significant methodological differences.
In the previous surveys, susceptibility testing
was performed at a single laboratory on isolates
from only a sample of areas. In contrast, in the
1991 and 1992 surveys, susceptibility tests were
performed at local laboratories, and researchers
attempted to collect results from all areas for
all of the cases reported during the study period.
Furthermore, in the previous surveys, attempts were
made to determine whether "new" cases
had a history of previous treatment and if so, to
exclude them from the study, whereas in the 1991
and 1992 surveys, classification of cases as "new"
or "recurrent" was not verified, and a
history of prior treatment was not sought. Although
the full effect of these methodological differences
cannot be determined, the most recent CDC survey
suggests that drug resistance has increased in the
United States after years of relative stability.
Some regional data suggest that the
increases in drug-resistant tuberculosis may be
concentrated in large urban areas. In the 1991 CDC
survey, 67% of the cases of drug resistance were
reported from only five areas: New York City, California,
Texas, New Jersey, and Florida. In both the 1991
and the 1992 survey, 61% of the cases of multidrug-resistant
tuberculosis were reported from New York City alone.
Frieden and colleagues conducted a survey in New
York City of drug susceptibility results on specimens
from all patients with a positive culture for M.
tuberculosis during April 1991 (14).
They found that of patients with no previous treatment,
23% had organisms resistant to at least one drug
and 7% had organisms resistant to both isoniazid
and rifampin. Beginning in 1993, results of drug
susceptibility tests were reported to CDC from all
50 state health departments and from New York City,
the District of Columbia, and Puerto Rico through
SURVS-TB, CDCs national TB surveillance system.
In an analysis of areas reporting susceptibility
results for at least 75% of culture-positive cases,
New York City accounted for 80% of the cases of
multidrug-resistant tuberculosis (CDC, unpublished
Factors associated with drug resistance
One important risk factor for drug resistance
is previous treatment with antituberculosis medications
Studies have found that rates of drug-resistance
increase as the duration of previous treatment increases
In most instances, drug resistance develops because
of inadequate or erratic therapy, although it has
been shown that persons previously treated for drug-susceptible
tuberculosis can be reinfected with drug-resistant
Another risk factor for drug-resistant
tuberculosis is contact with a person who has infectious,
drug-resistant tuberculosis. Recent nosocomial outbreaks
demonstrate a strong correlation between previous
exposure to a patient who has infectious, multidrug-resistant
tuberculosis and the subsequent development in the
contact of multidrug-resistant tuberculosis (19-23).
Drug resistance occurs more frequently in persons
from areas of the world with a high prevalence of
drug-resistant tuberculosis, such as Southeast Asia,
Latin America, Haiti and the Phillippines. Several
studies have found high rates of primary drug resistance
in these persons, indicating transmission of drug
resistant tuberculosis in the country of origin
(24-27). However, because
an accurate history of treatment may be difficult
to obtain, some previously treated patients may
be misclassified as having primary resistance. In
the CDC survey conducted from 1982 to 1986, the
rates of both primary and acquired drug resistance
were two times higher among foreign-born persons
than among persons born in the United States (12).
Outbreaks of Drug-Resistant Tuberculosis
Drug-resistant tuberculosis was described soon
after antituberculosis drugs were introduced, but
the first documented outbreak of drug-resistant
tuberculosis was not reported until 1970. Between
1970 and 1990, only a few outbreaks of isoniazid-resistant
tuberculosis and five outbreaks of multidrug-resistant
tuberculosis were reported. In general, these outbreaks
involved small numbers of cases among close contacts
who had prolonged or repeated exposure to source
From 1990 through August 1992, in
collaboration with state and local health departments,
CDC investigated outbreaks of multidrug-resistant
tuberculosis in seven hospitals in Florida, New
York, and New Jersey and in the New York State correctional
2 and 3)
The recent outbreaks differ considerably from previous
outbreaks of drug-resistant tuberculosis in several
ways. First, the recent outbreaks involved large
numbers of patients; nearly 300 cases have been
identified. In addition, in the recent outbreaks
tuberculosis was transmitted not only from patient
to patient but also from patient to health care
worker. The epidemiologic evidence of nosocomial
transmission was confirmed by DNA fingerprinting
data: strains from epidemiologically linked cases
were found to have identical patterns by restriction
fragment length polymorphism (RFLP) analysis. RFLP
analysis also suggested that several of the outbreaks
in New York State were connected.
Finally, the recent outbreaks involved
a large percentage of highly susceptible patients
who became infected with highly drug-resistant organisms
that are more difficult to treat. More than 80%
of the cases occurred in persons infected with HIV,
and all but six of the patients had organisms resistant
to both isoniazid and rifampin. Mortality in these
outbreaks was very high. In seven of the eight outbreaks,
more than 70% of the patients died. The median interval
between diagnosis and death ranged from 4 to 16
Factors associated with the outbreaks
of multidrug-resistant tuberculosis
Most of the outbreaks were centered in wards or
outpatient clinics where HIV-infected persons received
care. There is no evidence that persons with HIV
infection are more likely to be infected with tuberculosis
if exposed, but it is clear that, once infected
with tuberculosis, persons who are infected with
HIV have a much higher risk for the development
of active disease than persons who are not infected
with HIV. In addition, infection may progress to
active disease rapidly. The transmission of tuberculosis
to HIV-infected persons in these outbreaks was followed
by the rapid development of new cases of active
disease, which were sources of further transmission.
Prolonged infectiousness also promoted
transmission. The diagnosis of tuberculosis in HIV-infected
persons was sometimes delayed because of the unusual
radiographic presentations of tuberculosis, coinfection
with other pulmonary pathogens to which patients'
symptoms were attributed, and the overgrowth of
M. tuberculosis in the laboratory by other
mycobacteria. Delays in diagnosis lead to delays
in the initiation of isolation and treatment. In
addition, drug resistance was not recognized promptly
because of lengthy laboratory delays, which postponed
the initiation of effective treatment and resulted
in prolonged infectiousness.
Inadequate infection control practices
also facilitated transmission. Isolation rooms were
found to be at positive pressure relative to other
parts of the facility. Patients who had been assigned
to isolation rooms were found in hallways, patient
lounges, or other common areas. Furthermore, isolation
precautions were discontinued prematurely, after
an arbitrary number of days, rather than when there
was clinical or laboratory evidence of decreased
Finally, some patients who were given
appropriate therapy in the hospital were lost to
follow-up after discharge. A lack of consistent
follow-up after discharge promotes lapses in therapy
and heightens the potential for transmission both
in the hospital and in the community. This problem
was not specifically addressed in the outbreak investigations,
but it was described in an unrelated report by Brudney
and Dobkin. They studied 224 tuberculosis patients
admitted to Harlem Hospital in 1988. Of 178 patients
discharged on tuberculosis treatment, 89% were lost
to follow-up and did not complete therapy. Forty-eight
patients were readmitted to the hospital with infectious
tuberculosis within 1 year (41).
The Advisory Council for the Elimination of
Tuberculosis has issued recommendations aimed at
preventing drug-resistant tuberculosis (42).
Drug susceptibility tests should be performed on
all initial isolates of M. tuberculosis.
Additional isolates should be tested for patients
whose cultures remain positive after 3 months of
therapy or who have signs of failure or relapse.
Susceptibility testing not only guides clinical
therapeutic decisions, but also allows tuberculosis
control programs to monitor drug resistance trends
and evaluate tuberculosis control efforts.
Second, initial regimens for treating
tuberculosis should include four drugs: isoniazid,
rifampin, pyrazinamide, and either ethambutol or
streptomycin. When drug susceptibility results become
available, the regimen can be adjusted accordingly.
More drugs may be required for initial regimens
in institutions where outbreaks of multidrug-resistant
tuberculosis are occurring. In areas where resistance
to isoniazid or rifampin is less than 4%, an initial
regimen of three drugs may be adequate. The continued
surveillance of drug resistance is necessary to
detect changes in local drug resistance patterns
and to evaluate the appropriateness of initial regimens
in given areas.
Third, therapy for tuberculosis should
be directly observed by a health care provider.
Nonadherence to therapy is a major cause of treatment
failure, and it may contribute to the emergence
of drug resistance. Directly observed therapy (DOT)
is an effective way to ensure adherence, but the
method must be tailored to each patient's needs
Tuberculosis that is resistant to
isoniazid alone can be treated successfully by using
rifampin and ethambutol for a minimum of 12 months,
preferably supplemented by pyrazinamide for the
first 2 months. In addition, a four-drug regimen
has been shown to be highly effective for isoniazid-resistant
organisms. Rifampin resistance, however, significantly
reduces cure rates and increases the complexity
and the required length of treatment (43).
The treatment of multidrug-resistant
tuberculosis should be based on the in vitro
susceptibility test results and the patient's treatment
The regimen should include at least three drugs
preferably drugs that the patient has not
received before to which the patient's organism
is susceptible. The regimen should include an injectable
medication whenever possible. If the regimen must
be changed for any reason, two medications should
be added simultaneously to avoid selecting for drug-resistant
Medications used to treat multidrug-resistant
tuberculosis are less effective, more costly, and
more likely to cause adverse reactions than the
five first-line drugs (44-48).
Treatment is further complicated because of the
length of therapy needed to prevent relapse: generally,
therapy for multidrug-resistant tuberculosis should
continue an additional 18 to 24 months after culture
results convert to negative.
Because of the high failure and relapse
rates associated with multidrug-resistant tuberculosis,
surgical resection has been used by some clinicians
to supplement medical therapy. The surgical resection
of a major pulmonary focus is best performed once
aggressive medical therapy has achieved a clinical
response. The administration of antituberculosis
medications should continue for 18 to 24 months
after culture results convert to negative. Iseman
and associates reported that in a series of 99 patients
being treated for multidrug-resistant tuberculosis,
the combination of surgical resection and medical
therapy produced lower rates of failure and relapse
compared with that of historical controls (49).
Preventive Therapy for Persons
Exposed to Multidrug-Resistant Tuberculosis
When taken appropriately, isoniazid preventive
therapy is very effective in preventing the development
of active tuberculosis in persons infected with
susceptible strains of M. tuberculosis, even
in persons coinfected with HIV. Rifampin is recommended
for persons infected with isoniazid-resistant strains
In the outbreaks of multidrug-resistant
tuberculosis, numerous tuberculin skin test conversions
were documented among persons exposed to multidrug-resistant
tuberculosis. Preventive therapy for persons exposed
to multidrug-resistant tuberculosis has not been
studied, but CDC has published guidelines for the
management of such contacts (51).
Decisions regarding preventive therapy should be
based on the likelihood that the contact has been
newly infected, that the infecting organisms are
multidrug-resistant, and that active tuberculosis
will develop. If the likelihood of these factors
is low, standard preventive therapy is recommended.
Alternative regimens should be considered for persons
who are likely to be newly infected with a multidrug-resistant
strain and who are at high risk for the development
of active disease if infected. CDC recommends that
alternative regimens include at least two drugs
to which the infecting organism is known to be susceptible.
Potential alternative regimens include pyrazinamide
and ethambutol or pyrazinamide and a quinolone (e.g.,
ciprofloxacin) for 6 to 12 months.
Controlling the tuberculosis epidemic and preventing
drug-resistant tuberculosis necessitate that health
care providers diagnose tuberculosis early and initiate
effective therapy promptly and that tuberculosis
patients successfully complete therapy. Specifically,
directly observed therapy should be used more widely,
initial treatment regimens should be used that prevent
the development of drug-resistant tuberculosis,
and treatment activities should be coordinated between
public health departments and other facilities that
provide care for patients with tuberculosis. Surveillance
of drug resistance must be done to determine the
appropriate initial regimen for tuberculosis in
given areas, define risk factors for drug resistance,
and detect transmission of drug-resistant tuberculosis.
Furthermore, appropriate infection
control practices must be used to prevent the transmission
of tuberculosis in health care settings (52).
Different infection control measures interrupt the
transmission of tuberculosis at different points
in the transmission process. The most effective
infection control measures curb transmission at
the source by preventing the generation of infectious
droplet nuclei. Examples of administrative control
methods include the early diagnosis of disease and
prompt initiation of effective therapy for persons
with active tuberculosis, preventive therapy for
persons with tuberculosis infection, and instruction
of patients to cover their noses and mouths with
a tissue when coughing. Booths and hoods used for
aerosolized pentamidine or sputum induction are
other examples of source control measures.
Potentially infectious patients should
be placed in tuberculosis isolation in a private
room that has negative pressure relative to the
rest of the facility. The air from the room should
be exhausted directly to the outside or through
a high-efficiency particulate air (HEPA) filter,
if recirculation of air into the general ventilation
system from the room is unavoidable. Isolation should
be continued until the patient is no longer infectious.
Patients known or suspected to have active tuberculosis
should be considered infectious if they are coughing,
if they are undergoing cough-inducing procedures,
if their sputum smears contain acid-fast bacilli,
if they are not receiving antituberculosis chemotherapy,
if they recently started receiving chemotherapy,
or if they are not responding to therapy. Most patients
with drug-susceptible disease become noninfectious
after 2 to 3 weeks of therapy, but the period of
infectiousness varies from patient to patient. Patients
with drug-susceptible disease who are receiving
effective therapy and who show signs of response
to therapy (i.e., a reduction in cough, the resolution
of fever and a decreasing number of bacilli on sputum
smears) are probably no longer infectious. However,
patients with drug-resistant disease may take longer
to respond to therapy, especially if drug resistance
is not suspected and they are not receiving effective
therapy. Therefore, patients should be considered
infectious until their sputum smears are free of
bacilli on 3 consecutive days.
Ventilation and other engineering
controls can be used to eliminate infectious droplet
nuclei once they are released into the air, but
these infection control measures are less efficient
and less effective than administrative control methods.
Ventilation reduces airborne contaminants by introducing
uncontaminated air into the room, thereby diluting
the concentration of contaminants. The contaminants
are removed by exhausting the air from the room
directly to the outside. Potential supplemental
measures include HEPA filters and germicidal ultraviolet
irradiation. These supplemental measures require
proper installation and regular maintanence by qualified
personnel, and their use in preventing tuberculosis
transmission has not been well studied. Furthermore,
exposure to ultraviolet irradiation may pose substantial
health risks. Short-term exposure to germicidal
ultraviolet irradiation is known to cause keratoconjunctivitis
and erythema, and long-term exposure has been associated
with an increased risk of basal cell carcinoma.
Of all infection control methods,
the use of personal protective equipment is the
least efficient and least effective. These devices
protect only the wearer, and they function only
when they fit properly and are worn correctly. Administrative
controls and engineering controls are necessary
to protect all persons in the facility from airborne
contaminants. Personal protective devices should
be worn by health care workers in areas where the
air is likely to be contaminated with a higher concentration
of infectious droplet nuclei such as isolation rooms
or rooms used for cough-inducing procedures.
A tuberculosis screening and prevention
program for health care workers is an essential
component of infection control programs in health
care facilities. All persons working in health care
facilities should be skin tested upon employment.
Persons who have negative skin test results should
be retested periodically. Screening will detect
tuberculosis infection in persons for whom preventive
therapy may be appropriate. In addition, skin test
results must be analyzed to evaluate the effectiveness
of an infection control program by determining whether
tuberculosis is being transmitted in the facility.
Most cases of drug-resistant tuberculosis in
the United States can be prevented by using drug-susceptibility
surveillance to monitor trends, directly observed
therapy to ensure adherence to and completion of
therapy, and initial regimens that include four
drugs. Most of the transmission of drug-resistant
tuberculosis in health care settings could be prevented
by fully implementing the current CDC guidelines.
Additional research is needed to identify more rapid
diagnostic techniques, develop new drugs that are
less toxic and require shorter courses of treatment,
and evaluate the role of supplemental infection
Snider DE Jr.,
Kelly GD, Cauthen GM, Thompson NJ, Kilburn JO.
Infection and disease among contacts of tuberculosis
cases with drug resistant and drug susceptible
bacilli. Am Rev Respir Dis 1985;132(1):125-132.
David HL. Probability
distribution of drug-resistant mutants in unselected
populations of Mycobacteria tuberculosis. Applied
Canetti G. The
J. Burns Amberson Lecture. Present aspects of
bacterial resistance in tuberculosis. Am Rev
Respir Dis 1965;92:687-703.
Nunn AJ. Influence of initial drug resistance
on the response to short course chemotherapy
of pulmonary tuberculosis. Am Rev Respir Dis
Goble M, Horsburgh
CR Jr., Waite D, et al. Treatment of isoniazid
and rifampin-resistant tuberculosis. Am Rev
Respir Dis 1988;137(Suppl):24.
Expanded tuberculosis surveillance and tuberculosis
morbidity United States, 1993. MMWR 1994;43:361-366.
Health Service Cooperative Investigation. Prevalence
of drug resistance in previously untreated patients.
Am Rev Respir Dis 1964;89:327-336.
Doster B, Caras
GJ, Snider DE Jr. A continuing survey of primary
drug resistance in tuberculosis, 1961 to 1968.
A U.S. Public Health Service cooperative study.
Am Rev Respir Dis 1976;113:419-425.
Kilburn JO, Glassroth JL, et al. A continuing
survey of tuberculosis primary drug resistance
in the United States: March 1975-November 1977.
A U.S. Public Health Service cooperative study.
Am Rev Respir Dis 1978;118:835-842.
resistance to antituberculosis drugs
United States. MMWR 1980;29:345-346.
resistance to antituberculosis drugs
United States. MMWR 1983;32:521-523.
Snider DE Jr.,
Cauthen GM, Farer LS, et al. Drug resistant
tuberculosis (letter). Am Rev Respir Dis 1991;144:732.
Bloch AB, Cauthen
GM, Onorato IM, et al. Nationwide survey of
drug-resistant tuberculosis in the United States.
Sterling T, Pablos-Mendez A, Kilburn JO, Cauthen
GM, Dooley SW. The emergence of drug-resistant
tuberculosis in New York City. N Engl J Med
Caras GJ, Snider DE Jr. Drug resistance among
previously treated tuberculosis patients, a
brief report. Am Rev Respir Dis 1980;121:313-316.
resistant tuberculosis among the homeless
Boston. MMWR 1985;34:429-431.
McInnes B, Thomas B, Weidhaas S. Exogenous reinfection
with tuberculosis in a shelter for the homeless.
N Engl J Med 1986;315:1570-1575.
Small PM, Shafer
RW Hopewell PC, et al. Exogenous reinfection
with multidrug-resistant Mycobacterium tuberculosis
in patients with advanced HIV infection. N Engl
J Med 1993;328(16):1137-1144.
transmission of multidrug resistant TB to health-care
workers and HIV-infected patients in an urban
hospital Florida. MMWR 1990;39:718-722.
transmission of multidrug resistant tuberculosis
among HIV-infected persons Florida and
New York, 1988-1991. MMWR 1991;40:585-591.
Edlin BR, Tokars
JI, Grieco MH, et al. An outbreak of multidrug
resistant tuberculosis among hospitalized patients
with the acquired immunodeficiency syndrome.
N Engl J Med 1992;326:1514-1521.
Jereb JA, Friedman TR, et al. Nosocomial transmission
of multidrug resistant Mycobacterium tuberculosis.
A risk to patients and health care workers.
Ann Intern Med 1992;117:191-196.
C, Dooley SW, Hutton MD, et al. Outbreak of
multidrug resistant Mycobacterium tuberculosis
infections in a hospital: transmission to patients
with HIV infection and staff. JAMA 1992;268:1280-1286.
The influence of epidemiologic factors on drug
resistance rates in tuberculosis. Am Rev Respir
Riley LW, Arathoon
E, Loverde VD. The epidemiologic patterns of
drug resistant Mycobacterium tuberculosis: a
community-based study. Am Rev Respir Dis 1989;19:1282-1285.
CDC. Drug resistance
among Indochinese refugees with tuberculosis.
Russell BW, Cleary T, et al. The prevalence
of tuberculosis and drug resistance among Haitians.
N Engl J Med 1982;307:162-165.
tuberculosis in an urban high school
Oregon. MMWR 1980;29:194-196.
North Carolina. MMWR 1987;35(51,52):785.
- CDC. Outbreak of multidrug
resistant tuberculosis Texas, California,
and Pennsylvania. MMWR 1990;39(22):369.
Reeves R, Blakey
D, Snider DE Jr., Farer LS. Transmission of
multiple drug-resistant tuberculosis: report
of a school and community outbreak. Am J Epidemiol
Chaves AD, Lyons JA, et al. Primary drug-resistant
tuberculosis: report of an outbreak. N Engl
J Med 1970;283:1353.
outbreak of drug resistant tuberculosis involving
children California, Montana, Nevada,
Utah. MMWR 1983;32:516-518.
Fischl M, Uttamchandani
RB, Daikos GL, et al. An outbreak of tuberculosis
caused by multiple-drug resistant tubercle bacilli
among patients with HIV infection. Ann Intern
Fischl M, Daikos
GL, Uttamchandani RB, et al. Clinical presentation
and outcome of patients with HIV infection and
tuberculosis caused by multiple-drug resistant
bacilli. Ann Intern Med 1992;117:184-190.
of multidrug resistant tuberculosis among immunocompromised
persons in a correctional system New
York, 1991. MMWR 1992;41:507-509.
Jarvis WR, Martone WJ. Multidrug resistant tuberculosis
(editorial). Ann Intern Med 1992;117:257-258.
Geiter LJ, Simone PM. The multidrug resistant
tuberculosis challenge to public health efforts
to control tuberculosis. Public Health Rep 1992;107:616-625.
Greifinger RB, Papania M, et al. Multidrug-resistant
tuberculosis in the New York State prison system,
1990-1991. J Infect Dis 1994;170:151-156.
Richards SB, Kovacovich J, Greifinger RB, Crawford
JT, Dooley SW. Outbreak of multidrug-resistant
tuberculosis in a New York State prison, 1991.
Am J Epidemiol 1994;140(2):113-122.
Dobkin J. Resurgent tuberculosis in New York
City. Human immunodeficiency virus, homelessness
and the decline of tuberculosis control programs.
Am Rev Respir Dis 1991;144:745-749.
therapy for tuberculosis in the era of multidrug-resistance:
recommendations of the Advisory Council for
the Elimination of Tuberculosis. MMWR 42(RR-7):1-8.
Thoracic Society/CDC. Treatment of tuberculosis
and tuberculosis infection in adults and children.
Am J Respir Crit Care Med 1994;149:1359-1374.
Madsden LA. Drug-resistant tuberculosis. Clin
Chest Med 1989;10:341-353.
Goble M. Drug
resistant tuberculosis. Semin Respir Infect
Adverse effects of antituberculosis drugs. Drugs
Davidson PT. Tuberculosis II: toxicity and intolerance
to antituberculosis drugs. Drug Ther 1974:39-43.
The antimycobacterial drugs. Semin Respir Med
Madsden LA, Goble M, Pomerantz M. Surgical intervention
in the treatment of pulmonary disease caused
by drug resistant Mycobacterium tuberculosis.
Am Rev Respir Dis 1990;141:623-625.
CDC. The use
of preventive therapy for tuberculous infection
in the United States: recommendations of the
Advisory Committee for the Elimination of Tuberculosis.
of persons exposed to multidrug-resistant tuberculosis.
for preventing the transmission of Mycobacterium
tuberculosis in health-care facilities, 1994.
MMWR 1994;43(No. RR-13):1-132.