Treatment of 171 Patients with Pulmonary

Tuberculosis Resistant to Isoniazid and Rifampin

Marian Goble, Michael D. Iseman, Lorie A. Madsen, Dennis Waite, Lynn
Ackerson, and C. Robert Horsburgh
ABSTRACT
Background and Methods The frequency of infection with multidrug-resistant

Mycobacterium tuberculosis is increasing. We reviewed the clinical

courses of 171
patients with pulmonary disease due to M. tuberculosis

resistant to rifampin and
isoniazid who were referred to our

hospital between 1973 and 1983. The patients'
records were analyzed

retrospectively. Their regimens were selected individually and

preferably included three medications that they had not been

given previously and to
which the strain was fully susceptible.


Results The 171 patients (median age, 46 years) had previously

received a median
of six drugs and shed bacilli that were resistant

to a median of six drugs. Thus, their
regimens were frequently

not optimal. Of 134 patients with sufficient follow-up data,

87 (65 percent) responded to chemotherapy (as indicated by negative

sputum
cultures for at least three consecutive months); 47 patients

(35 percent) had no
response, as shown by continually positive

cultures. The median stay in the hospital
was more than seven

months. In a multivariate analysis, an unfavorable response

was significantly associated with a greater number of drugs

received before the
current course of therapy (odds ratio, 4.0;

95 percent confidence interval, 1.6 to 9.9;
P<0.001) and

with male sex (odds ratio, 2.5; 95 percent confidence interval,

1.1 to
6.2; P<0.03). Twelve of the patients with responses

subsequently had relapses. The
overall response rate was 56

percent over a mean period of 51 months. Of the 171
patients,

63 (37 percent) died, and 37 of these deaths were attributed

to tuberculosis.


Conclusions For patients with pulmonary tuberculosis that is

resistant to rifampin and
isoniazid, even the best available

treatment is often unsuccessful. Only about half of
such patients

eventually have negative sputum cultures despite carefully selected

regimens administered for extended periods. Failure to control

this resistant infection
is associated with high mortality and

ominous implications for the public health.



Modern chemotherapy, appropriately prescribed and administered,

cures 98 to 99 percent of
cases of previously untreated pulmonary

tuberculosis if the disease is caused by drug-
susceptible Mycobacterium

tuberculosis
1
. Tubercle bacilli not previously exposed to
antituberculosis

drugs may manifest drug resistance as a result of random mutation
2
.

Whereas
such resistance can be overcome by appropriate multiple-drug

regimens, inadequate
antimicrobial therapy can lead to the emergence

of drug-resistant strains. These resistant
bacilli can in turn

be passed on to previously uninfected persons, who may subsequently

contract tuberculosis that is initially drug-resistant. Early

in the chemotherapeutic era, 1 to 3
percent of patients were

noted to have drug-resistant organisms, typically resistant

to a single
drug
3,4
. During the period 1982 through 1986, however,

8.8 percent of previously untreated
patients in the United States

were excreting M. tuberculosis resistant to at least one
antituberculosis

drug, and 23 percent of previously treated patients were shedding

tubercle
bacilli resistant to one or more medications
5
.



The majority of cases of resistance involve resistance to isoniazid

and streptomycin. Until
recently, resistance to rifampin has

been relatively infrequent
6
. Introduced in the United
States

in 1971, rifampin has been prescribed widely, and resistance

to it has emerged.
Resistance to this drug was found in 0.6

percent of strains from previously untreated patients
and 3.3

percent of strains from previously treated patients in the United

States during the
period 1982 through 1986
5
. Some regions of

the country have a higher prevalence of
resistance
7,8
.


Resistance to rifampin is of extraordinary importance in modern

chemotherapy. Rifampin and
isoniazid are clearly the two most

active antituberculosis drugs. The availability of rifampin

allows successful and well-tolerated treatment in patients with

organisms resistant to
isoniazid, streptomycin, or other agents
9,10,11,12
.

However, when resistance to rifampin occurs
in the presence

of resistance to isoniazid, the prospects for successful chemotherapy

are
greatly diminished
6
. In the United States, several outbreaks

of tuberculosis due to strains
resistant to isoniazid, rifampin,

and other agents have recently been reported, in both patients

with and patients without infection with the human immunodeficiency

virus (HIV)
13,14,15
.


We present here our experience in treating a large series of

patients with pulmonary
tuberculosis resistant to both rifampin

and isoniazid, and we discuss factors influencing
outcomes and

the implications for both the individual patient and the future

of tuberculosis
control.


Methods
The records of 231 patients hospitalized at our institution

between January 1, 1973, and
December 31, 1983, with pulmonary

tuberculosis due to drug-resistant M. tuberculosis were
reviewed

retrospectively. All 171 patients shedding M. tuberculosis resistant

to rifampin are
discussed in this report. One of us was actively

involved in the direct care of these patients at
the center

during the entire study period.


Susceptibility testing of all M. tuberculosis strains was performed

in our laboratory on 7H11
agar according to standard proportionality

techniques
2
. Resistance was indicated by the
growth of more

than 1 percent of the colonies on drug-containing medium, as

compared with
growth on drug-free (control) medium (Table 1).

A drug was designated as "previously
unused" if given for less

than three months. Individually tailored regimens
16,17
were

selected
for the patients on the basis of the results of in

vitro susceptibility tests and the limited
previous use or the

nonuse of the drugs. The drugs and the dosages used are listed

in Table 1.
When possible, we administered three drugs not given

previously to which the tubercle bacilli
were fully susceptible

at the lowest concentration tested in vitro, including one parenteral

agent (an aminoglycoside or polypeptide) and two oral agents

that met these criteria. Since
many patients did not have such

a regimen available to them, we also used drugs to which the

organisms were at least partially susceptible (no growth at

the higher concentrations tested, or
2 to 33 percent of control

value for growth at the lowest concentration) or drugs previously

given for a relatively short time; because of a lack of confidence

in the full efficacy of drugs
so selected, more than three medications

were included in these regimens. The 171 patients
received a

median of four drugs; 32 patients received six or more drugs.


View this
table:
Table 1. Concentrations of Drugs Tested and Dosages Administered in 171
Patients with Tuberculosis.
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To ensure compliance, nurses observed the patients while they

took their medications.
Ethionamide, pyrazinamide, aminosalicylic

acid (para-amino salicylate), and cycloserine
were given in

divided doses to increase drug tolerance. Great efforts were

made to continue
therapy even if adverse drug reactions other

than those considered life-threatening occurred.
Patients usually

remained in the hospital until a series of sputum cultures remained

negative
for at least three months or until treatment failure

was evident after at least three months of
therapy, as shown

by continually positive sputum cultures. Success was indicated

by three
consecutive months of consistently negative cultures.

While the patients were hospitalized,
spontaneous or induced

sputum specimens were examined every one to two weeks by
fluorochrome

staining of the concentrated specimen and culture on 7H11 agar

and
Lowenstein-Jensen medium. If patients resumed shedding tubercle

bacilli after their cultures
had been negative for three consecutive

months, they were considered to have relapsed,
whether or not

they were still receiving therapy. After hospitalization, they

returned to the
care of the referring physician or agency, with

the recommendation that oral
antimycobacterial therapy should

continue for at least two years after the last positive culture

and that injectable antibiotics be given for four to six months

after the initial date of culture
conversion.


For this analysis, data on all 171 patients were reviewed, including

identifying information,
potential risk factors (alcoholism,

bronchopleural fistula, cancer, diabetes, emphysema,
fungal

disease, gastrectomy, use of immunosuppressive drugs, interstitial

lung disease, lung
surgery, and silicosis), previous therapy

with drugs given for at least three months, the
referring agency's

assessment of compliance, the results of in vitro susceptibility

testing by
direct or indirect methods of isolates obtained before

the start of the new regimen,
antituberculosis drugs initially

administered at our hospital, drugs discontinued because of

adverse effects, and the results of pretreatment smears and

cultures and of the first sputum
smear and culture obtained

during each month of therapy. Adverse drug reactions not
requiring

the permanent discontinuation of a drug were not tabulated.

In many cases, follow-
up information was obtained from questionnaires

sent to the physicians last known to be
caring for the patients.


Statistical Analysis
To test for relations between outcome and each of several possible

predictor variables, odds
ratios with 95 percent confidence

intervals were calculated separately for each variable
18
.
When

a variable had more than two categories, the odds ratio was

calculated with respect to
the lowest (reference) category.

All these variables were entered into a stepwise logistic-
regression

model with use of SAS software with the Proc Logistic procedure
19
.

The survival
distribution was estimated with the Kaplan-Meier

method in the SAS Proc Lifetest. This
method includes the information

on the subjects who were lost to follow-up or who died of
causes

other than tuberculosis during the time they were observed.


Results
Demographic Characteristics
The 171 patients with drug-resistant pulmonary tuberculosis

were referred from 37 states and
5 foreign countries after treatment

by physicians in their own communities had failed. Forty-
eight

were women, and 123 were men; their ages ranged from 17 to 79

years (median, 46).
Ninety-six were white, 26 black, 29 Hispanic,

17 Asian, and 3 Native American.


Disease Characteristics
The patients had had tuberculosis for a median of 6 years (range,

1 to 39) and had received a
median of 6 antituberculosis drugs

(range, 2 to 11) before coming to our institution: 167 had
previously

received isoniazid, 163 rifampin, 163 ethambutol, 137 streptomycin,

107
pyrazinamide, 93 aminosalicylic acid, 76 cycloserine, 68

ethionamide, 47 capreomycin, 41
kanamycin, 17 viomycin, and

2 amikacin. The disease generally was advanced; 144 patients

(84 percent) had bilateral disease with at least one cavity,

and 126 (74 percent) had one or
more organisms per field (x40)

in concentrated sputum smears. All patients were shedding
tubercle

bacilli with resistance to a median of six drugs, including

rifampin (Figure 1). All
strains but one were also resistant

to isoniazid; this strain occurred in a patient with severe

toxic reactions that precluded the use of isoniazid.



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Figure 1. Drug Resistance of M. tuberculosis in 171
Patients on Admission.


Emergence of Resistance to Rifampin
In 119 (70 percent) of the 171 patients with rifampin-resistant

tubercle bacilli, the acquisition
of the resistance was apparently

associated with irregular administration of medications
(which

was due in 74 cases to documented noncompliance and in 12 to

adverse reactions to
medications), the administration of rifampin

as the single effective agent, or both factors. In
43 cases,

rifampin was added as a single drug to a failing regimen. In

16 cases, one new drug,
rifampin, was added when treatment was

resumed after noncompliance; in 2 cases, patients
with tubercle

bacilli initially resistant to isoniazid were treated with a

regimen of only
isoniazid and rifampin.


A less common factor was poor absorption of medications, which

probably contributed to the
emergence of resistance to rifampin

in two additional patients who had previously undergone
abdominal

surgery (ileocolostomy in one and gastrojejunostomy in the other).

Other factors
that may have contributed to the emergence of

resistance in 18 other patients included very
extensive tuberculosis

(12 patients), bronchopleural fistula (3), diabetes mellitus

(2), and
gastrectomy (1). During their initial medical encounter

before referral to our center, three
patients presented with

organisms already resistant to rifampin, including two nurses

who
presumably acquired these organisms from patients for whom

they were caring. Factors
relating to the emergence of resistance

to rifampin could not be identified in 29 patients.


Duration of Hospitalization
The median stay in the hospital was 7.3 months for patients

whose treatment was successful
and 7.8 months for those whose

treatment failed.


Adverse Reactions
Fifty-one (30 percent) of 171 patients had adverse reactions

that led to the discontinuation of
one or more antimycobacterial

medications (Table 2). Twenty of these patients had serious

toxic reactions to one or more drugs during the first three

months of therapy.


View this table:
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Table 2. Drug Toxicity Leading to Withdrawal of Treatment.


Adjunctive Surgery
Nine patients underwent surgical procedures as an adjunct to

their antituberculosis
chemotherapy. Three patients underwent

right upper lobectomy, two left upper lobectomy,
and two left

pneumonectomy. The sputum cultures of all of these seven subsequently

became
negative. (Two patients had consistently negative cultures

before surgery and were
considered to have responded to chemotherapy,

three had decreases in the number of tubercle
bacilli in their

sputum, and two had no bacteriologic response to chemotherapy

alone.) The
cultures of the two other patients remained positive;

one patient underwent surgery to
collapse a left-upper-lobe

cavity with paraffin plombage, and in the other patient an Eloesser

flap was created for drainage. The only surgical complication

was a bronchopleural fistula,
which resolved spontaneously by

two months after the operation.


Exclusions from the Outcome Analysis
Of the 171 patients, 37 were excluded from the analysis of the

outcome of chemotherapy for
the following reasons: 8 died after

receiving therapy for two months or less; 22 were lost to
follow-up

before they were observed long enough during chemotherapy; 3

did not meet the
criterion of three months of negative sputum

cultures before surgical resection, although they
had had favorable

responses; 1 deferred definitive therapy because of pregnancy;

and 3 had
had no positive cultures within the month before therapy

started.


Outcomes of Chemotherapy
One hundred thirty-four patients were eligible for the analysis

of the outcomes of
chemotherapy. The sputum cultures of 87 of

these patients (65 percent) became negative. The
interval from

the beginning of therapy to the first of a series of negative

cultures ranged from
one to eight months (median, two). Treatment

failure, defined as the inability of
chemotherapy to sterilize

cultures, occurred in 47 patients (35 percent). Of the 87 patients

who originally had negative cultures, 12 (14 percent) had relapses

5 to 62 months after the
initiation of therapy, and 9 of these

12 had relapses within the first 2 years. Overall, 75
patients

(56 percent) remained free of disease throughout a mean follow-up

period of 51
months (range, 10 to 167), and 59 patients (44

percent) had unfavorable outcomes.


Deaths
Death due to tuberculosis occurred in 27 of the 59 patients

(46 percent) with treatment failure
or a relapse. The mean interval

from the initial diagnosis to death was 11 years (median, 13),

and the mean age at death was 52 years (range, 26 to 74). Four

other patients with treatment
failure died of causes unrelated

to tuberculosis. Of the 87 patients with successful treatment,

15 died during the follow-up period; 13 died of causes not related

to tuberculosis, and 2 died
of undetermined causes. The estimated

survival of the patients who could be evaluated and
for whom

the cause of death was known is shown in Figure 2. Among the

37 patients
excluded from the analysis of the outcomes of chemotherapy,

10 (27 percent) died of
tuberculosis and 7 (19 percent) died

of other causes during the follow-up period. Thus, a total
of

63 of the 171 patients died.



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Figure 2. Survival of 134 Patients with Tuberculosis
Resistant to Isoniazid and Rifampin, from the Initiation
of Study Therapy to Death or the Most Recent Follow-
up Examination.
Successful treatment was indicated by consistently
negative sputum cultures for three consecutive months,
and relapse by the resumption of shedding of tubercle
bacilli; patients with relapses are included among those
with successful treatment. Treatment failure was
indicated by an inadequate response to at least three
months of therapy. The events represented are deaths
due to tuberculosis.

Factors Influencing Outcome
In univariate analyses, four factors were associated with the

failure of drug therapy to sterilize
sputum cultures: previous

administration of more drugs, regimens including fewer previously

unused drugs, in vitro resistance to more drugs, and male sex

(this factor was marginally
associated with failure) (Table 3).

When all the factors were included in a multivariate model,

only sex (odds ratio, 2.5; 95 percent confidence interval, 1.1

to 6.2) and the number of drugs
received previously (odds ratio,

4.0; 95 percent confidence interval, 1.6 to 9.9) were
significantly

associated with treatment failure (P<0.03 and P<0.001,

respectively).


View this Table 3. Predictors of Outcome of Chemotherapy in 134 Patients with
table:
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Pulmonary Tuberculosis Resistant to Isoniazid and Rifampin.


Many regimens were employed. The most frequently used regimens

consisted of
combinations of pyrazinamide, ethionamide, cycloserine,

and aminosalicylic acid with one of
the injectable aminoglycoside

or polypeptide antimicrobial agents. Because of the small
numbers

of patients in each group, the efficacy of individual regimens

could not be analyzed.


Discussion
Treatment of patients with pulmonary tuberculosis due to M.

tuberculosis resistant to
rifampin, isoniazid, and other medications

is complicated, risky, and of limited efficacy. Fully
46 percent

of our patients with treatment failure or relapses died. Physicians

and society must
recognize that multidrug-resistant tuberculosis

is an ominous, deadly disease.


Patients who are treated unsuccessfully but remain alive pose

a major public health problem.
They must be isolated because

of the risk of transmitting virtually untreatable drug-resistant

disease. Drug-resistant tubercle bacilli were once believed

less likely to be spread to contacts
because the virulence of

these organisms was diminished. However, a recent report
20

demonstrated

that rates of infection (as detected with the tuberculin skin

test) among contacts
of patients with drug-resistant tuberculosis

were comparable overall to those among
susceptible persons.

In fact, because of their prolonged shedding of tubercle bacilli,

previously treated patients with drug resistance had higher

numbers of tuberculin-positive
contacts than patients without

resistance. Epidemics have been reported in which disease,
including

fatal meningitis and highly destructive lung disease, has evolved

among persons
infected with these drug-resistant microbes
13,14,15,21,22,23
.

Quarantine of patients with treatment
failure in their homes

is a potential remedy but is seldom achievable. Confinement

of patients
may protect others, but they must then bear the

additional burdens of isolation and
stigmatization.


Because the number of drugs available was limited, our regimens

for retreatment frequently
entailed the use of agents known

to be toxic or difficult to tolerate. When side effects
occurred

that were not potentially life-threatening and substitution

of another medication was
not feasible, we made great efforts

to coach the patient through the drug intolerance, using
both

symptomatic palliation and psychological support. This required

familiarity with each of
the medications, as well as a great

deal of time in giving care. Nonetheless, our success rate
(65

percent) in treating disease due to multidrug-resistant isolates

was less favorable than the
rates in some earlier series of

patients given retreatment in the pre-rifampin era
24,25,26
.

The
poorer results in the current study may be due to the larger

number of drugs to which the
isolates from our patients were

resistant.


In our study an unsuccessful response to the therapy prescribed

was strongly associated with
a greater number of drugs received

previously and with male sex. The reason for the
association

with male sex is not readily apparent, but it may be related

to behavioral as well as
biologic factors. The association with

previous treatment with a greater number of drugs
emphasizes

the importance of thoroughly studying the patient's treatment

history. Suboptimal
previous therapy leads to the development

of in vitro resistance. Thus, if the patient has
already received

a large number of drugs, few agents will still be available

to which the
isolate will be susceptible, and the chances for

successful outcome decline.


However, some patients received drugs to which their organisms

were susceptible according
to conventional testing, yet they

did not respond clinically. This suggests that improved
methods

of susceptibility testing are needed to provide more useful

laboratory guidelines for
retreatment regimens. We are currently

exploring the use of the rapid radiometric system
(Bactec) to

determine minimal inhibitory concentrations
27,28
-- values that

we anticipate will
replace the traditional "critical concentration"

determined in solid agar.


Surgical resection as an adjunct to antituberculosis therapy

was performed in patients who
had amenable lesions and who were

being treated with medical regimens deemed unlikely to
effect

permanent control of their disease. We attempted to schedule

surgery so that it could be
performed when the mycobacterial

count in sputum reached its expected nadir. Three patients
with

indeterminate responses to medical therapy and two without bacteriologic

responses to
chemotherapy were clearly helped by resection.

In the other two patients, whose sputum
cultures had already

become negative, the benefit of surgery was less clear.


When rifampin was introduced in 1971, it represented a major

advance in antituberculosis
treatment, leading to both short-course

chemotherapy
1
and highly effective, well-tolerated
management

of tuberculosis due to isoniazid-resistant organisms
10
. However,

as anticipated,
29

resistance to rifampin has emerged in substantial

numbers of patients, frequently in
association with the previous

use of rifampin in an inadequate regimen and with
noncompliance.

Noncompliance contributed to the development of resistance to

rifampin in
74 of our patients (43 percent of this series of

171 patients), and was suspected in many more.
Noncompliance

with prescribed treatment is extremely common
30
. The most effective

safeguard is the directly observed administration of medications.

The treatment of patients
with multidrug-resistant tuberculosis

entails five to seven visits per week. The cost of
retreatment

of patients in whom treatment fails and resistance to rifampin

emerges should be
considered when the economics of a tuberculosis-control

program are being evaluated
31
. Our
very limited rates of success

in treating multidrug-resistant disease raise serious concerns

about the future of tuberculosis control. If we, with all our

resources, can successfully treat
less than 60 percent of such

patients, what will happen in less ideal circumstances? To avoid

squandering the potential effectiveness of rifampin because

of noncompliance or inept
prescribing, systematic efforts are

required to preserve the potency of this crucial drug against

tuberculosis.


This report includes patients first seen between 1973 and 1983.

Thus, it is likely that few, if
any, of these patients were

infected with HIV. However, many patients who have contracted

multidrug-resistant tuberculosis have HIV infection
14,15
; their

response to treatment appears to
be very poor, with high rates

of treatment failure and mortality
32
. Their response to
antituberculosis

therapy may be suboptimal, even when the organisms are susceptible

to the
drugs used
33,34
. Thus, although we recommend similar

strategies for the therapy of drug-
resistant tuberculosis whether

or not it accompanies HIV infection, the efficacy of such
therapy

in patients with HIV remains to be determined. New antimycobacterial

agents are
urgently needed to expand our therapeutic options

for multidrug-resistant tuberculosis.