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Outcomes of Patients With

Multidrug-Resistant Pulmonary Tuberculosis


Treated With
Ofloxacin/Levofloxacin-Containing Regimens
*
Wing Wai Yew, Chi Kuen Chan, Chi Hung Chau, Cheuk Ming Tam, Chi
Chiu Leung, Poon Chuen Wong and Joseph Lee
Chest 2000;117;744-751
DOI 10.1378/chest.117.3.744
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2000 American College of Chest Physicians

Outcomes of Patients With


Multidrug-Resistant Pulmonary
Tuberculosis Treated With Ofloxacin/
Levofloxacin-Containing Regimens*
Wing Wai Yew, MB, FCCP; Chi Kuen Chan, MB; Chi Hung Chau, MB;
Cheuk Ming Tam, MB, FCCP; Chi Chiu Leung, MB;
Poon Chuen Wong, MB, FCCP; and Joseph Lee, MB, FCCP

Objective:To analyze outcomes of patients with multidrug-resistant tuberculosis (MDR-TB)


treated with ofloxacin/levofloxacin-containing regimens.
Materials and methods:From February 1990 through June 1997, 63 MDR-TB patients (with bacillary
resistance to at least isoniazid and rifampin in vitro) were analyzed retrospectively. Twenty-two
patients (34.9%) had had no previous antituberculosis chemotherapy. Each patient received either
ofloxacin (53) or levofloxacin (10) even though 13 patients had bacilli resistant to ofloxacin in vitro.
The other accompanying drugs mainly included aminoglycosides, cycloserine, ethionamide/prothionamide, and pyrazinamide. Sputum smear and culture examinations for acid-fast bacilli (AFB) were
performed monthly for the initial 6 months and then at 2- to 3-month intervals until the end of
treatment. Comparison was made between clinical successes and failures using univariate and
multiple logistic regression analyses for the following variables: age, sex, presence of cavitation, extent
of disease, sputum smear positivity, in vitro resistance to ofloxacin, in vitro resistance to streptomycin
and/or ethambutol, treatment adherence, and the number of drugs per regimen.
Results:Fifty-one patients (81.0%) were cured, nine patients (14.3%) failed, and three patients (4.7%)
died. For the entire group, the mean duration of treatment was 14.0 months, and the mean number
of drugs was 4.7. Mean durations of chemotherapy in successful and failed patients were 14.5 and
14.2 months, respectively. Mean time for sputum smear and culture conversions were 1.7 and 2.1
months, respectively. Only cavitation, resistance to ofloxacin, and poor adherence were found to be
variables independently associated with adverse outcomes (p < 0.05; odds ratios 15.9, 13.5, 12.8,
respectively). Negative sputum cultures after 2 and 3 months of therapy were 100% predictive of
cure. Positive sputum cultures after 2 and 3 months were 52.3% and 84.6% predictive of failure,
respectively. One patient (2.1%) relapsed after apparent cure. Twenty-five patients experienced
adverse drug reactions, but only 12 of them needed drug modifications.
Conclusion:Most MDR-TB patients can be treated effectively with ofloxacin/levofloxacin-containing
regimens. Presence of cavitation, resistance to ofloxacin in vitro, and poor adherence to therapy
portend treatment failure. Monitoring monthly sputum culture for AFB in the initial months of
chemotherapy helps predict clinical outcomes.
(CHEST 2000; 117:744 751)
Key words: multidrug resistance; ofloxacin/levofloxacin; tuberculosis
Abbreviations: AFB acid-fast bacilli; MDR-TB multidrug-resistant tuberculosis; MIC minimum inhibitory concentration; TB tuberculosis

were found to have good in


T hevitrofluoroquinolones
activity against Mycobacterium tuberculosis
in the 1980s.15 Subsequent observations have sug*From the Tuberculosis and Chest Unit, Grantham Hospital
(Drs. Yew, Chau, Wong, and Lee), and the Tuberculosis Service,
Department of Health, Wanchai Chest Clinic (Drs. Chan, Tam,
and Leung), Hong Kong, China.
Presented in abstract form at the 1999 Annual Congress of the
European Respiratory Society at Madrid, Spain.
Manuscript received May 11, 1999; revision accepted October 5, 1999.
Correspondence to: Wing Wai Yew, MB, FCCP, Tuberculosis and
Chest Unit, Grantham Hospital, 125 Wong Chuk Hang Rd, Hong
Kong, China

gested in vivo efficacy.6 11 Thus, incorporation of


fluoroquinolones in second-line regimens for the management of multidrug-resistant tuberculosis (MDRTB) has been recommended by many authorities,
including the World Health Organization.1214 Despite
this, there is still a dearth of evidence on the role of
fluoroquinolones in the management of MDR-TB.13
Randomized, controlled clinical trials on MDR-TB are
difficult to conduct and have additional ethical constraints. We therefore performed a retrospective analysis of a cohort of MDR-TB patients treated with
fluoroquinolone-containing regimens in the 1990s. We

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2000 American College of Chest Physicians

hoped to evaluate the overall contribution of fluoroquinolones to the therapy of MDR-TB and the optimal
duration of such treatment.
The fluoroquinolones studied were ofloxacin and
levofloxacin. The former has been used by us for
treatment of MDR-TB since the late 1980s.7,9 More
recent observations suggest in vitro activity of levofloxacin (active S-() enantiomer of ofloxacin)
against M tuberculosis, although cross-resistance has
also been demonstrated.15,16 This superior in vitro
activity, in addition to clinical data suggesting that
levofloxacin causes less neurotoxicity,17 resulted in a
preference for levofloxacin in the later part of this
study.
Materials and Methods
Data Collection
The inpatient and outpatient medical records of 79 patients
with MDR-TB were reviewed. These patients had been admitted
to Grantham Hospital, a tertiary referral center for tuberculosis
(TB), from chest clinics under the administration of the Department of Health in Hong Kong between February 1990 and June
1997. All 79 patients were seronegative for the HIV antibody by
the enzyme-linked immunosorbent assay. M tuberculosis was
identified by sputum culture or by both smear and culture. In
vitro drug susceptibility indicated resistance to at least isoniazid
and rifampin. Sixteen patients were excluded from the analysis
for various reasons described below. Thus, 63 patients were
available for evaluation. The details of demographic data, clinical
characteristics, chemotherapy, adverse reactions to drugs, and
follow-up assessment as well as regular sputum bacteriology and
chest radiography results were recorded.
Drug Susceptibility Tests
The drug susceptibility tests were performed using the absolute minimum inhibitory concentration (MIC) method for isoniazid and the resistance-ratio method for all other drugs.18 The
inoculum size was standardized by suspending 2 mg of M
tuberculosis organisms in 0.4 mL of sterile distilled water,
followed by plating one loopful of organisms onto the Lowenstein-Jensen medium. Growth was defined as the presence of
20 colonies at the end of 4 to 6 weeks. The resistance ratio was
defined as the minimum concentration inhibiting the growth of
the test strain divided by the minimum concentration inhibiting
the growth of the standard susceptible H37Rv strain in the same
set of tests. A resistance ratio of 2 was defined as susceptible
and one of 4 to 8, as resistant. For streptomycin, rifampin,
ethambutol, pyrazinamide, ethionamide, kanamycin, ofloxacin,
cycloserine, and p-aminosalicylic acid, the usual MICs for H37Rv
in different batches were 4 to 8 mg/L, 4 to 8 mg/L, 1 to 2 mg/L,
25 to 50 mg/L, 10 to 20 mg/L, 4 to 8 mg/L, 0.63 to 1.25 mg/L, 10
to 20 mg/L, and 0.25 to 0.5 mg/L, respectively. For isoniazid, an
absolute MIC 0.2 mg/L was used as the break point for
susceptibility. Drug susceptibility studies were not performed for
amikacin, amoxicillin-clavulanic acid, clofazimine, or levofloxacin.
Design of Chemotherapy Regimens and Drug Administration
All 63 patients in the main analysis received a fluoroquinolone,
either ofloxacin or levofloxacin. The choice was based on the

preference and experience of the physician initiating therapy.


The other accompanying drugs included aminoglycosides (kanamycin, streptomycin, or amikacin), ethionamide/prothionamide,
cycloserine, pyrazinamide, ethambutol, p-aminosalicylic acid,
amoxicillin-clavulanic acid, and clofazimine; these were largely
selected on the basis of results of in vitro susceptibility tests.
After discharge from the hospital, patients continued to receive
directly observed treatment, by clinic staff in most cases and by
family members in a small number.
Monitoring of Sputum Bacteriology and Definitions of
Outcomes
After the pretreatment sputum smear and culture, each patient
had sputum evaluated monthly for 6 months. After that, the
sputum was evaluated every 2 or 3 months, at the discretion of
the attending physician. Success or cure was defined as sustained
bacteriologic conversion of sputum culture of AFB from positive
to negative for at least 6 consecutive months during therapy and
after its cessation. Temporary conversion of sputum culture to
negative not meeting the above was labeled as failure; so was the
absence of sputum culture conversion to negative throughout
treatment.
Statistical Analysis
Data were expressed in means SD and ranges. In identification of variables that might affect treatment outcomes, namely,
age, male sex, presence of cavitation, extensive disease, sputum
smear positivity, in vitro resistance to ofloxacin, in vitro resistance to streptomycin and/or ethambutol, poor adherence, and
the number of drugs used, comparison of the success and failure
or death groups was made using Students independent samples
t tests for numeric variables and 2 test for categoric variables.
Where an expected value in a certain cell in a contingency table
was 5, the Fishers Exact Test was used. A p value 0.05 was
considered significant. A multiple logistic regression analysis was
then performed to identify the variables that were independently
associated with adverse outcomes of chemotherapy.

Results
Patients Excluded
Sixteen patients were excluded because they received treatment for 6 months. Two patients left
against medical advice and did not receive any
chemotherapy. Another two patients succumbed before chemotherapy could be initiated; they had
severe COPD and carcinomatosis. Three patients
died of diseases other than TB: the first was a
72-year-old man who died of chronic renal failure
after 5 months of drug treatment. Sputum smear and
culture for AFB had converted from positive to
negative after 1 month of treatment. The second was
a 66-year-old man who died of acute myocardial
infarction. Sputum smear and culture for AFB had
become negative after 2 months of therapy. The
third was a 61-year-old man who died suddenly of
cerebrovascular accident after he had received 4
months of chemotherapy. Sputum smear and culture
for AFB were still positive. Three more patients who
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745

did not receive fluoroquinolone-containing drug regimens were also excluded. Each of these three
patients had bacilli resistant to ofloxacin. They received a mean of 4.3 0.6 drugs (range, 4 to 5
drugs), and only one of them achieved treatment
success. Finally, six more patients abandoned treatment after they had received chemotherapy for 6
months (2.8 1.6 months; range, 1 to 5 months).
Demographic and Clinical Characteristics
Sixty-three patients were included in the final
analysis. Sixty-two were Chinese and one was British.
Forty-seven (74.6%) were male, and 16 (25.4%)
were female. Mean age was 45.2 16.0 years
(range, 12 to 77 years). Mean body weight was
51.4 8.8 kg (range, 29 to 73 kg). All had radiographic and bacteriologic evidence of pulmonary TB.
Two patients had extrapulmonary involvement: meningitis and spondylitis. Concomitant medical diseases
were present in 23 patients (36.5%). These included
COPD, hypertension, diabetes mellitus, hyperlipidemia, and chronic viral or alcoholic liver diseases.
Forty-one patients (65.1%) had previous therapy.
The mean number of previous treatment courses was
2.0 1.4 (range, 1 to 5). Each treatment course
lasted 4 weeks. Thus, 34.9% of patients had initial
resistance to isoniazid and rifampin (with or without
associated resistance to streptomycin and/or ethambutol), whereas 65.1% of patients may have acquired
resistance to the aforementioned drugs. A comparison of the various characteristics of the patients
included in and those excluded from the final analysis is presented in Table 1. There are no significant
differences, except that the excluded patients were
older.
Drug Regimens and Durations
As a group, all patients included in the final
analysis received a mean of 4.7 0.7 drugs (range, 3
to 6 drugs) on commencement of therapy. Ofloxacin
was used in 53 patients and levofloxacin in 10
patients. The other common drugs in the regimens
included aminoglycosides, ethionamide/prothionamide,
cycloserine, pyrazinamide, and ethambutol (Table
2). The fluoroquinolone was administered until cessation of chemotherapy in all 63 patients. Aminoglycosides were usually administered for 3 to 6 months
depending on tolerance. The duration of therapy
with other agents was tailored to patient tolerance
and individual physician judgment. The minimum
duration of therapy for patients who responded
microbiologically was 1 year. The variables considered at discontinuation of treatment included time of
sputum smear and culture conversion, extent of
radiographic disease and rapidity of improvement,

Table 1Comparison of Demographic, Clinical, and


Bacteriologic Characteristics Between Patients
Included in and Excluded From Analysis*
Patients
Included
(N 63)

Characteristic
Sex (M:F)
Age, yr
Body weight, kg
Previous treatment (lots)
Comorbidities
Extensive disease
Cavity
Positive sputum smear
Resistance to first-line
drugs, n
Resistance to ofloxacin

Patients
Excluded
(N 16)

p
Value

47:16
45.2
51.4
1.3
22 (34.9%)
34 (54.0%)
32 (50.8%)
57 (90.5%)
3.3

13:3
61.8
48.4
1.4
6 (37.5%)
10 (62.5%)
11 (68.8%)
15 (93.8%)
3.2

NS
0.01
NS
NS
NS
NS
NS
NS
NS

13 (20.6%)

4 (25.0%)

NS

*NS not significant.


Total radiographic extent greater than one lung.
With reference to (isoniazid and rifampin) (streptomycin and/or
ethambutol).

rapidity and completeness of closure of cavities,


extent of drug resistance in vitro, presence of diabetes mellitus or silicosis, and extrapulmonary disease.
Presence of unfavorable variables prompted the
decision to prolong therapy beyond 1 year. Patients
who had not responded microbiologically after 9 to
12 months of chemotherapy would have treatment
reviewed. Treatment was stopped then or continued
for a few more months. The mean number of drugs
received by patients at the seventh month was
3.6 0.6 drugs (range, 3 to 5 drugs). Dosages of the
second-line drugs are depicted in Table 3. The mean
duration of chemotherapy in 63 patients was
14.0 3.7 months (range, 0.5 to 24 months). Three
patients died of TB after 0.5, 7, and 7 months of
chemotherapy. Excluding those three patients, the
mean duration of chemotherapy was 14.4 3.1
months (range, 9 to 24 months).
Adherence to Therapy
Fourteen patients (22.2%) had poor adherence to
chemotherapy, which was defined as missing 20%
of the designated number of drug doses. The rest
received 80% of the designated treatment doses.
Outcomes
Fifty-one patients were cured. These included the
two patients with extrapulmonary disease. Their
sputum smear for AFB converted from positive to
negative at a mean of 1.7 1.0 months (range, 1 to
5 months) after chemotherapy commencement.
Their sputum culture converted from positive to
negative at a mean of 2.1 1.2 months (range, 1 to

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2000 American College of Chest Physicians

Table 2Profile of Susceptibility Patterns to Conventional Short-Course Chemotherapeutic Drugs and Treatment
Regimens for 63 Patients With MDR-TB*
First-Line
Drugs

Number of Patients on Second-Line Drugs

Number of Patients
Resistant

O/L

K/S/A

Et/Pt

Cyc

PAS

Aug

Clo

12
9
17
25
63

12
9
17
25
63

10
6
17
25
58

10
5
17
25
57

5
9
11
21
46

7
3
10
14
34

12
0
14
3
29

0
2
0
5
7

0
1
0
3
4

0
1
0
2
3

HR
HRM
SHR
SHRM
Total

*A amikacin; Aug amoxicillin-clavulanic acid; Clo clofazimine; Cyc cycloserine; Et/Pt ethionamide/prothionamide; H isoniazid;
K kanamycin; L levofloxacin; M ethambutol; O ofloxacin; PAS p-aminosalicylic acid; R rifampin; S streptomycin;
Z pyrazinamide.
8 patients received 5 drugs; 4 patients received 4 drugs.
1 patients received 5 drugs; 7 patients received 4 drugs; 1 patient received 3 drugs.
3 patients received 6 drugs; 12 patients received 5 drugs; 2 patients received 4 drugs.
2 patients received 6 drugs; 19 patients received 5 drugs; 4 patients received 4 drugs.

5 months) after starting chemotherapy. The bacteriologic conversion of the successful patients was
sustained. Nine patients failed and three died of TB.
The mean duration of chemotherapy in the 51
successful patients was 14.5 3.0 months (range, 9
to 24 months). Four patients in this group discontinued chemotherapy at their own will after receiving 9
to 11 months of drug treatment. However, all of
them had sputum culture converted to negative at a
mean of 2.3 1.3 months (range, 1 to 4 months)
after initiation of chemotherapy. One patient with
extensive drug resistance received 24 months of
treatment. The mean duration of chemotherapy in

Table 3Dosages of Second-Line Antituberculosis


Drugs Used in 63 Patients With MDR-TB*
Drug

Dosage
645.3 84.5 mg
(600800 mg)
640 84.4 mg
(600800 mg)
735.8 66.7 mg

Ofloxacin
Levofloxacin
Kanamycin/streptomycin/
amikacin

(500750 mg)
800.0 111.8 mg

Kanamycin/streptomycin/
amikacin
Ethionamide/prothionamide
Cycloserine
Pyrazinamde
Ethambutol
p-Aminosalicylic acid
Amoxicillin-clavulanic acid
Clofazimine

(7501000 mg)
728.1 64.8 mg
(500 750 mg)
720.0 82.1 mg
(500750 mg)
1.8 0.3 g
(12 g)
956 339.2 mg
(6001700 mg)
5g
750 mg375 mg
100 mg

Frequency
once daily
once daily
5 times
per week
3 times per
week
once daily
once daily
once daily
once daily
bid
bid
once daily

*Dosage is reported as mean SD, with range in parentheses.

the nine living patients with treatment failure was


14.2 3.4 months (range, 10 to 18 months). Thus,
there was no difference in the durations of chemotherapy between the treatment success and failure
groups (p 0.05).
Of the variables that might be associated with the
treatment outcome, only the presence of cavitation,
resistance to ofloxacin in vitro, and poor adherence
emerged as variables significantly associated with
adverse outcomes (Table 4). When the total number
of drugs used, as well as the number of active drugs
at different junctures of treatment, namely, at commencement, seventh month, and cessation of treatment, was compared by univariate analysis between
the success and failure or death groups, no significant difference was noted. Active drugs referred to
those drugs with activity demonstrated by susceptibility tests in vitro. Further analysis was made after
stratification of patients receiving fluoroquinolones
into those who received ofloxacin (n 53) and levofloxacin (n 10). Forty-three of 53 patients in the
ofloxacin group had bacilli susceptible to ofloxacin,
and 37 achieved treatment success. Among the
remaining 10 patients with bacillary resistance to
ofloxacin, only 5 were cured. In the levofloxacin
group, 7 of 10 patients had bacilli susceptible to
ofloxacin, and all had treatment success with levofloxacin-containing regimens. Of the remaining
three patients with bacillary resistance to ofloxacin,
two were successfully treated with levofloxacin-containing regimens. The three variables independently
associated with adverse outcomes persisted when
multiple logistic regression analysis was applied to
the 53 patients given ofloxacin only (p 0.01 [cavity], p 0.004 [resistance to ofloxacin], p 0.01
[poor adherence]; odds ratios, 17.5, 18.2, and 10.8,
respectively).
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Table 4 Demographic, Clinical, Bacteriologic, and Treatment Characteristics in 63 MDR-TB Patients With
Different Outcomes and Their Comparison by Univariate and Multiple Logistic Regression Analyses*
Treatment Outcomes

Success (n 51)

Variable
Age
Male sex
Presence of cavity
Extensive disease
Positive smear
Resistance to ofloxacin
Resistance to number of
first-line drugs
Poor adherence
Number of drugs used

Failure/Death
(n 12)

Univariate
Analysis
p
Value

Multiple Logistic Regression Analysis


p
Value

Odds
Ratio

95%
Confidence
Interval

45.0 (mean)
37 (72.5%)
22 (43.1%)
26 (51.0%)
45 (88.2%)
7 (13.7%)
3.3 (mean)

46.3 (mean)
10 (83.3%)
10 (83.3%)
9 (75.0%)
12 (100.0%)
6 (50.0%)
3.3 (mean)

NS
NS
0.03
NS
NS
0.01
NS

NS
NS
0.01
NS
NS
0.005
NS

15.9

13.5

1.9135.3

2.283.1

8 (15.7%)
4.7 (mean)

6 (50.0%)
4.9 (mean)

0.02
NS

0.006
NS

12.8

2.179.9

*See footnote of Table 1 for abbreviation.

Adverse Drug Reactions


Twenty-five of the treated patients (39.7%) experienced adverse drug reactions of varying severity.
The most common ones were related to the otovestibular and gastrointestinal systems and the CNS.
Some patients had multiple adverse reactions (Table
5). However, modification of drug regimens was
needed in only 12 patients. Nine of them required
termination of aminoglycoside treatment after a
mean of 3.0 1.6 months (range, 1 to 5 months)
because of otovestibular toxicity or nephrotoxicity.
Five patients had CNS dysfunction, namely, depression (n 3) and seizures (n 2), which necessitated
withdrawal of cycloserine at a mean of 4.0 3.6
months (range, 1 to 9 months). Four patients had
intolerable bloating, nausea, and vomiting that required withdrawal of ethionamide/prothionamide
from the regimen after a mean of 4.0 3.6 months
(range, 1 to 9 months). Two patients had pyrazinamide withdrawn after 3 months of therapy because
of severe clinical gout and drug-induced hepatitis.
Two patients had ethambutol withdrawn because of

Table 5Adverse Reactions to Second-Line Drugs


Experienced by 25 Patients With MDR-TB

System

Clinical/Functional Manifestations

Gastrointestinal
Otovestibular
Central nervous
Skeletal
Renal
Ophthalmic
Hepatobiliary
Dermatologic

Nausea, vomiting, epigastric discomfort


Vertigo, tinnitus, impaired hearing
Insomnia, depression, seizure
Arthralgia, gout
Renal function impairment
Visual blurring
Liver function impairment
Rash

Number
of
Patients
13
9
11
5
2
2
1
1

blurring of vision after 4 months of treatment.


Finally, one patient had persistent dizziness despite
withdrawal of cycloserine. This necessitated change
of the fluoroquinolone from ofloxacin 600 mg daily
to levofloxacin 300 mg daily 4 months from commencement of therapy. There was no significant
difference in the incidence of adverse effects from
the drugs between the success and failure groups
(p 0.05).
Follow-up Assessment
Four of the 51 patients cured were lost to followup. The remaining 47 were followed up for a mean of
24.5 16.5 months (range, 3 to 75 months). Only
one patient (2.1%) was found to have radiographic
and bacteriologic relapse 6 months after treatment
cessation. This patient had 24 months of treatment
and initial bacillary resistance to ofloxacin in vitro.
She eventually had a right upper lobectomy performed 6 months after retreatment with drugs.
Three of the nine patients with treatment failure
were lost to follow-up on completion of chemotherapy. The remaining six patients with treatment failure were followed up for a mean of 28.0 21.9
months (range, 3 to 66 months). Two subsequently
died of TB 48 and 52 months after discontinuation of
chemotherapy. None of the failed patients was suitable for surgical treatment, largely because of the
presence of bilateral disease.
Monitoring of Sputum Bacteriology
The relationship between sputum culture after 2
and 3 months of chemotherapy and final outcomes
was also assessed. Information was available in all
patients except one who died of TB within the first
month of chemotherapy. All 41 patients with nega-

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2000 American College of Chest Physicians

tive sputum cultures after 2 months of chemotherapy


and all 49 patients with negative sputum cultures
after 3 months of chemotherapy eventually achieved
success. Thus, the predictive values of negative
sputum cultures after 2 and 3 months of treatment
for success were both 100%. Eleven of 21 patients
with positive sputum cultures after 2 months of
chemotherapy and 11 of 13 patients with positive
sputum cultures after 3 months of chemotherapy
eventually failed or died. Thus, the predictive values
of positive sputum cultures after 2 and 3 months of
treatment for failure were 52.4% and 84.6%, respectively.

Discussion
In this community, the initial MDR-TB prevalence rates ranged from 0.4 to 0.7%, and the combined MDR-TB prevalence rates ranged from 0.9 to
1.0% in the study period (unpublished data, Department of Health, Hong Kong). The demographic and
clinical characteristics of MDR-TB patients in our
analyzed cohort were similar to other series, with a
predominance of male patients.19 24 Approximately
40% of our patients did not receive any previous
antituberculosis drugs. Our high initial MDR-TB
proportion concurred with data from some series20 22 but not others.19,24 The overall success rate
of approximately 80% corroborates the best results
of published studies or analyses.14,20,24
Among the three variables that were found to be
independently associated with adverse outcomes of
patients, the presence of cavitation might impede
drug penetration and thus attenuate the therapeutic
efficacy of antimicrobial agents. In a study on retreatment cases, it was found that cavitary disease
per se, irrespective of drug-resistance status, was
associated with poor treatment outcomes.25 Poor
adherence linked with adverse treatment outcomes
is not unexpected and emphasizes the importance of
directly observed therapy in the treatment of TB,
which should be mandatory for all patients with
MDR-TB.26 Contrary to one important study undertaken in the United States, male sex was not found to
be an important determinant for adverse outcomes.19 This might be related to particular factors
linked to the male population in that study but not in
ours. As the details of previous history of chemotherapy were generally incomplete for our patients, we
could not study the relationship between the number
of previously used drugs and the likelihood of adverse treatment outcomes. Some investigators have
found this relationship significant.19
Previous studies on the outcomes of chemotherapy in patients with MDR-TB have stressed the

negative impact of extensiveness of drug resistance


and the positive impact of the number of appropriate
drugs ( 2) administered in accordance to drug
susceptibility tests.19,22,24 However, it has also been
shown that some patients who received drugs to
which their organisms were susceptible in vitro did
not respond microbiologically.19,24 At least one possible explanation for this discrepancy between in
vitro activity and in vivo efficacy is that susceptibility
testing for second-line agents needs greater standardization. For practical purposes, it would be
useful to find a single drug resistance that could help
predict the outcome of therapy. We focused our
attention on ofloxacin resistance as such a potential
marker for several reasons. First, the MICs of ofloxacin against strains of M tuberculosis have been
consistent irrespective of the methodology or culture
medium used, with MICs against 90% of ofloxacinsusceptible strains 1.25 mg/L.15,7 Many other
fluoroquinolones behave similarly.15 Second, ofloxacin or other fluoroquinolones are very commonly
included in second-line drug regimens for MDRTB.12,13 Third, preliminary data have suggested a
good correlation between activity in vitro and efficacy in vivo for ofloxacin.6,7 In our analysis, bacillary
resistance to ofloxacin was indeed found to be an
important variable significantly associated with adverse treatment outcomes. This finding implicates
the likely pivotal role of ofloxacin/levofloxacin in
multidrug regimens used for treatment of patients
with MDR-TB. The six patients with bacillary resistance to ofloxacin in vitro who failed ofloxacin/
levofloxacin-containing regimens still received a
mean of 2.7 active drugs (range, 2 to 3 drugs).
Aside from in vivo efficacy, ofloxacin/levofloxacin
has the favorable therapeutic characteristics of high
peak serum drug concentration: MIC ratio,7 good
tissue penetration, particularly into lungs,27 and good
tolerance by patients on long-term administration.28,29 Our patients tolerated the fluoroquinolones
even at high doses, corroborating the experience of
others. Fluoroquinolones must be used carefully to
prevent the emergence of cross-resistance among
other members of this class of drugs.15 This has been
experienced in certain communities.30 32 In our
present cohort of patients, only one of the six failed
patients who had ofloxacin-susceptible M tuberculosis strains developed acquired resistance to ofloxacin
with treatment. This patient also had poor adherence
to therapy. Further, our data suggest that levofloxacin, when used at a dose of 600 to 800 mg daily, is
more effective than ofloxacin at a similar dose.
However, the difference in efficacy of the two
fluoroquinolones for patients with ofloxacin-susceptible and ofloxacin-resistant bacilli did not reach
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2000 American College of Chest Physicians

749

statistical significance (p 0.05). Evaluation with a


larger sample size might allow a more definitive
conclusion.
The optimal duration of therapy for patients with
MDR-TB is unknown. A number of authorities
including the World Health Organization have recommended a total duration of 18 months after
culture conversion, even for non-HIV-infected subjects.12,13 However, our data suggest that at least
some non-HIV-infected patients who managed to
achieve sustained sputum culture conversion to negative status could be adequately treated with 12
months of fluoroquinolone-containing second-line
chemotherapy regimens. In our patients, only those
at risk because of diabetes mellitus, silicosis, extensive radiographic disease with or without cavities,
extensive drug resistance in vitro, delayed sputum
culture conversion (ie, after 3 months of chemotherapy), and extrapulmonary involvement were
treated for 12 months, often for 15 to 18 months
in toto. Although our relapse rate of 2.1% is gratifying, it is important to note that approximately 50% of
our patients were followed up for 24 months;
some of these may have relapsed subsequently. We
believe that in formulating the optimal duration of
therapy for MDR-TB, multiple factors must be
considered, particularly the bactericidal capacity and
dosage of the drugs used, cost, and drug toxicity as
well as anticipated patient adherence.
In this retrospective analysis of MDR-TB patients,
those who responded achieved sputum culture negativity during the early months of treatment, usually
within 3 months. This concurs with a study of
HIV-negative subjects with MDR-TB.20 Negative
sputum culture at 2 and 3 months was predictive of
eventual cure in 100% of patients. The predictive
value for failure of positive sputum cultures at 2 and
3 months was 52.4% and 84.6%, respectively. The
predictive values of negative and positive sputum
cultures for failure or success both reached 100%
after 6 months. Thus, monitoring monthly sputum
culture for AFB in the initial 6 months of treatment
helps greatly in predicting outcome. Such monitoring has been our practice since 1990 and currently is
recommended by the World Health Organization.13
ACKNOWLEDGMENT: The authors thank Professor David
Schlossberg for reviewing the manuscript.

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751

Outcomes of Patients With Multidrug-Resistant Pulmonary


Tuberculosis Treated With Ofloxacin/Levofloxacin-Containing
Regimens*
Wing Wai Yew, Chi Kuen Chan, Chi Hung Chau, Cheuk Ming Tam, Chi Chiu
Leung, Poon Chuen Wong and Joseph Lee
Chest 2000;117; 744-751
DOI 10.1378/chest.117.3.744
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