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* 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.
Correspondence to: Wing Wai Yew, MB, FCCP, Tuberculosis and Chest Unit, Grantham Hospital, 125 Wong Chuk Hang Rd, Hong Kong, China
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Abstract |
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 TOP Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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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.
Key Words: multidrug resistance • ofloxacin/levofloxacin • tuberculosis
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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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.
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Materials and Methods |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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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
Lowënstein-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 Student’s 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 Fisher’s 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.
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Results |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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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.
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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
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 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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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 negative 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.
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Discussion |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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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 ofloxacin-susceptible strains 1.25
mg/L.1
2
3
4
5
7
Many other fluoroquinolones behave
similarly.1
2
3
4
5
Second, ofloxacin or other fluoroquinolones
are very commonly included in second-line drug regimens for
MDR-TB.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 31 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 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
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Acknowledgements |
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Footnotes |
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Presented in abstract form at the 1999 Annual Congress of the European Respiratory Society at Madrid, Spain.
Received for publication May 11, 1999. Accepted for publication October 5, 1999.
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References |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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