Between July 2002 and December 2003 a total of 548 patients with newly diagnosed culture confirmed TB were identified. Pulmonary TB was diagnosed in 451 of them (82.3%), including 38 (6.9%) who had concomitant pulmonary and extrapulmonary TB. The remaining 97 patients (17.7%) had only extrapulmonary involvement. Serological tests for HIV were performed in 296 patients and were positive in 17. Of the 252 patients with unknown HIV serostatus, all were free of other AIDS defined illnesses during follow up.
Seventy nine of the 548 patients (14.4%) received a fluoroquinolone (FQ group) and 218 (39.8%) received non‐FQ antibiotics (AB group) before the diagnosis of TB. Antibiotics including FQs were prescribed more than once in 65 patients. The FQ prescribed was ciprofloxacin in 42 patients, levofloxacin in 21, and moxifloxacin in the remaining 16, and the mean (SD) duration of use was 9.5 (6.0) days. The initial diagnosis was community acquired pneumonia in 69 patients (87.3%), septic arthritis in four (5.1%), bacterial peritonitis in three (3.8%), and one (1.3%) each for urinary tract infection, meningitis, and fever of unknown origin.
In 18 patients M tuberculosis
isolates before and after the use of FQs were preserved. Half of them had clinical specimens collected
7 days after the use of FQs (range 7–18 days). All of the 36 isolates were susceptible to ofloxacin, except one from a patient after using a FQ for 7 days. The patient presented with right knee arthralgia for 1 week and had not taken any medication before coming to our hospital. Among the 469 patients without empirical FQ use, 177 had previously been treated by local doctors and 76 of them had received antibiotics (non‐FQ antibiotics in 52, unknown in the remainder). Of the other 292 patients, 137 were not likely to have been treated owing to the short duration of symptoms (
The clinical characteristics of the 548 patients are summarised in table 1. The age, presence of underlying disease, extrapulmonary involvement, respiratory or constitutional symptoms, duration of symptoms, pulmonary cavitation, serum albumin level, and result of sputum AFS were significantly different in the three groups. Of the 50 asymptomatic patients, 24 (48%) had only one positive mycobacterial culture; 23 of these had a pulmonary lesion which resolved after anti‐TB treatment and only one (0.2%) with TB peritonitis had normal chest images.
Table 1Characteristics of the 548 patients with culture confirmed tuberculosis
Anti‐TB treatment was started within 14 days of the initial visit in 249 patients (45.4%), including nine (11.4%) in the FQ group, 90 (41.3%) in the AB group, and 150 (59.8%) in the control group. In comparison with patients in the other two groups, for those in the FQ group there was a delay in testing (p
0.037 for non‐FQ antibiotic group; p
0.040 for no antibiotic group) and treatment for TB (p<0.001 for both groups), and patients in this group had a worse prognosis (p<0.001 for no antibiotic group) (table 2). For patients with smear negative specimens, those in the FQ group were treated a median of 42 days after the initial visit and 31 days after mycobacterial culture was ordered while, in the other two groups, patients were treated 27 and 13 days after the initial visit and only 16 and 1 days after mycobacterial culture was requested, respectively (p<0.001 for both groups). Fifty two patients in the FQ group (65.8%) experienced clinical improvement in symptoms (n
40), chest radiographic findings (n
19), or laboratory data (n
14) in a mean of 4 days after empirical use of FQs (range 1–14 days).
Table 2Management and outcome
Of the 12 patients in the FQ group who died of TB (table 2), the cause of death was septic shock without any bacteriological evidence other than M tuberculosis
infection in eight, respiratory failure due to extensive pulmonary inflammation in three, and sputum impaction in one. No events of sudden death as a result of prolongation of the corrected QT interval (QTc) were noted. In the other two groups, 15 patients died of septic shock without any evidence of concomitant bacterial infection other than M tuberculosis
and eight died of respiratory failure (seven due to severe caseous pneumonia and one to sputum impaction). A total of 45 patients (13 in the FQ group, 30 in the AB group, and two in the control group) died within 3 months of the initial visit. At the terminal stage ciprofloxacin resistant bacteria were isolated from eight (61.5%), eight (26.7%), and one (50.0%) of the three groups, respectively (p
0.090). Among these, multidrug resistant Pseudomonas aeruginosa
or Acinetobacter baumannii
, defined as resistance to two or more classes of antipseudomonal agents,14
were isolated from four, two, and one, respectively (p
0.052). One patient in the FQ group, two in the non‐FQ antibiotic group, and five in the no antibiotic group died after completion of TB treatment.
To identify the factors associated with the different prognosis in the three groups, survival analysis was performed on the 11 variables with significant inter‐group differences as well as the factor “empirical antibiotic use” itself. Multivariate survival analysis for the 548 patients showed that the poor prognostic factors included empirical FQ use (hazard ratio (HR) 2.39 (95% CI 1.20 to 4.76)), age >65 years (HR 4.13 (95% CI 2.3 to 7.42)), presence of underlying disease (HR 2.79 (95% CI 1.61 to 4.84)), serum albumin level <3.5 g/dl (HR 3.14 (95% CI 1.73 to 5.71)), and lack of anti‐TB treatment within 14 days of the initial visit (HR 2.04 (95% CI 1.18 to 3.57)). Because a patient with underlying disease is more likely to have a low serum albumin level and empirical treatment with an FQ is more likely for an acute illness, we excluded this subgroup and analysed the effect on prognosis of empirical antibiotic use in the 318 patients without underlying disease (table 3). From table 2 it appears that empirical antibiotic use (including FQs and non‐FQ antibiotics) is associated with increased mortality in univariate analysis but that, after adjustment for confounders, the effect of non‐FQ antibiotics is not significantly different from no antibiotic treatment whereas the increased mortality with FQs remains strong and significant. Other independent factors for a poor prognosis included age >65 years, hypoalbuminaemia, and lack of early anti‐TB treatment.
Table 3Survival analysis for the 318 patients who did not have underlying disease