Jon Warkentin

Fluoroquinolone resistance in Mycobacterium tuberculosis: the effect of duration and timing of fluoroquinolone exposure.

RATIONALE Fluoroquinolones are the most commonly prescribed antibiotic class in the United States. They have the potential to become first-line antituberculosis therapy, but the effect of fluoroquinolone use on fluoroquinolone resistance in Mycobacterium tuberculosis is not well characterized. OBJECTIVES To determine the prevalence of and risk factors for fluoroquinolone-resistant tuberculosis in a large United States population. METHODS We identified all people with culture-confirmed tuberculosis enrolled in TennCare (Medicaid) and reported to the Tennessee Department of Health from January 2002 to December 2006. People with fluoroquinolone-resistant M. tuberculosis isolates (cases) were compared with those with susceptible isolates (control subjects). Fluoroquinolone resistance was determined by agar proportion using ofloxacin 2 microg/ml. Outpatient fluoroquinolone exposure in the 12 months before tuberculosis diagnosis was ascertained from TennCare pharmacy data. MEASUREMENTS AND MAIN RESULTS Of 640 study patients, 116 (18%) had fluoroquinolone exposure in the 12 months before diagnosis, and 16 (2.5%; 95% confidence interval [CI], 1.4-4.0%) M. tuberculosis isolates were fluoroquinolone resistant. Among the 54 patients with more than 10 days of fluoroquinolone exposure, 7 (13%) had fluoroquinolone resistance. In multivariable logistic regression analyses using propensity score to control for age, sex, race, HIV serostatus, and site of disease, more than 10 days of fluoroquinolone exposure before tuberculosis diagnosis was associated with fluoroquinolone resistance (odds ratio 7.0; 95% CI, 2.3-20.6; P = 0.001). Fluoroquinolone exposure for more than 10 days that occurred more than 60 days before tuberculosis diagnosis was associated with the highest risk of resistance (20.8%; odds ratio 17.0; 95% CI, 5.1-56.8; P < 0.001 compared with no exposure). CONCLUSIONS Overall, fluoroquinolone resistance was relatively low. However, receipt of fluoroquinolones for more than 10 days, particularly more than 60 days before tuberculosis diagnosis, was associated with a high risk of fluoroquinolone-resistant tuberculosis.

Black race, sex, and extrapulmonary tuberculosis risk: an observational study

BackgroundExtrapulmonary tuberculosis is likely a marker of underlying immune compromise. Our objective was to determine race and sex differences in extrapulmonary tuberculosis risk in order to identify the optimal population in which to assess for host factors associated with extrapulmonary tuberculosis.MethodsWe performed an observational study of all tuberculosis cases reported to the Tennessee Department of Health, January 1, 2000 to December 31, 2006. We compared the incidence of extrapulmonary tuberculosis by race and sex. We also examined risk factors associated with extrapulmonary disease among all persons with tuberculosis.ResultsExtrapulmonary tuberculosis incidence per 100,000 population was 5.93 in black men, 3.21 in black women, 1.01 in non-black men, and 0.58 in non-black women. Among those with tuberculosis, black women were most likely to have extrapulmonary disease (38.6%), followed by black men (28.1%), non-black women (24.6%) and non-black men (21.1%). In multivariate logistic regression among persons with tuberculosis, black women (OR 1.82 (95% CI 1.24-2.65), p = 0.002), black men (OR 1.54 (95% CI 1.13-2.09, p = 0.006), foreign birth (OR 1.55 (95% CI 1.12-2.14), p = 0.009), and HIV infection (OR 1.45 (95% CI 0.99-2.11), p = 0.06) were associated with extrapulmonary tuberculosis.ConclusionsBlack men and black women had the highest incidence of extrapulmonary tuberculosis, and high odds of extrapulmonary disease among persons with tuberculosis. These data suggest that factors in addition to tuberculosis exposure contribute to extrapulmonary tuberculosis risk in blacks.

High Proportion of Fluoroquinolone-Resistant Mycobacterium tuberculosis Isolates with Novel Gyrase Polymorphisms and a gyrA Region Associated with Fluoroquinolone Susceptibility

ABSTRACT Fluoroquinolone resistance in Mycobacterium tuberculosis can be conferred by mutations in gyrA or gyrB. The prevalence of resistance mutations outside the quinolone resistance-determining region (QRDR) of gyrA or gyrB is unclear, since such regions are rarely sequenced. M. tuberculosis isolates from 1,111 patients with newly diagnosed culture-confirmed tuberculosis diagnosed in Tennessee from 2002 to 2009 were screened for phenotypic ofloxacin resistance (>2 μg/ml). For each resistant isolate, two ofloxacin-susceptible isolates were selected: one with antecedent fluoroquinolone exposure and one without. The complete gyrA and gyrB genes were sequenced and compared with M. tuberculosis H37Rv. Of 25 ofloxacin-resistant isolates, 11 (44%) did not have previously reported resistance mutations. Of these, 10 had novel polymorphisms: 3 in the QRDR of gyrA, 1 in the QRDR of gyrB, and 6 outside the QRDR of gyrA or gyrB; 1 did not have any gyrase polymorphisms. Polymorphisms in gyrA codons 1 to 73 were more common in fluoroquinolone-susceptible than in fluoroquinolone-resistant strains (20% versus 0%; P = 0.016). In summary, almost half of fluoroquinolone-resistant M. tuberculosis isolates did not have previously described resistance mutations, which has implications for genotypic diagnostic tests.

Fluoroquinolone susceptibility in Mycobacterium tuberculosis after pre-diagnosis exposure to older- versus newer-generation fluoroquinolones

Fluoroquinolone exposure before tuberculosis (TB) diagnosis is common. We anticipated that exposure to older-generation fluoroquinolones is associated with greater fluoroquinolone MICs in Mycobacterium tuberculosis than exposure to newer agents. A nested case-control study was performed among newly diagnosed TB patients reported to the Tennessee Department of Health (January 2002-December 2009). Each fluoroquinolone-resistant case (n=25) was matched to two fluoroquinolone-susceptible controls (n=50). Ciprofloxacin and ofloxacin were classified as older-generation fluoroquinolones; levofloxacin, moxifloxacin and gatifloxacin were considered newer agents. There was no difference between median ofloxacin MIC for isolates from 9 patients exposed only to older fluoroquinolones, 25 exposed only to newer fluoroquinolones, 6 exposed to both and 35 fluoroquinolone-unexposed patients (Kruskal-Wallis, P=0.35). Using multivariate proportional odds logistic regression adjusting for age and sex, duration of exposure to newer fluoroquinolones was independently associated with higher MIC (OR=1.79, 95% CI 1.22-2.64), but duration of exposure to older fluoroquinolones was not (OR=0.94, 95% CI 0.50-1.78). Isolates from patients exposed only to newer fluoroquinolones tended to have mutations at gyrA codons 90, 91 or 94 more frequently than those exposed only to older fluoroquinolones (44% vs. 11%). We were surprised to find that duration of exposure to newer fluoroquinolones, but not older ones, was independently associated with higher ofloxacin MIC. This suggests that the mutant selection window lower boundary is likely to have clinical relevance; caution is warranted when newer fluoroquinolones are prescribed to patients with TB risk factors.

Chronic lung disease and HIV infection are risk factors for recurrent tuberculosis in a low-incidence setting

SETTING Programmatic data from the United States on tuberculosis (TB) recurrence are limited. OBJECTIVES To determine the TB recurrence rate and to determine if chronic lung disease (CLD) and human immunodeficiency virus (HIV) infection are risk factors for recurrence in this population. DESIGN Nested case-control study among TB cases reported to the Tennessee Department of Health between 1 January 2000 and 31 December 2006. Time at risk for recurrence was through 31 December 2007. Multiple imputation accounted for missing data. RESULTS Of 1431 TB cases, 20 cases recurred (1.4%, 95%CI 0.9-2.1). Median time at risk for recurrence was 4.5 years (interquartile range 2.7-6.1). Initial and recurrent Mycobacterium tuberculosis isolates were available for genotyping for 15 patients; 12 were consistent with relapse (0.8%, 95%CI 0.4-1.5) and three with re-infection (0.2%, 95%CI 0.04-0.6). HIV infection (OR 5.01, P = 0.04) and CLD (OR 5.28, P = 0.03) were independently associated with recurrent TB, after adjusting for a disease risk score. HIV infection was a risk factor for TB re-infection (P < 0.001). CONCLUSIONS In this low-incidence US population, the TB recurrence rate was low, but CLD and HIV were independent risk factors for recurrence. HIV infection was also a risk factor for TB re-infection.

Fluoroquinolone exposure prior to tuberculosis diagnosis is associated with an increased risk of death.

SETTING Fluoroquinolone (FQ) exposure before tuberculosis (TB) diagnosis is common, but its effect on outcomes, including mortality, is unclear. DESIGN Among TB patients reported to the Tennessee Department of Health from 2007 to 2009, we assessed FQ exposure within 6 months before TB diagnosis. The primary outcome was the combined endpoint of death at the time of TB diagnosis and during anti-tuberculosis treatment. RESULTS Among 609 TB cases, 214 (35%) received FQs within 6 months before TB diagnosis. A total of 71 (12%) persons died; 10 (2%) were dead at TB diagnosis and 61 (10%) died during anti-tuberculosis treatment. In multivariable logistic regression analysis, factors independently associated with death were older age (OR 1.05 per year, 95%CI 1.04-1.07), human immunodeficiency virus infection (OR 8.08, 95%CI 3.83-17.06), US birth (OR 3.03, 95%CI 1.03-9.09), and any FQ exposure before TB diagnosis (OR 1.82, 95%CI 1.05-3.15). Persons with FQ exposure before TB diagnosis were more likely to have culture- and smear-positive disease than unexposed persons. CONCLUSIONS Among this patient population, FQ exposure before TB diagnosis was associated with an increased risk of death. These findings underscore the need for cautious use of FQs in persons with possible TB.

Public health response to a multidrug-resistant tuberculosis outbreak among Guatemalans in Tennessee, 2007.

Background: In June 2007, the Tennessee Department of Health notified the Centers for Disease Control and Prevention of four multidrug-resistant tuberculosis (MDR TB) cases in individuals of Guatemalan descent, and requested onsite epidemiologic assistance to investigate this outbreak. Methods: A case was defined as either culture-confirmed MDR TB with a drug-susceptibility pattern closely resembling that of the index case, or a clinical diagnosis of active TB disease and corroborated contact with a person with culture-confirmed MDR TB. Medical records were reviewed, and patients and their contacts were interviewed. Results: Five secondary TB cases were associated with the index case. Of 369 contacts of the index case, 189 (51%) were evaluated. Of those, 97 (51%) had positive tuberculin skin test (TST) results, 79 (81%) began therapy for latent TB infection (LTBI), and 38 (48%) completed LTBI therapy. Conclusion: Despite consistent follow up by public health officials, a low proportion of patients diagnosed with LTBI completed therapy. Clinicians and public health practitioners who serve immigrant communities should be vigilant for MDR TB.

Non-adherence and drug-related interruptions are risk factors for delays in completion of treatment for tuberculosis

SETTING A key program performance objective established by the Centers for Disease Control and Prevention (CDC) is that ≥93% of tuberculosis (TB) cases complete treatment within 12 months. OBJECTIVE To determine the rate of and risk factors for delay in anti-tuberculosis treatment completion. DESIGN Nested case-control study among TB cases reported to the Tennessee Department of Health between 1 January 2000 and 31 December 2010. Time to complete treatment was calculated using treatment start and stop dates documented in the Tuberculosis Information Management System (TIMS). RESULTS Of 2627 cases, 261 (9.9%) required >12 months to complete treatment. In adjusted conditional logistic regression analyses, cavitary disease and positive cultures after 2 months of therapy (OR 5.85, 95%CI 1.98-17.32, P = 0.001), non-adherence (OR 4.13, 95%CI 1.76-9.72, P < 0.001), and interruptions in treatment due to drug-related issues (OR 6.91, 95%CI 3.76-12.70, P < 0.001) were independently associated with delay in completion of TB treatment. CONCLUSION From 2000 to 2010, the proportion of TB cases completing treatment within 12 months increased from 84.6% to 94.9%, and remained above the CDC target during 2009-2010. Efforts to improve patient adherence and reduce interruptions in treatment due to anti-tuberculosis drug-related issues could improve the proportion of TB cases completing treatment within 12 months.

Tuberculosis and the risk of infection with other intracellular bacteria: a population-based study

SUMMARY Persons who develop tuberculosis (TB) may have subtle immune defects that could predispose to other intracellular bacterial infections (ICBIs). We obtained data on TB and five ICBIs (Chlamydia trachomatis, Salmonella spp., Shigella spp., Yersinia spp., Listeria monocytogenes) reported to the Tennessee Department of Health, USA, 2000-2011. Incidence rate ratios (IRRs) comparing ICBIs in persons who developed TB and ICBIs in the Tennessee population, adjusted for age, sex, race and ethnicity were estimated. IRRs were not significantly elevated for all ICBIs combined [IRR 0.87, 95% confidence interval (CI) 0.71-1.06]. C. trachomatis rate was lowest in the year post-TB diagnosis (IRR 0.17, 95% CI 0.04-0.70). More Salmonella infections occurred in extrapulmonary TB compared to pulmonary TB patients (IRR 14.3, 95% CI 1.67-122); however, this appeared to be related to HIV co-infection. TB was not associated with an increased risk of other ICBIs. In fact, fewer C. trachomatis infections occurred after recent TB diagnosis. Reasons for this association, including reduced exposure, protection conferred by anti-TB drugs or macrophage activation by Mycobacterium tuberculosis infection warrant further investigation.

A comparison of interview methods to ascertain fluoroquinolone exposure before tuberculosis diagnosis

SUMMARY Fluoroquinolone use before tuberculosis (TB) diagnosis delays the time to diagnosis and treatment, and increases the risk of fluoroquinolone-resistant TB and death. Ascertainment of fluoroquinolone exposure could identify such high-risk patients. We compared four methods of ascertaining fluoroquinolone exposure in the 6 months prior to TB diagnosis in culture-confirmed TB patients in Tennessee from January 2007 to December 2009. The four methods included a simple questionnaire administered to all TB suspects by health department personnel (FQ-Form), an in-home interview conducted by research staff, outpatient and inpatient medical record review, and TennCare pharmacy database review. Of 177 TB patients included, 72 (41%) received fluoroquinolones during the 6 months before TB diagnosis. Fluoroquinolone exposure determined by review of inpatient and outpatient medical records was considered the gold standard for comparison. The FQ-Form had 61% [95% confidence interval (CI) 48-73] sensitivity and 93% (95% CI 85-98) specificity (agreement 79%, kappa = 0.56) while the in-home interview had 28% (95% CI 18-40) sensitivity and 99% (94-100%) specificity (agreement 68%, kappa = 0.29). A simple questionnaire administered by health department personnel identified fluoroquinolone exposure before TB diagnosis with moderate reliability.