Joseph S. Cavanaugh

Epidemiology of Pyrazinamide-Resistant Tuberculosis in the United States, 1999–2009

BACKGROUND Pyrazinamide (PZA) is essential in tuberculosis treatment. We describe the prevalence, trends, and predictors of PZA resistance in Mycobacterium tuberculosis complex (MTBC) in the United States. METHODS We analyzed culture-positive MTBC cases with reported drug susceptibility tests for PZA in 38 jurisdictions routinely testing for PZA susceptibility from 1999 to 2009. National Tuberculosis Genotyping Service data for 2004-2009 were used to distinguish M. tuberculosis from Mycobacterium bovis and determine phylogenetic lineage. RESULTS Overall 2.7% (2167/79 321) of MTBC cases had PZA resistance, increasing annually from 2.0% to 3.3% during 1999-2009 (P < .001), largely because of an increase in PZA monoresistance. PZA-monoresistant MTBC (vs drug-susceptible) was associated with an age of 0-24 years (adjusted prevalence ratio [aPR],1.50; 95% confidence interval [CI], 1.31-1.71), Hispanic ethnicity (aPR, 3.52; 95% CI, 2.96-4.18), human immunodeficiency virus infection (aPR, 1.43; 95% CI, 1.15-1.77), extrapulmonary disease (aPR, 3.02; 95% CI, 2.60-3.52), and normal chest radiograph (aPR, 1.88; 95% CI, 1.63-2.16) and was inversely associated with Asian (aPR, 0.59; 95% CI, .47-.73) and black (aPR, 0.37; 95% CI, .29-.49) race. Among multidrug-resistant (MDR) cases, 38.0% were PZA-resistant; PZA resistance in MDR MTBC was associated with female sex (aPR, 1.25; 95% CI, 1.08-1.46) and previous tuberculosis diagnosis (aPR, 1.37; 95% CI, 1.16-1.62). Of 28 080 cases with genotyping data, 925 (3.3%) had PZA resistance; 465 of 925 (50.3%) were M. bovis. In non-MDR M. tuberculosis cases, PZA resistance was higher in the Indo-Oceanic than the East Asian lineage (2.2% vs 0.9%, respectively; aPR, 2.26; 95% CI, 1.53-3.36), but in MDR cases it was lower in the Indo-Oceanic lineage (22.0% vs 43.4%, respectively; aPR, 0.54; 95% CI, .32-.90). CONCLUSIONS Specific human and mycobacterial characteristics were associated with PZA-resistant MTBC, reflecting both specific subgroups of the population and phylogenetic lineages of the mycobacteria.

Epidemiology of smear-negative pulmonary tuberculosis in the United States, 1993-2008.

BACKGROUND Smear-negative tuberculosis (TB) is difficult to diagnose and has been associated with poor treatment outcomes and excessive mortality, particularly in high human immunodeficiency virus (HIV) prevalent settings. However, few studies have used mycobacterial culture to rigorously confirm all smear-negative TB cases in a population-based cohort. DESIGN We included all culture-confirmed, pulmonary TB cases reported to the US National TB Surveillance System from 1993 to 2008. We analyzed smear-negative TB risk factors and survival, as compared to smear-positive TB. We calculated prevalence ratios (PRs) and adjusted for confounders (aPR). RESULTS From 1993 to 2008, 159,121 cases of culture-confirmed pulmonary TB were reported in the United States, of which 58,786 (37%) were sputum smear-negative. Smear-negative TB cases were more likely to be foreign-born (aPR 1.10, 95%CI 1.08-1.12), incarcerated (aPR 1.52, 95%CI 1.48-1.56) or HIV-infected (aPR 1.27, 95%CI 1.24-1.30). Hispanics and non-Hispanic Blacks were less likely to have smear-negative TB (respectively aPR 0.87, 95%CI 0.85-0.89 and aPR 0.90, 95%CI 0.89-0.92). Smear-negative TB cases had lower mortality (aRR 0.78, 95%CI 0.74-0.81), independent of HIV status. CONCLUSION Smear-negative TB represents a large proportion of TB cases in the United States, and occurs more often among persons in groups more likely to undergo TB screening. The lower mortality may indicate earlier TB detection, and underscores the need for continued vigilance in screening of high-risk persons.

Tuberculosis and diabetes mellitus in the Republic of Kiribati: a case–control study

To better inform local management of TB–diabetes collaborative activities, we aimed to determine the prevalence of diabetes among persons with and without TB and to determine the association between TB and diabetes in Kiribati, a Pacific Island nation.

Human Tuberculosis Caused by Mycobacterium bovis in the United States, 2006-2013.

BACKGROUND Using genotyping techniques that have differentiated Mycobacterium bovis from Mycobacterium tuberculosis since 2005, we review the epidemiology of human tuberculosis caused by M. bovis in the United States and validate previous findings nationally. METHODS All tuberculosis cases with a genotyped M. tuberculosis complex isolate reported during 2006-2013 in the United States were eligible for analysis. We used binomial regression to identify characteristics independently associated with M. bovis disease using adjusted prevalence ratios (aPRs) and corresponding 95% confidence intervals (CIs). RESULTS During 2006-2013, the annual percentages of tuberculosis cases attributable to M. bovis remained consistent nationally (range, 1.3%-1.6%) among all tuberculosis cases (N = 59 273). Compared with adults 25-44 years of age, infants aged 0-4 years (aPR, 1.9 [95% CI, 1.4-2.8]) and children aged 5-14 years (aPR, 4.0 [95% CI, 3.1-5.3]) had higher prevalences of M. bovis disease. Patients who were foreign-born (aPR, 1.4 [95% CI, 1.2-1.7]), Hispanic (aPR, 3.9 [95% CI, 3.0-5.0]), female (aPR, 1.4 [95% CI, 1.3-1.6]), and resided in US-Mexico border counties (aPR, 2.0 [95% CI, 1.7-2.4]) also had higher M. bovis prevalences. Exclusively extrapulmonary disease (aPR, 3.7 [95% CI, 3.3-4.2]) or disease that was both pulmonary and extrapulmonary (aPR, 2.4 [95% CI, 2.1-2.9]) were associated with a higher prevalence of M. bovis disease. CONCLUSIONS Children, foreign-born persons, Hispanics, and females are disproportionately affected by M. bovis, which was independently associated with extrapulmonary disease. Targeted prevention efforts aimed at Hispanic mothers and caregivers are warranted.

Performance of Clinical Screening Algorithms for Tuberculosis Intensified Case Finding among People Living with HIV in Western Kenya.

Objective To assess the performance of symptom-based screening for tuberculosis (TB), alone and with chest radiography among people living with HIV (PLHIV), including pregnant women, in Western Kenya. Design Prospective cohort study Methods PLHIV from 15 randomly-selected HIV clinics were screened with three clinical algorithms [World Health Organization (WHO), Ministry of Health (MOH), and “Improving Diagnosis of TB in HIV-infected persons” (ID-TB/HIV) study], underwent chest radiography (unless pregnant), and provided two or more sputum specimens for smear microscopy, liquid culture, and Xpert MTB/RIF. Performance of clinical screening was compared to laboratory results, controlling for the complex design of the survey. Results Overall, 738 (85.6%) of 862 PLHIV enrolled were included in the analysis. Estimated TB prevalence was 11.2% (95% CI, 9.9–12.7). Sensitivity of the three screening algorithms was similar [WHO, 74.1% (95% CI, 64.1–82.2); MOH, 77.5% (95% CI, 68.6–84.5); and ID-TB/HIV, 72.5% (95% CI, 60.9–81.7)]. Sensitivity of the WHO algorithm was significantly lower among HIV-infected pregnant women [28.2% (95% CI, 14.9–46.7)] compared to non-pregnant women [78.3% (95% CI, 67.3–86.4)] and men [77.2% (95% CI, 68.3–84.2)]. Chest radiography increased WHO algorithm sensitivity and negative predictive value to 90.9% (95% CI, 86.4–93.9) and 96.1% (95% CI, 94.4–97.3), respectively, among asymptomatic men and non-pregnant women. Conclusions Clinical screening missed approximately 25% of laboratory-confirmed TB cases among all PLHIV and more than 70% among HIV-infected pregnant women. National HIV programs should evaluate the feasibility of laboratory-based screening for TB, such as a single Xpert MTB/RIF test for all PLHIV, especially pregnant women, at enrollment in HIV services.

Tuberculosis among Children in Kenya: Epidemiology and Impact of HIV in Two Provinces

We collected clinical register data on children in two provinces of Kenya and conducted bivariate and multivariate analyses to assess characteristics associated with death. Among 987 children with tuberculosis (TB), pulmonary disease was diagnosed in 689 (70%) children. Final outcomes were known for 830 children, 40 (5%) of whom died during TB treatment. HIV test results were available for 670 (68%) children; 371 (55%) of whom tested positive. Only 63 of 134 (47%) of children <1 year were tested for HIV. There were no data on CD4 or anti-retroviral use. The relative risk for death for HIV-infected children compared to HIV-uninfected children was 9.3 for children <1 year [95% confidence interval (CI) 1.2-69.2], 3.9 for children aged 1-4 (95% CI 0.9-17.7) and 0.9 for children aged 5-14 (95% CI 0.3-2.6). In Kenya, HIV infection in children with TB is common, and our data suggest that HIV is particularly deadly in TB patients <1 year, the group with the lowest rate of testing. Poor data recording and reporting limit our understanding of TB in this age group. Expansion of HIV testing may improve survival, and more complete data recording and reporting will enhance our understanding of pediatric TB.

Effect of diabetes on tuberculosis presentation and outcomes in Kiribati

To determine the association between diabetes and the clinical features and treatment outcomes of TB in Kiribati.

Comparative Yield of Different Diagnostic Tests for Tuberculosis among People Living with HIV in Western Kenya

Background Diagnosis followed by effective treatment of tuberculosis (TB) reduces transmission and saves lives in persons living with HIV (PLHIV). Sputum smear microscopy is widely used for diagnosis, despite limited sensitivity in PLHIV. Evidence is needed to determine the optimal diagnostic approach for these patients. Methods From May 2011 through June 2012, we recruited PLHIV from 15 HIV treatment centers in western Kenya. We collected up to three sputum specimens for Ziehl-Neelsen (ZN) and fluorescence microscopy (FM), GeneXpert MTB/RIF (Xpert), and culture, regardless of symptoms. We calculated the incremental yield of each test, stratifying results by CD4 cell count and specimen type; data were analyzed to account for complex sampling. Results From 778 enrolled patients, we identified 88 (11.3%) laboratory-confirmed TB cases. Of the 74 cases who submitted 2 specimens for microscopy and Xpert testing, ZN microscopy identified 25 (33.6%); Xpert identified those plus an additional 18 (incremental yield = 24.4%). Xpert testing of spot specimens identified 48 (57.0%) of 84 cases; whereas Xpert testing of morning specimens identified 50 (66.0%) of 76 cases. Two Xpert tests detected 22/24 (92.0%) TB cases with CD4 counts <100 cells/μL and 30/45 (67.0%) of cases with CD4 counts ≥100 cells/μl. Conclusions In PLHIV, Xpert substantially increased diagnostic yield compared to smear microscopy and had the highest yield when used to test morning specimens and specimens from PLHIV with CD4 count <100 cells/μL. TB programs unable to replace smear microscopy with Xpert for all symptomatic PLHIV should consider targeted replacement and using morning specimens.

Susceptibilities of MDR Mycobacterium tuberculosis isolates to unconventional drugs compared with their reported pharmacokinetic/pharmacodynamic parameters

Background The second-line drugs recommended to treat drug-resistant TB are toxic, expensive and difficult to procure. Given increasing resistance, the need for additional anti-TB drugs has become more urgent. But new drugs take time to develop and are expensive. Some commercially available drugs have reported anti-mycobacterial activity but are not routinely used because supporting laboratory and clinical evidence is sparse. Methods We analysed 217 MDR M. tuberculosis isolates including 153 initial isolates from unique patients and 64 isolates from follow-up specimens during the course of treatment. The resazurin microdilution assay was performed to determine MICs of trimethoprim/sulfamethoxazole, mefloquine, thioridazine, clofazimine, amoxicillin/clavulanate, meropenem/clavulanate, nitazoxanide, linezolid and oxyphenbutazone. Isoniazid was used for validation. We calculated the MIC 50 and MIC 90 as the MICs at which growth of 50% and 90% of isolates was inhibited, respectively. Results The MIC 50 s, in mg/L, for initial isolates were as follows: trimethoprim/sulfamethoxazole, 0.2/4; mefloquine, 8; thioridazine, 4; clofazimine, 0.25; amoxicillin/clavulanate, 16/8; meropenem/clavulanate, 1/2.5; nitazoxanide, 16; linezolid, 0.25; and oxyphenbutazone, 40. The MIC 90 s, in mg/L, for initial isolates were as follows: trimethoprim/sulfamethoxazole, 0.4/8; mefloquine, 8; thioridazine, 8; clofazimine, 0.5; amoxicillin/clavulanate, 32/16; meropenem/clavulanate, 8/2.5; nitazoxanide, 16; linezolid, 0.25; and oxyphenbutazone, 60. By comparison, the MIC 90 of isoniazid was >4 mg/L, as expected. There was no evidence that previous treatment affected susceptibility to any drug. Conclusions Most drugs demonstrated efficacy against M. tuberculosis . When these MICs are compared with the published pharmacokinetic/pharmacodynamic profiles of the respective drugs in humans, trimethoprim/sulfamethoxazole, meropenem/clavulanate, linezolid, clofazimine and nitazoxanide appear promising and warrant further clinical investigation.

Comparison of Sputum-Culture Conversion for Mycobacterium bovis and M. tuberculosis

Current US guidelines recommend longer treatment for tuberculosis (TB) caused by pyrazinamide-resistant organisms (e.g., Mycobacterium bovis) than for M. tuberculosis TB. We compared treatment response times for patients with M. bovis TB and M. tuberculosis TB reported in the United States during 2006–2013. We included culture-positive, pulmonary TB patients with genotyping results who received standard 4-drug treatment at the time of diagnosis. Time to sputum-culture conversion was defined as time between treatment start date and date of first consistently culture-negative sputum. We analyzed 297 case-patients with M. bovis TB and 30,848 case-patients with M. tuberculosis TB. After 2 months of treatment, 71% of M. bovis and 65% of M. tuberculosis TB patients showed conversion of sputum cultures to negative. Likelihood of culture conversion was higher for M. bovis than for M. tuberculosis, even after controlling for treatment administration type, sex, and a composite indicator of bacillary burden.