Robert Belknap

Interferon-γ Release Assays and Tuberculin Skin Testing for Diagnosis of Latent Tuberculosis Infection in Healthcare Workers in the United States

RATIONALE IFN-γ release assays (IGRAs) are alternatives to tuberculin skin testing (TST) for diagnosis of latent tuberculosis infection. Limited data suggest IGRAs may not perform well for serial testing of healthcare workers (HCWs). OBJECTIVES Determine the performance characteristics of IGRAs versus TST for serial testing of HCWs. METHODS A longitudinal study involving 2,563 HCWs undergoing occupational tuberculosis screening at four healthcare institutions in the United States, where the average tuberculosis case rate ranged from 4 to 9 per 100,000 persons. QuantiFERON-TB Gold In-Tube (QFT-GIT), T-SPOT.TB (T-SPOT), and TST were performed at baseline and every 6 months for 18 months between February 2008 and March 2011. MEASUREMENTS AND MAIN RESULTS A total of 2,418 HCWs completed baseline testing, which was positive for 125 (5.2%) by TST, 118 (4.9%) by QFT-GIT, and 144 (6.0%) by T-SPOT. A baseline positive TST with negative IGRAs was associated with bacillus Calmette-Guérin (BCG) vaccination (odds ratio: 25.1 [95% confidence interval: 15.5, 40.5] vs. no BCG). Proportions of participants with test conversion during the study period were 138 of 2,263 (6.1%) for QFT-GIT, 177 of 2,137 (8.3%) for T-SPOT, and 21 of 2,293 (0.9%) for TST (P < 0.001 for QFT-GIT vs. TST and for T-SPOT vs. TST; P = 0.005 for QFT-GIT vs. T-SPOT). Of the QFT-GIT and T-SPOT converters, 81 of 106 (76.4%) and 91 of 118 (77.1%), respectively, were negative when retested 6 months later. There was negative/positive discordance for 15 of 170 (8.8%) participants by QFT-GIT and for 19 of 151 (12.6%) by T-SPOT when blood was drawn 2 weeks later. CONCLUSIONS Most conversions among HCWs in low TB incidence settings appear to be false positives, and these occurred six to nine times more frequently with IGRAs than TST; repeat testing of apparent converters is warranted.

Prophylactic antibiotics in open fractures: a pilot randomized clinical safety study.

Objective: To develop preliminary data on Staphylococcus aureus colonization and surgical site infections (SSIs) in patients with open fractures who received standard antibiotic prophylaxis compared with a regimen including targeted methicillin-resistant Staphylococcus aureus (MRSA) coverage. Design: Randomized prospective clinical trial. Patients: Adult patients who presented to the emergency department with an open fracture between April 2009 and July 2011. Interventions: One hundred thirty patients were randomized to receive prophylaxis with either cefazolin alone (control arm) or vancomycin and cefazolin (experimental arm) from presentation to the emergency department until 24 hours after the surgical intervention. Screening for S. aureus carriage was performed with nares swabs and predebridement and postdebridement open fracture wound swabs. Patients underwent prospective assessment for the development of SSI for no less than 30 days and up to 12 months. Results: Nasal colonization of methicillin-sensitive S. aureus and MRSA among the sample was 20% and 3%, respectively. No significant difference in the rates of SSI was observed between the study arms (15% vs 19%, respectively, P = 0.62). Staphylococcus aureus caused 55% of the deep incisional/organ space SSI, with 18% attributed to MRSA. A significantly higher rate of MRSA SSIs was observed among MRSA carriers compared with noncarriers (33% vs 1%, respectively, P = 0.003). Conclusions: Staphylococcus aureus nasal colonization in trauma patients with open fractures is similar to that of the general community. In this pilot study, the addition of vancomycin to standard antibiotic prophylaxis was found safe, but its efficacy should be evaluated in a larger multiinstitutional trial. Level of Evidence: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Translating basic science insight into public health action for multidrug- and extensively drug-resistant tuberculosis.

Multidrug (MDR)‐ and extensively drug‐resistant (XDR) tuberculosis (TB) impose a heavy toll of human suffering and social costs. Controlling drug‐resistant TB is a complex global public health challenge. Basic science advances including elucidation of the genetic basis of resistance have enabled development of new assays that are transforming the diagnosis of MDR‐TB. Molecular epidemiological approaches have provided new insights into the natural history of TB with important implications for drug resistance. In the future, progress in understanding Mycobacterium tuberculosis strain‐specific human immune responses, integration of systems biology approaches with traditional epidemiology and insight into the biology of mycobacterial persistence have potential to be translated into new tools for diagnosis and treatment of MDR‐ and XDR‐TB. We review recent basic sciences developments that have contributed or may contribute to improved public health response.

The Role of Prophylactic Antibiotics in Open Fractures in an Era of Community-acquired Methicillin-resistant Staphylococcus aureus

Infection is a feared complication and a common cause of loss of function following open fractures. Despite the evidence supporting the administration of prophylactic antibiotics after open fractures, data demonstrating the optimal regimen is lacking. We reviewed the data supporting the current prophylaxis recommendations and the changing epidemiology of Staphylococcus aureus, the most common cause of surgical site infection in patients with open fractures. Although widespread emergence of methicillin-resistant Staphylococcus aureus (MRSA) has been described in both hospital and community settings, to date, no studies have addressed the need for prophylaxis against MRSA in patients with open fractures. Until well-designed randomized trials are conducted, we recommend that providers consider selecting antibiotics active against MRSA for open fracture prophylaxis based on the local prevalence of MRSA carriage and individualized risk factors.

Self-administered versus directly observed once-weekly isoniazid and rifapentine treatment of latent tuberculosis infection

Background Expanding latent tuberculosis treatment is important to decrease active disease globally. Once-weekly isoniazid and rifapentine for 12 doses is effective but limited by requiring direct observation. Objective To compare treatment completion and safety of once-weekly isoniazid and rifapentine by self-administration versus direct observation. Design An open-label, phase 4 randomized clinical trial designed as a noninferiority study with a 15% margin. Seventy-five percent or more of study patients were enrolled from the United States for a prespecified subgroup analysis. (ClinicalTrials.gov: NCT01582711). Setting Outpatient tuberculosis clinics in the United States, Spain, Hong Kong, and South Africa. Participants 1002 adults (aged ≥18 years) recommended for treatment of latent tuberculosis infection. Intervention Participants received once-weekly isoniazid and rifapentine by direct observation, self-administration with monthly monitoring, or self-administration with weekly text message reminders and monthly monitoring. Measurements The primary outcome was treatment completion, defined as 11 or more doses within 16 weeks and measured using clinical documentation and pill counts for direct observation, and self-reports, pill counts, and medication event-monitoring devices for self-administration. The main secondary outcome was adverse events. Results Median age was 36 years, 48% of participants were women, and 77% were enrolled at the U.S. sites. Treatment completion was 87.2% (95% CI, 83.1% to 90.5%) in the direct-observation group, 74.0% (CI, 68.9% to 78.6%) in the self-administration group, and 76.4% (CI, 71.3% to 80.8%) in the self-administration-with-reminders group. In the United States, treatment completion was 85.4% (CI, 80.4% to 89.4%), 77.9% (CI, 72.7% to 82.6%), and 76.7% (CI, 70.9% to 81.7%), respectively. Self-administered therapy without reminders was noninferior to direct observation in the United States; no other comparisons met noninferiority criteria. A few drug-related adverse events occurred and were similar across groups. Limitation Persons with latent tuberculosis infection enrolled in South Africa would not routinely be treated programmatically. Conclusion These results support using self-administered, once-weekly isoniazid and rifapentine to treat latent tuberculosis infection in the United States, and such treatment could be considered in similar settings when direct observation is not feasible. Primary Funding Source Centers for Disease Control and Prevention.

Interferon-gamma release assays.

Diagnosis of latent tuberculosis infection (LTBI) should be targeted toward individuals and groups with high risk of progression to active tuberculosis (TB). Low-risk populations should not be screened. Interferon-gamma release assays (IGRAs) perform as well or better than the tuberculin skin test in most targeted populations. IGRAs are preferred for bacille Calmette-Guérin (BCG)-vaccinated populations. A positive IGRA in a person at low risk for TB exposure should be confirmed with a repeat test or another method before recommending LTBI treatment. The choice of which IGRA to use is generally based on the costs and feasibility of performing the test.

Successful Limb-sparing Treatment Strategy for Diabetic Foot Osteomyelitis

BACKGROUND Diabetic foot osteomyelitis is common and causes substantial morbidity, including major amputations, yet the optimal treatment approach is unclear. We evaluated an approach to limb salvage that combines early surgical debridement or limited amputation with antimicrobial therapy. METHODS We conducted a retrospective cohort study of patients treated between May 1, 2005, and May 31, 2007. The primary end point was cure, defined as not requiring further treatment for osteomyelitis of the affected limb. The secondary end point was limb salvage, defined as not requiring a below-the-knee amputation or a more proximal amputation. RESULTS Fifty patients with diabetic foot osteomyelitis met the study criteria. Initial surgical management included local amputation in 43 patients (86%) and debridement without amputation in seven (14%). Most infections (n = 30; 60%) were polymicrobial, and Staphylococcus aureus was the most common pathogen (n = 23; 46%). Parenteral antibiotics were used in 45 patients (90%). Patients who had pathologic evidence of osteomyelitis at the surgical margin received therapy for a median of 43 days (interquartile range [IQR], 36-56 days), whereas those without evidence of residual osteomyelitis received therapy for a median of 19 days (IQR, 13-40 days). Overall, 32 patients (64%) were considered cured after a median follow-up of 26 months (IQR, 12-38 months). Fifteen of 18 patients (83%) who failed initial therapy were treated again with limb-sparing surgery. Limb salvage was achieved in 47 patients (94%), with only three patients (6%) requiring below-the-knee amputation. CONCLUSIONS In patients with diabetic foot osteomyelitis, surgical debridement or limited amputation plus antimicrobial therapy is effective at achieving clinical cure and limb salvage.

Clostridium butyricum sepsis in an injection drug user with an indwelling central venous catheter.

Clostridium novyi has been associated with a large outbreak of severe infections in injection drug users. A case of bacteraemia with Clostridium butyricum in an injection drug user is reported. During treatment for Staphylococcus aureus osteomyelitis, the patient used an indwelling central venous catheter to inject cocaine. He was admitted with C. butyricum sepsis that responded to broad spectrum antibiotics, including vancomycin. Local investigation for other cases was unrevealing; however, growth of an unusual pathogen in clinical specimens should be investigated as it may represent a sentinel event with public health implications.

High Rates of Tuberculosis and Opportunities for Prevention among International Students in the United States

RATIONALE Foreign-born persons traveling on a student visa are not currently screened for tuberculosis on entry into the United States, despite residing in the United States for up to several years. OBJECTIVES To characterize the risk of tuberculosis in international students entering the United States and to identify strategies for early diagnosis and prevention in this population. METHODS Data were collected in 18 tuberculosis control jurisdictions in the United States. A cohort of 1,268 foreign-born patients of known visa status, diagnosed with active tuberculosis between 2004 and 2007, was used for analysis. Incidence rates were estimated on the basis of immigration data from study jurisdictions. MEASUREMENTS AND MAIN RESULTS Tuberculosis was diagnosed in 46 student residents, providing an annual estimate of 308 cases nationally. The estimated tuberculosis case rate in student residents was 48.1 cases per 100,000 person-years (95% confidence interval, 35.6-64.8), more than twice that of the general foreign-born population. Students identified by tuberculosis screening programs were more likely to be diagnosed within 6 months of U.S. arrival (75 vs. 6%; P < 0.001), and those with pulmonary disease were less likely to have a positive sputum smear for acid-fast bacilli compared with those not screened (18 vs. 63%; P = 0.05). In unscreened students, 71% were diagnosed more than 1 year after U.S. arrival and only 6% were previously treated for latent tuberculosis infection. CONCLUSIONS The tuberculosis case rate in foreign-born students is significantly higher than in other foreign-born individuals. Screening this group after arrival to the United States is an effective strategy for earlier diagnosis of active tuberculosis.

Updates in the Treatment of Active and Latent Tuberculosis

First-line therapy for active tuberculosis (TB) has remained unchanged for nearly 40 years. Isoniazid, rifampin, pyrazinamide, and ethambutol for the initial two-month phase followed by isoniazid and rifampin for 4 to 7 months is standard treatment for people at low risk for drug-resistant disease. Directly-observed therapy (DOT) remains the standard of care for pulmonary TB. Virtual treatment monitoring using digital technologies is becoming more common as a way to provide a more patient-centered approach to care. Attempts to shorten treatment duration have been unsuccessful based on recent clinical trials evaluating the role of fluoroquinolones. Treatment-shortening trials using higher doses of rifamycins are currently underway. Recently approved medications for TB treatment are recommended only for drug-resistant disease, but novel agents in varying stages of development are being evaluated. Rifamycin-based regimens for latent TB infection (LTBI) have been successful in preventing progression to TB disease. Once-weekly isoniazid and rifapentine for 12 weeks by DOT was shown to be safe and effective compared with 9 months of isoniazid. The same regimen was shown to have acceptable treatment completion when given self-administered. Newer studies are investigating even shorter LTBI treatment with durations of less than 2 months. Treatment of LTBI in people likely infected with multidrug resistant TB is very limited, but one observational study found that fluoroquinolones appear to be effective. The first randomized trials for treating LTBI in contacts to MDR-TB are currently enrolling.