Phase 3 adaptive trial design options in treatment of complicated urinary tract infection.

New antimicrobial drugs for treatment of complicated urinary tract infection (cUTI) are generally assessed in randomized, double-blind, noninferiority clinical trials. Robust historical data for the active comparator inform on treatment effect estimation, yet typically do not substitute for the active comparator data in the proposed trial. We report design options for a phase 3 trial of cUTI using a Bayesian hierarchical model and historical data from 2 well-executed phase 3 registrational trials of doripenem. The methodology is directly applicable to other phase 3 noninferiority settings. In addition to the research design application, we provide a novel methodology for assessing the robustness of type I error control. The model borrows heavily from the prior data when the current active comparator parameter estimate approximated the historical estimate. In contrast, the model had restricted borrowing when the 2 estimates were very different. The alternative trial design, with or without the inclusion of futility stopping criteria, provides a framework for future cUTI phase 3 trials.

Community-Acquired Pneumonia Case Validation in an Anonymized Electronic Medical Record-Linked Expert System.

An electronic anonymized patient portal analysis using radiographic reports and admission and discharge diagnoses had sensitivity, specificity, positive predictive value, and negative predictive value of 84.7%, 78.2%, 75%, and 87%, respectively, for community-acquired pneumonia validated against a blinded expert medical review. This approach can help to track antimicrobial use and resistance.

Systematic Review and Meta-Analysis To Estimate Antibacterial Treatment Effect in Acute Bacterial Skin and Skin Structure Infection.

A systematic literature review and meta-analysis were conducted to estimate the antibacterial treatment effect for linezolid and ceftaroline to inform on the design of acute bacterial skin and skin structure infection (ABSSSI) noninferiority trials. The primary endpoints included an early clinical treatment response (ECTR) defined as cessation of lesion spread at 48 to 72 h postrandomization and the test-of-cure (TOC) response defined as total resolution of the infection at 7 to 14 days posttreatment. The systematic review identified no placebo-controlled trials in ABSSSI, 4 placebo-controlled trials in uncomplicated skin and soft tissue infection as a proxy for placebo in ABSSSI, 12 linezolid trials in ABSSSI, 3 ceftaroline trials in ABSSSI, and 2 trials for nonantibacterial treatment. The ECTR rates at 48 to 72 h and corresponding 95% confidence intervals (CI) were 78.7% (95% CI, 61.1 to 96.3%) for linezolid, 74.0% (95% CI, 69.7 to 78.3%) for ceftaroline, and 59.0% (95% CI, 52.8 to 65.3%) for nonantibacterial treatment. The early clinical treatment effect could not be estimated, given no available placebo or proxy for placebo data for this endpoint. Clinical, methodological, and statistical heterogeneity influenced the selection of trials for the meta-analysis of the TOC treatment effect estimation. The pooled estimates of the TOC treatment response were 31.0% (95% CI, 6.2 to 55.9%) for the proxy for placebo, 88.1% (95% CI, 81.0 to 95.1%) for linezolid, and 86.1% (95% CI, 83.7 to 88.6%) for ceftaroline. The TOC clinical treatment effect estimation was 25.1% for linezolid and 27.8% for ceftaroline. The antibacterial treatment effect estimation at TOC will inform on the design and analysis of future noninferiority ABSSSI clinical trials.

Tuberculin skin test and QuantiFERON-TB Gold In-tube Test for latent tuberculosis in Thai HIV-infected adults.

BACKGROUND AND OBJECTIVE: Limited data exist for the performance of QuantiFERON-TB Gold In-tube Test (QFT-IT) in comparison to tuberculin skin test (TST) for detecting latent tuberculosis (LTB) in patients with human immunodeficiency virus (HIV) infection from tuberculosis (TB)-endemic Asia-Pacific countries. METHODS: A cohort study of Thai HIV-infected patients without history of TB or LTB treatment was conducted from March 2012 through March 2013. Each patient underwent simultaneous TST and QFT-IT. RESULTS: Among the 150 enrolled subjects, the median age was 40 years (range 17-65), 53% were male, and the median CD4 count was 367 cells/µL (range 8-1290). Reactive TST and positive QFT-IT were 16% and 13%, respectively, with low concordance between tests (kappa = 0.26); correlation between TST reaction size and level of interferon-γ was moderate (r = 0.34). Independent factors associated with discordant results were long-term smoking (adjusted odds ratio (aOR) 5.74; P = 0.002) for TST-reactive, QFT-IT-negative subjects, and age greater than 52 years (aOR 5.56; P = 0.02) and female gender (aOR 4.40; P = 0.04) for TST non-reactive, QFT-IT-positive subjects. The level of agreement between both tests improved when using a TST cut-off of ≥ 10 mm (kappa = 0.39). CONCLUSIONS: In our setting where QFT-IT is available but has limited use due to cost, TST with a cut-off of 10 mm for reactivity should be the initial LTB test. HIV-infected women and persons older than 52 years with non-reactive TST and long-term smokers with reactive TST may benefit from subsequent QFT-IT.

Systematic review and meta-analysis of antimicrobial treatment effect estimation in complicated urinary tract infection.

Noninferiority trial design and analyses are commonly used to establish the effectiveness of a new antimicrobial drug for treatment of serious infections such as complicated urinary tract infection (cUTI). A systematic review and meta-analysis were conducted to estimate the treatment effects of three potential active comparator drugs for the design of a noninferiority trial. The systematic review identified no placebo trials of cUTI, four clinical trials of cUTI with uncomplicated urinary tract infection as a proxy for placebo, and nine trials with reports of treatment effect estimates for doripenem, levofloxacin, or imipenem-cilastatin. In the meta-analysis, the primary efficacy endpoint of interest was the microbiological eradication rate at the test-of-cure visit in the microbiological intent-to-treat population. The estimated eradication rates and corresponding 95% confidence intervals (CI) were 31.8% (26.5% to 37.2%) for placebo, 81% (77.7% to 84.2%) for doripenem, 79% (75.9% to 82.2%) for levofloxacin, and 80.5% (71.9% to 89.1%) for imipenem-cilastatin. The treatment effect estimates were 40.5% for doripenem, 38.7% for levofloxacin, 34.7% for imipenem-cilastatin, and 40.8% overall. These treatment effect estimates can be used to inform the design and analysis of future noninferiority trials in cUTI study populations.

Access to antiretroviral therapy during excess black-water flooding in central Thailand.

Excess black-water flooding in central Thailand resulted in closure of several healthcare facilities in the Fall of 2011. Persons living with human immunodeficiency virus (HIV) infection were presumably at risk for interruption of antiretroviral therapy (ART), with consequent treatment failure. We conducted a retrospective cohort study of ART use among patients in care at a Thai HIV clinic that closed due to excess flood water. Among 217 patients on ART who had clinic appointments within the one-month interval before the floods through the one-month interval after the clinic re-opened, seven (3%) reported non-sustained ART access. Non-sustained ART access was independently associated with prior low self-reported ART adherence (P<0.001) and less than six-months duration on the ART regimen (P=0.03). Advanced ART receipt or procurement at other flood-free healthcare facilities were strategies associated with ART access. During a flood disaster, identification and close monitoring of at-risk patients, patient-staff communication, flood preparedness plans, "HIV care access for all" policies, and collaboration among patients, healthcare providers and the government are relevant issues within preparedness plans to optimize ART access.

Postflood pseudofungemia due to Penicillium species.

We report an outbreak investigation of fungemia due to Penicillium species after prolonged flooding of a Thai hospital. Contaminated rubber diaphragms of blood culture bottles were identified, and the pseudo-outbreak was resolved after environmental cleaning, use of high-efficiency particulate air filtration, and strict compliance with basic infection control practices for blood culture procurement.

The high comorbidity burden of the hepatitis C virus infected population in the United States.

BACKGROUND: Chronic hepatitis C (HCV) disease can be complicated with comorbid conditions that may impact treatment eligibility and outcomes. The aim of the study was to systematically review comorbidities and symptoms in an HCV infected population, specifically assessing comorbidities associated with HCV anti-viral treatment and disease, as well as comparing comorbidities between an HCV infected and uninfected control population. METHODS: This was a retrospective cohort study within a United States medical claims database among patients with chronic HCV designed to estimate the two-year period prevalence of comorbidities. Patients with two HCV diagnosis codes, 24 months of continuous health insurance coverage, and full medical and pharmacy benefits were included. RESULTS: Among a chronic HCV cohort of 7411 patients, at least one comorbid condition was seen in almost all patients (> 99%) during the study period. HCV-infected patients reported almost double the number of comorbidities compared to uninfected controls. Of the 25 most common comorbidities, the majority of the comorbidities (n = 22) were known to be associated with either HCV antiviral treatment or disease. The five most frequent comorbidities were liver disease [other] (37.5%), connective tissue disease (37.5%), abdominal pain (36.1%), upper respiratory infections (35.6%), and lower respiratory disease (33.7%). Three notable comorbidities not known to be associated with antiviral treatment or disease were benign neoplasms (24.3%), genitourinary symptoms & ill-defined conditions (14.8%), and viral infections (13.8%). CONCLUSIONS: This US medically insured HCV population is highly comorbid. Effective strategies to manage these comorbidities are necessary to allow wider access to HCV treatment and reduce the future burden of HCV disease and its manifestations.

Predictors for recombinant HIV infection in a Thai cohort.

Recombinant human immunodeficiency virus (HIV) infection was associated with exchange of sex for money, ≥1 sex partner within the prior 6 months, and decline in CD4 cell count in this Thai cohort study. These findings suggest that recombinant HIV infection may have implications for HIV disease progression, safer sex practices, and vaccine development.

Ferric Carboxymaltose for Anemic Perioperative Populations: A Systematic Literature Review of Randomized Controlled Trials.

IMPORTANCE: Perioperative anemia is a common comorbid condition associated with increased risk of morbidity and mortality in patients undergoing elective surgical procedures. OBJECTIVE: We conducted a systematic literature review (SLR) to determine the efficacy and safety of the use of intravenous ferric carboxymaltose (FCM) for the treatment of perioperative anemia in preoperative, intraoperative, and postoperative elective surgical care. EVIDENCE REVIEW: Studies meeting inclusion criteria for the SLR reported on treatment efficacy in an adult study population randomly allocated to FCM for the treatment of perioperative anemia during the perioperative period. After screening, 10 of 181 identified studies from searches in MEDLINE and EMBASE databases were identified for inclusion in this review. FINDINGS: Preoperative treatment was reported in six studies, intraoperative treatment in one study, postoperative treatment in two studies, and both pre- and postoperative treatment in one study. Together, 1975 patients were studied, of whom 943 were randomized to FCM, of whom 914 received FCM treatment. The 10 studies reported elective surgical populations for colorectal, gastric, orthopedic, abdominal, urologic, plastic, neck, gynecologic, and otolaryngologic procedures. Given the clinical and methodological heterogeneity of the studies, the analyses were limited to qualitative assessments without meta-analyses. All 10 studies reported statistically greater changes in hemoglobin concentration, serum ferritin, and/or transferrin saturation with FCM treatment compared with comparators (placebo, oral iron, standard care, or a combination of these). Two studies reported statistically significant differences in transfusion rate and 2 studies reported significant differences in length of hospital stay between FCM and its comparator(s). CONCLUSIONS AND RELEVANCE: This SLR adds to existing data that administration of FCM in preoperative and postoperative settings improves hematologic parameters. Several studies in the review supported the beneficial effects of FCM in reducing transfusion rate and length of stay. Larger, well-designed, longer-term studies may be needed to further establish the efficacy and safety of FCM in elective surgery patients with perioperative anemia.

Randomized Placebo-Controlled Trial of Ferric Carboxymaltose in Heart Failure With Iron Deficiency: Rationale and Design.

BACKGROUND: Iron deficiency (ID) has a prevalence of ≈40% to 50% among patients in heart failure (HF) with reduced ejection fraction and is associated with worse prognosis. Several trials demonstrated that intravenous ferric carboxymaltose leads to early and sustained improvement in patient-reported outcomes and functional capacity in patients with HF with reduced ejection fraction with ID, yet morbidity and mortality data are limited. METHODS: The objective of the HEART-FID trial (Ferric Carboxymaltose in Heart Failure With Iron Deficiency) is to assess efficacy and safety of ferric carboxymaltose compared with placebo as treatment for symptomatic HF with reduced ejection fraction with ID. HEART-FID is a multicenter, randomized, double-blind, placebo-controlled trial enrolling ≈3014 patients at ≈300 international centers. Eligible patients are aged ≥18 years in stable chronic HF with New York Heart Association functional class II to IV symptoms, ejection fraction ≤40%, ID (ferritin <100 ng/mL or ferritin 100-300 ng/mL with a transferrin saturation <20%), and documented HF hospitalization or elevated N-terminal pro-brain natriuretic peptide. Consented patients are assigned to ferric carboxymaltose or placebo at baseline, with repeated visits/assessments every 6 months for additional study drug based on hemoglobin and iron indices for the trial duration. The primary end point is a hierarchical composite of death and HF hospitalization at 12 months and change from baseline to 6 months in the 6-minute walk test distance. CONCLUSIONS: The HEART-FID trial will inform clinical practice by clarifying the role of long-term treatment with intravenous ferric carboxymaltose, added to usual care, in ambulatory patients with symptomatic HF with reduced ejection fraction with ID. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03037931.

Serum sickness-like reaction associated with inactivated influenza vaccination among Thai health care personnel: risk factors and outcomes.

Fourteen (3%) of 495 Thai health care personnel were identified as having a serum sickness-like reaction in 2008 after receipt of inactivated influenza vaccine manufactured in Thailand. These health care personnel experienced fever, myalgia, centrifugal arthralgias, and injection site erythema. A history of allergic reactions to food or drugs (adjusted odds ratio, 5.9; 95% confidence interval, 1.54-25.4) was independently associated with a serum sickness-like reaction.

Outcomes of extended-spectrum beta-lactamases producing Enterobacteriaceae colonization among patients abdominal surgery patients.

Preoperative enteric screening for extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae was conducted in 360 patients prospectively observed for surgical site infection (SSI). ESBL colonization (adjusted odds ratio [aOR], 2.4) and dirty wound classification (aOR, 3.6) were associated with SSI; no association between carbapenem prophylaxis and reduction in SSI was detected.

A nationally coordinated laboratory system for human avian influenza A (H5N1) in Thailand: program design, analysis, and evaluation.

BACKGROUND: The first phase of national surveillance for avian influenza (H5N1) human disease in Thailand occurred over a 4-month period that began on 1 December 2003. Subsequently, a nationally coordinated laboratory system (NCLS) for avian influenza (H5N1) was created to assess population-based surveillance, specimen procurement, case detection, and reporting at the national level. METHODS: We conducted a pre- and postintervention study to evaluate the NCLS designed during the 6-week interval from 1 April through 15 May 2004. During the pre-NCLS period (1 December 2003 through 31 March 2004), 12 cases of human avian influenza (H5N1) were confirmed. During the post-NCLS period (16 May 2004 through 31 December 2006), interventions were implemented for human avian influenza (H5N1) surveillance, case detection, and expedited, computer-based reporting. RESULTS: During the pre- and post-NCLS periods, 777 (85%) of 915 and 10,434 (95%) of 11,042 clinical respiratory specimens, respectively, were adequate for confirmatory testing (P<.001), the median time from procurement to results decreased from 17 days (range, 14-24 days) to 1.8 days (range, 0.25-4 days; P<.001), and the duration of specimen shipment decreased from 46.5 h to 21.1 h (P<.001). Thirteen cases of avian influenza (H5N1) were detected during the 31-month postintervention period. H5N1 reverse-transcriptase polymerase chain reaction and real-time reverse-transcriptase polymerase chain reaction sensitivity was 100% and specificity was 99.8%. CONCLUSIONS: The NCLS exemplifies a systematic approach to national surveillance for avian influenza A (H5N1). This NCLS program in Thailand serves as a model for human avian influenza (H5N1) preparedness that can be adopted or modified for use in other countries.

Nonjudicious dispensing of antibiotics by drug stores in Pratumthani, Thailand.

Mock patient presentations of 6 common syndromic ailments to drug stores in Pratumthani, Thailand, were conducted. Appropriate dispensing of antibiotic therapy for all 6 presentations occurred at 56 (20%) of 280 drug stores. By multivariate analysis, drug stores' proximity to a hospital was associated with appropriate dispensing of antibiotics (adjusted odds ratio, 34 [95% confidence interval, 15-83]; P < .001).