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Objective: Employ the hollow fiber infection model (HFIM) to study sequential antibiotic administration (ampicillin, ciprofloxacin and fosfomycin) using human pharmacokinetic profiles to measure changes in the rate of antibiotic resistance development and compare this to simultaneous combination therapy with the same antibiotic combinations. Methods: Escherichia coli CFT073, a clinical uropathogenic strain, was exposed individually to clinically relevant pharmacokinetic concentrations of ampicillin on day 1, ciprofloxacin on day 2 and fosfomycin on day 3. This sequence was continued for 10 days in the HFIM. Bacterial samples were collected at different time points to enumerate total and resistant bacterial populations. The results were compared with the simultaneous combination therapy previously studied. Results: Sequential antibiotic treatment (ampicillin-ciprofloxacin-fosfomycin sequence) resulted in the early emergence of single and multi-antibiotic-resistant subpopulations, while the simultaneous treatment regimen significantly delayed or prevented the emergence of resistant subpopulations. Conclusion: Sequential administration of these antibiotic monotherapies did not significantly delay the emergence of resistant subpopulations compared to simultaneous treatment with combinations of the same antibiotics. Further studies are warranted to evaluate different sequences of the same antibiotics in delaying emergent resistance. [ABSTRACT FROM AUTHOR]

This is the third of three articles in the November 2007 issue on developing new drug treatments for tuberculosis. The Pressing Need for MDR-TB Clinical Trials Drug-resistant strains of Mycobacterium [...]

Digital health technology (DHT), including wearable and environmental sensors, video cameras and other electronic tools, has provided new opportunities for the measurement of movement and functionality in Parkinson's disease. Compared to current standards for evaluation of the disease (MDS-UPDRS), DHT may offer new possibilities for more frequent objective measurements of the duration, severity and frequency of disease manifestations over time, that may provide more information than periodic clinic visits. However, DHT measurements are only scientifically and medically useful if they are accurate, reliable and clinically meaningful. Verification and validation, also known as analytical validation and clinical validation, of DHT performance is important to ensure the accuracy and precision of measurements, and the specificity of findings. Given the wide range of clinical manifestations associated with Parkinson's disease and the many tools and metrics to assess them, the challenge is to identify those that may represent a standard for use in clinical trials, and to confirm when digital measurements succeed or fall short of capturing meaningful benefits during drug development. [ABSTRACT FROM AUTHOR]

Mobile technology has become a ubiquitous part of everyday life, and the practical utility of mobile devices for improving human health is only now being realized. Wireless medical sensors, or mobile biosensors, are one such technology that is allowing the accumulation of real-time biometric data that may hold valuable clues for treating even some of the most devastating human diseases. From wearable gadgets to sophisticated implantable medical devices, the information retrieved from mobile technology has the potential to revolutionize how clinical research is conducted and how disease therapies are delivered in the coming years. Encompassing the fields of science and engineering, analytics, health care, business, and government, this report explores the promise that wearable biosensors, along with integrated mobile apps, hold for improving the quality of patient care and clinical outcomes. The discussion focuses on groundbreaking device innovation, data optimization and validation, commercial platform integration, clinical implementation and regulation, and the broad societal implications of using mobile health technologies. [ABSTRACT FROM AUTHOR]

Randomized clinical trials are regarded as the gold standard for evaluating the effectiveness and safety of interventions. The US Food and Drug Administration (FDA) has made efforts to promote inclusive eligibility criteria. The objective of this study is to identify common trends in eligibility criteria and identify patterns of exclusion criteria among different diseases. The authors evaluated the inclusion and exclusion criteria of 38 pivotal clinical trials representing 38 novel drugs approved between 2014 and 2017. Additionally, the authors reviewed the demographic characteristics of participants enrolled across 38 trials. Eighty two percent of trials in our study excluded participants based on hepatic related criteria and 79% trials excluded participants based on renal related criteria and specific infectious diseases. For trials in conditions that affected both men and women, there were no exclusions based on gender and race. More than 90% of trials excluded pregnant, lactating women and women not on adequate contraception. Of the 36,644 patients enrolled in trials for which both men and women were eligible, 62% were men. The most frequent exclusion criteria were pregnancy, lactation/breastfeeding, renal and hepatic abnormalities, and specific infectious diseases. The preponderance of men in our study likely indicates that factors other than exclusion criteria affect enrollment. The lower representation of women may have been influenced by two large cardiovascular trials that included 75% men. Our study marks an important step in the ongoing efforts of the Agency to increase inclusivity in clinical trials by understanding common clinical trial eligibility criteria patterns. [ABSTRACT FROM AUTHOR]

Discusses a study which examined the effectiveness of adjunctive aerosol aminoglycosides as salvage therapy for a population of patients with tuberculosis who failed to respond to traditional therapy. Characteristics of the patients; Data and methodology; Duration of aerosol therapy; Sputum smear results.

Provides information on a study which reported the first outbreak of nosocomial multidrug-resistant tuberculosis (MDR-TB) in human immunodeficiency virus (HIV)-infected people in South Africa. How the study was conducted; Results; Discussion of the results.

CD4+ T lymphocyte measurements are used frequently in clinical practice and have important prognostic implications. In this study, we describe mortality patterns for 5,204 human immunodeficiency virus (HIV)—infected patients classified in different CD4+ cell strata; patients with and patients without a history of disease progression were included. Patients were enrolled in studies sponsored by the Terry Beirn Community Programs for Clinical Research on AIDS of the National Institute of Allergy and Infectious Diseases between September 1990 and December 1993. Over a median follow-up period of 23.6 months, 1,703 of the 5,204 patients died. For those with CD4+ cell counts (/mm3) of <25, 25–49, 50–99, 100–199, and 200–499, the cumulative mortality rates after 24 months were 72%, 58%, 47%, 27%, and 10%, respectively. The median survival time was 15 months for those with CD4+ cell counts of <25 cells/mm3 ; 21 months for those with CD4+ cell counts of 25–49 cells/mm3 ; and 40 months for patients with CD4+ cell counts of 100–199/mm3. In each CD4+ cell stratum, mortality rates were higher for those with a history of disease progression at entry into the study; across all CD4+ cell strata, mortality was 60% greater (relative risk = 1.6; 95% confidence interval = 1.5–1.8). These data should be useful in planning clinical trials, and they have implications in terms of the frequency with which CD4+ cell counts should be measured to monitor the progression of HIV infection. [ABSTRACT FROM PUBLISHER]

Urinary tract infections (UTI) are common worldwide and are becoming increasingly difficult to treat because of the development of antibiotic resistance. Immunocompetent murine models of human UTI have been used to study pathogenesis and treatment but not for investigating resistance development after treatment with antibiotics. In this study, intravesical inoculation of uropathogenic Escherichia coli CFT073 in immunocompetent Balb/c mice was used as a model of human UTI. The value of the model in investigating antibiotic exposure on in vivo emergence of antibiotic resistance was examined. Experimentally infected mice were treated with 20 or 200 mg/kg ampicillin, 5 or 50 mg/kg ciprofloxacin, or 100 or 1000 mg/kg of fosfomycin. Ampicillin and ciprofloxacin were given twice daily at 8 h intervals, and fosfomycin was given once daily. Antibiotic treatment began 24 h after bacterial inoculation and ended after 72 h following the initial treatment. Although minimum inhibitory concentrations (MIC) for the experimental strain of E. coli were exceeded at peak concentrations in tissues and consistently in urine, low levels of bacteria persisted in tissues in all experiments. E. coli from bladder tissue, kidney, and urine grew on plates containing 1× MIC of antibiotic, but none grew at 3× MIC. This model is not suitable for studying emergent resistance but might serve to examine bacterial persistence. [ABSTRACT FROM AUTHOR]

Background Multi and extensively drug-resistant (MDR and XDR) tuberculosis (TB) remains a treatment challenge due to drug adverse events (AEs) and long regimens. Our aim was to identify AEs which resulted from repurposing drugs for MDR and XDR-TB. Methods A PubMed search for case reports of repurposed drugs for MDR and XDR-TB from January 1, 2014 to October 23, 2018 identified 130 patients (78 MDR, 52 XDR) in 91 articles. There were 31 extrapulmonary, 81 pulmonary TB cases, and 18 with both. Drugs were regarded as repurposed if they were either not approved for TB by the FDA, or they were approved for TB but were used in novel populations, novel combinations, or nonstandard doses. Drug labels were reviewed for AEs. Results Linezolid (n = 65) and moxifloxacin (n = 48) were the most commonly repurposed drugs. The following were also frequently used: clofazimine (n = 47), levofloxacin (n = 45), amikacin (n = 43), amoxicillin-clavulanate (n = 40), kanamycin (n = 36), carbapenems (n = 22), and clarithromycin (n = 17). Of the drugs that are approved for TB, the following were repurposed in a novel population, dose, or combination: cycloserine (n = 20), bedaquiline (n = 13), capreomycin (n = 4), ethambutol (n = 3), and isoniazid (n = 3). Treatments were discontinued due to AEs in 41 patients. There were no discontinuations for amoxicillin-clavulanate and levofloxacin. Extended drug exposure is a unique treatment feature for MDR and XDR-TB, which often requires ~2 years of treatment. Approximately 87% of treatment discontinuations due to AEs occurred after >1 month of exposure. AEs leading to treatment discontinuation after > 6 months of drug exposure were seen in 15 cases, of which 12 were due to linezolid and cycloserine. Peripheral and optic neuropathy was the most common AE reported (linezolid n = 12, cycloserine n = 1). Most AEs were labeled events. Conclusion Several antimicrobials are being repurposed to treat MDR and XDR-TB. There were no AEs reported after prolonged use that was not described in drug labels. Physicians should review information in labeling if prescribing drugs in this manner. There is a need for comparative safety data for repurposed drugs assessed through clinical trials. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]

In this Viewpoint, Janet Woodcock and CDER colleagues discuss recent FDA initiatives to investigate the adequacy of electronic health record (EHR) and patient database data for research purposes and to understand if and how real-world observational data might be analyzed in ways that mimic or can be as reliable as randomized trials. [ABSTRACT FROM AUTHOR]

Presents a study which described the clinical and radiological features of patients in South Africa with tuberculomas of the brain. Etiology of intracranial tuberculomas; Requirements for the bacteriological diagnosis of lesions; Laboratory findings on cerebrospinal fluid.

Summary: Simplifying and shortening treatment for drug-sensitive tuberculosis and providing new treatment options for drug-resistant tuberculosis constitute two principal goals in the development of novel drugs for tuberculosis. Demonstration of clinical efficacy in drug-sensitive tuberculosis is challenging, given high success rates for existing regimens, concerns about substituting an investigational agent for the most effective agents in a regimen and difficulties in determining the effect size of the components of a combination regimen. Large and prolonged studies would be needed either to show superiority over existing regimens or statistically defensible non-inferiority compared to existing regimens. In contrast, exploring efficacy of novel treatments in the setting of drug-resistant disease may present certain opportunities. In drug-resistant disease, the efficacy of existing regimens is comparatively poor, and companion drugs used to treat drug-resistant disease are weak or ineffective, enabling demonstration of the effect of the new drug. Other advantages of this approach, which has been used successfully in the development of antiretroviral agents, include the possibility of demonstrating drug efficacy using smaller studies, the possibility of accelerated approval based on a surrogate endpoint and the opportunity to address an urgent public health need. Experience with the activity and the safety of new agents in drug-resistant disease may provide a platform from which their indication can be broadened to include drug-sensitive disease. [Copyright &y& Elsevier]

• Escherichia coli CFT073 develops resistance to ampicillin (AMP), ciprofloxacin (CIP) and fosfomycin (FOF) monotherapies. • AMP, CIP and FOF combinations delayed antibiotic resistance emergence in E. coli. • The HFIM system could potentially be used to identify clinically relevant antibiotic combinations. Antibiotic resistance is one of the major threats to public health today. To address this problem requires an urgent comprehensive approach. Strategic and multitargeted combination therapy has been increasingly used clinically to treat bacterial infections. The hollow-fibre infection model (HFIM) is a well-controlled in vitro bioreactor system that is increasingly being used in the assessment of resistance emergence with monotherapies and combination antibiotic therapies. In this study, the HFIM was evaluated as a reliable in vitro method to quantitatively and reproducibly analyse the emergence of antibiotic resistance using ampicillin, fosfomycin and ciprofloxacin and their simultaneous combinations against Escherichia coli CFT073, a clinical uropathogenic strain. Bacteria were exposed to clinically relevant pharmacokinetic (PK) concentrations of the drugs for 10 days. Drug and bacterial samples were collected at different time points for PK analysis and to enumerate total and resistant bacterial populations, respectively. The results demonstrated that double or triple combinations significantly delayed the emergence of resistant E. coli CFT073 subpopulations. These findings suggest that strategic combinations of antimicrobials may play a role in controlling the emergence of resistance during treatment. Further animal and human trials will be needed to confirm this and to ensure that there is no adverse impact on the host microbiome or unexpected toxicity. The HFIM system could potentially be used to identify clinically relevant combination dosing regimens for use in a clinical trial evaluating the appearance of resistance to antibacterial drugs. Image, graphical abstract [ABSTRACT FROM AUTHOR]