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Infections remain a leading cause of death in neonates. The sparse antibiotic development pipeline and challenges in conducting neonatal research have resulted in few effective antibiotics being adequately studied to treat multidrug-resistant (MDR) infections in neonates, despite the increasing global mortality burden caused by antimicrobial resistance. Of 40 antibiotics approved for use in adults since 2000, only four have included dosing information for neonates in their labelling. Currently, 43 adult antibiotic clinical trials are recruiting patients, compared with only six trials recruiting neonates. We review the World Health Organization (WHO) priority pathogens list relevant to neonatal sepsis and propose a WHO multiexpert stakeholder meeting to promote the development of a neonatal priority antibiotic development list. The goal is to develop international, interdisciplinary consensus for an accelerated neonatal antibiotic development programme. This programme would enable focused research on identified priority antibiotics for neonates to reduce the excess morbidity and mortality caused by MDR infections in this vulnerable population.

Background. A randomized, double-blind, multicenter trial involving patients with a broad range of complicated skin and skin-structure infections due to either gram-positive or gram-negative bacteria was conducted to compare ceftobiprole monotherapy with treatment with vancomycin plus ceftazidime. Methods. Patients were randomized 2:1 to receive ceftobiprole or to receive vancomycin plus ceftazidime. Outcomes were determined at a test-of-cure visit (7–14 days after completion of therapy) and were analyzed for all patients with complicated skin and skin-structure infections, as well as for subgroups, on the basis of major types of infections and severity of disease. Results. Among the clinically evaluable and the intent-to-treat populations, clinical cure rates at the test-of-cure visit were similar in the ceftobiprole and comparator treatment arms (clinical cure rate, 90.5% [439 of 485 patients] and 90.2% [220 of 244 patients] in the clinically evaluable population, respectively; 81.9% [448 of 547 patients] and 80.8% [227 of 281 patients] in the intent-to-treat population, respectively). Clinical cure rates in ceftobiprole-treated patients ranged from 86.2% (125 of 145 patients) among those with diabetes who had foot infections to 93.0% (80 of 86 patients) among those with cellulitis. Among patients treated with ceftobiprole, clinical cure rates were similar among patients from whom gram-negative bacteria were isolated (87.9% [109 of 124 patients]) and among patients from whom gram-positive bacteria were isolated (91.8% [292 of 318 patients]) and were not statistically different from the clinical cure rates among comparator-treated patients (89.7% [61 of 68 patients] and 90.3% [149 of 165 patients], respectively). Rates of adverse events and serious adverse events in the 2 treatment groups were similar. Conclusions. Ceftobiprole monotherapy is as effective as vancomycin plus ceftazidime for treating patients with a broad range of complicated skin and skin-structure infections and infections due to gram-positive and gram-negative bacteria.

The dearth of age-appropriate formulations of many medicines for children poses a major challenge to pediatric therapeutic practice, adherence, and health care delivery worldwide. We provide information on current administration practices of pediatric medicines and describe key stakeholder preferences for new formulation characteristics. We surveyed children aged 6-12 years, parents/caregivers over age 18 with children under age 12, and healthcare workers in 10 regions of Tanzania to determine current pediatric medicine prescription and administration practices as well as preferences for new formulations. Analyses were stratified by setting, pediatric age group, parent/caregiver education, and healthcare worker cadre. Complete data were available for 206 children, 202 parents/caregivers, and 202 healthcare workers. Swallowing oral solid dosage forms whole or crushing/dissolving them and mixing with water were the two most frequently reported methods of administration. Children frequently reported disliking medication taste, and many had vomited doses. Healthcare workers reported medicine availability most significantly influences prescribing practices. Most parents/caregivers and children prefer sweet-tasting medicine. Parents/caregivers and healthcare workers prefer oral liquid dosage forms for young children, and had similar thresholds for the maximum number of oral solid dosage forms children at different ages can take. There are many impediments to acceptable and accurate administration of medicines to children. Current practices are associated with poor tolerability and the potential for under- or over-dosing. Children, parents/caregivers, and healthcare workers in Tanzania have clear preferences for tastes and formulations, which should inform the development, manufacturing, and marketing of pediatric medications for resource-limited settings.

Infections remain a leading cause of death in neonates. The sparse antibiotic development pipeline and challenges in conducting neonatal research have resulted in few effective antibiotics being adequately studied to treat multidrug-resistant (MDR) infections in neonates, despite the increasing global mortality burden caused by antimicrobial resistance. Of 40 antibiotics approved for use in adults since 2000, only four have included dosing information for neonates in their labelling. Currently, 43 adult antibiotic clinical trials are recruiting patients, compared with only six trials recruiting neonates. We review the World Health Organization (WHO) priority pathogens list relevant to neonatal sepsis and propose a WHO multiexpert stakeholder meeting to promote the development of a neonatal priority antibiotic development list. The goal is to develop international, interdisciplinary consensus for an accelerated neonatal antibiotic development programme. This programme would enable focused research on identified priority antibiotics for neonates to reduce the excess morbidity and mortality caused by MDR infections in this vulnerable population.

Background. The etiology of hospital-acquired or ventilator-associated bacterial pneumonia (HABP/VABP) is often multidrug-resistant infections. The evaluation of new antibacterial drugs for efficacy in this population is important, as many antibacterial drugs have demonstrated limitations when studied in this population. HABP/VABP trials are expensive and challenging to conduct due to protocol complexity and low patient enrollment, among other factors. The Clinical Trials Transformation Initiative (CTTI) seeks to advance antibacterial drug development by streamlining HABP/VABP clinical trials to improve efficiency and feasibility while maintaining ethical rigor, patient safety, information value, and scientific validity. Methods. In 2013, CTTI engaged a multidisciplinary group of experts to discuss challenges impeding the conduct of HABP/VABP trials. Separate workstreams identified challenges associated with HABP/VABP protocol complexity. The Project Team developed potential solutions to streamline HABP/VABP trials using a Quality by Design approach. Results. CTTI recommendations focus on 4 key areas to improve HABP/VABP trials: informed consent processes/practices, protocol design, choice of an institutional review board (IRB), and trial outcomes. Informed consent processes should include legally authorized representatives. Protocol design decisions should focus on eligibility criteria, prestudy antibacterial therapy considerations, use of new diagnostics, and sample size. CTTI recommends that sponsors use a central IRB and discuss trial endpoints with regulators, including defining a clinical failure and evaluating the impact of concomitant antibacterial drugs. Conclusions. Streamlining HABP/VABP trials by addressing key protocol elements can improve trial startup and patient recruitment/retention, reduce trial complexity and costs, and ensure patient safety while advancing antibacterial drug development.

Completing its initial phases of drug development in the mid 1990s as the one of the first fluoroquinolones that could be used with confidence to treat respiratory tract infections, levofloxacin went on to become one of the most widely prescribed antibiotics in the world. Available in both oral (po) and intravenous (IV) formulations and with characteristics of over 90% bioavailability, distribution into both extracellular and intracellular pulmonary compartments, highly predictable pharmacokinetics with over 90% of the drug being excreted unchanged in urine, and reliable activity against a broad spectrum of clinically important pathogens, levofloxacin has been used successfully to treat patients with a variety of serious infectious diseases as well as common infections most often treated outside of the hospital setting. Results of clinical trials involving patients with respiratory tract, urinary tract, and skin infections have consistently shown rates of clinical success and bacteriological eradication that were comparable to other widely used broad-spectrum agents. Regimens of levofloxacin, initially involving total daily doses of 250 mg to 500 mg, but more recently regimens involving 750 mg doses, have been shown to be safe and effective. Nearly a decade and a half of clinical experience has defined a safety and tolerability profile that permits data-driven assessment of the risks and benefits of using levofloxacin. As resistance to currently available fluoroquinolones has emerged, the clinical value of levofloxacin deserves continued evaluation. However, consistently high rates of susceptibility of clinically important bacteria, especially among those bacteria that commonly cause respiratory tract infections, such as Streptococcus pneumoniae and Haemophilus influenzae, suggest that this agent will continue to be a widely used well past the 20-year anniversary of its introduction into the antibacterial armamentarium.

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality in the United States, and the incidence has been increasing within the geriatric age group as the population ages. There are many factors that are unique to this subgroup, including normal aging processes, differences in pathophysiology, and inherent medical comorbidities that affect their outcomes, treatment, and therefore, the allocation of medical and social services. The geriatric population has age-appropriate strength, coordination and balance deficits that make them predisposed to falls and subsequent TBI. The aging brain often has premorbid atrophy and increased susceptibility to the inflammatory, excitatory, and vascular processes that facilitate neurologic damage during the acute phases after injury. The aged also can have premorbid neurodegenerative and medical comorbidities that also affect their rehabilitation course, recovery, and outcomes once a TBI has occurred. Pharmacological strategies to maximize rehabilitation and recovery require specific considerations of the potential for adverse effects and contraindications specific to common comorbidities in the aged population. The management of geriatric TBI requires a coordinated effort between physicians and other healthcare providers with focus on risk factor modification, medical optimization, and successful return to the community by setting goals that emphasize level of function and quality of life.

Intravenous immune gamma-globulin (IVIG) is used successfully in the treatment of Kawasaki disease, with dose-dependent rapid resolution of symptoms such as fever and irritability and a decrease in ESR, WBCs, and platelets. The mode of action of IVIG in reducing this inflammatory response is not clearly understood. Recently anticytokine antibodies in IVIG have been demonstrated. Serum levels of proinflammatory cytokines have been shown to be elevated in patients with Kawasaki disease. The cytokine interleukin-6 (IL-6) is involved in the de novo production of acute-phase proteins by hepatocytes and cause thrombocytosis and fever in response to tissue injury. Patients receiving parenteral recombinant human IL-6 have dose-dependently experienced fever, malaise, chills, and acute-phase reaction. With high IL-6 concentrations, central nervous system toxicity has also been reported and IL-6 has been thought to mediate endothelial damage. We evaluated the response of stimulated blood cells of 12 normal children to IVIG in the release of the cytokines IL-6, IL-8, TNF-alpha. and IL-6 receptor (sIL-6R). The levels of cytokines IL-6, IL-8, and TNF-alpha (but not sIL-6R) in peripheral blood induced by stimulation with LPS were markedly reduced (P < 0.008) within 3 hr when incubated with IVIG compared to without IVIG. Thus we demonstrated that cells of normal children respond to IVIG in vitro by reducing cytokines such as IL-8, TNF-alpha, and IL-6 without affecting the level of receptor sIL-6R during an acute inflammatory response. We also found significantly higher IL-6 levels in children with Kawasaki disease compared to children with blood culture-negative febrile illnesses. In five children with Kawasaki disease we measured serum IL-6 before and after IVIG and assessed the clinical response to IVIG therapy. Therapy with IVIG was followed by a rapid resolution of symptoms in Kawasaki disease, with a significant decrease in serum IL-6. The attenuation of proinflammatory cytokine responses, especially IL-6, following infusions of IVIG may play an integral role in the rapid resolution of symptoms and decrease in the acute-phase proteins in children with Kawasaki disease. Cells of normal children were found to respond to the IVIG in a manner similar to that of the Kawasaki children.