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Contains fulltext : 208938.pdf (Publisher’s version ) (Open Access) Gametocyte density and sex ratio can predict the proportion of mosquitoes that will become infected after feeding on blood of patients receiving nongametocytocidal drugs. Because primaquine and methylene blue sterilize gametocytes before affecting their density and sex ratio, mosquito feeding experiments are required to demonstrate their early transmission-blocking effects.

Background The impact of 13-valent pneumococcal conjugate vaccine (PCV13) on pneumococcal meningitis (PM) in US children is unknown. We compared the serotype distribution, antibiotic susceptibility, hospital course, and outcomes of children with PM 3 years before and 3 years after the introduction of PCV13. Methods We identified patients ≤ 18 years of age with PM at 8 children's hospitals in the United States. Pneumococcal isolates were collected prospectively. Serotyping and antibiotic susceptibility were performed in a central laboratory. Clinical data were abstracted from medical records. Patients were divided into 3 subgroups: pre-PCV13 (2007-2009), transitional year (2010), and post-PCV13 (2011-2013). Categorical variables were analyzed by the χ(2) test and continuous variables by the Mann--Whitney U test. Results During the study period, 173 of 1207 episodes (14%) of invasive pneumococcal disease were identified as PM; 76 of 645 (12%) were during 2007-2009 and 69 of 394 (18%) during 2011-2013 (50% increase; P = .03). The proportion of PCV13 serotype cases decreased from 54% in 2007-2009 to 27% in 2011-2013 (P = .001). Non-PCV13 serotype cases represented 73% of the isolates in 2011-2013. Isolates with ceftriaxone minimum inhibitory concentration ≥ 1 µg/mL decreased (13% to 3%) from 2007-2009 to 2011-2013 (P = .03). No significant differences were identified for hospital course or outcome, with the exception that a greater proportion of patients had subdural empyema and hemiparesis in 2011-2013. Conclusions After the introduction of PCV13, the number of cases of PM in children remained unchanged compared with 2007-2009, although the proportion of PCV13 serotypes decreased significantly. Serotype 19A continued to be the most common serotype in 2011-2013. Antibiotic resistance decreased significantly. Morbidity and case-fatality rate due to PM remain substantial.

Infections caused by antibiotic-resistant bacteria, especially the "ESKAPE" pathogens, continue to increase in frequency and cause significant morbidity and mortality. New antimicrobial agents are greatly needed to treat infections caused by gram-negative bacilli (GNB) resistant to currently available agents. The Infectious Diseases Society of America (IDSA) continues to propose legislative, regulatory, and funding solutions to this continuing crisis. The current report updates the status of development and approval of systemic antibiotics in the United States as of early 2013. Only 2 new antibiotics have been approved since IDSA's 2009 pipeline status report, and the number of new antibiotics annually approved for marketing in the United States continues to decline. We identified 7 drugs in clinical development for treatment of infections caused by resistant GNB. None of these agents was included in our 2009 list of antibacterial compounds in phase 2 or later development, but unfortunately none addresses the entire spectrum of clinically relevant GNB resistance. Our survey demonstrates some progress in development of new antibacterial drugs that target infections caused by resistant GNB, but progress remains alarmingly elusive. IDSA stresses our conviction that the antibiotic pipeline problem can be solved by the collaboration of global leaders to develop creative incentives that will stimulate new antibacterial research and development. Our aim is the creation of a sustainable global antibacterial drug research and development enterprise with the power in the short term to develop 10 new, safe, and efficacious systemically administered antibiotics by 2020 as called for in IDSA's "10 × '20 Initiative."

Efficacy endpoints for previous registrational trials of antimicrobials for acute bacterial skin and skin structure infections (ABSSSIs) and community-acquired bacterial pneumonia (CABP) were based on nonstandardized, clinician-based observations and decisions, as well as on patient reports. More quantifiable, reproducible, and externally verifiable endpoints could improve the design of future noninferiority trials. At the request of the Food and Drug Administration, the Foundation for the National Institutes of Health convened a broadly representative scientific project team to evaluate potential endpoints for such registrational trials. Review of historical and modern data led to the conclusion that antimicrobial treatment effects are most apparent early in therapy; later outcomes provide important supportive information. Although evidence is incomplete, early response endpoints can anchor noninferiority hypotheses in ABSSSI and CABP registrational trials, thereby allowing evidence-based drug development to continue. Further research is underway to establish which short- and long-term outcomes are well-defined, reliable, and reflective of how patients feel, function, or survive.

(See the editorial commentary by Jain et al, on pages 707–709.) Background. Peramivir, an investigational intravenous neuraminidase inhibitor in Phase 3 trials for hospitalized patients, was made available during the 2009 H1N1 influenza pandemic under the Emergency Investigational New Drug (eIND) regulations. We describe the clinical characteristics and outcomes of all patients for whom peramivir was requested under the eIND. Methods. After obtaining eIND approval from the Food and Drug Administration and local institutional review board approval, clinicians caring for hospitalized patients with influenza administered intravenous peramivir and collected information on demographic characteristics, clinical characteristics, and outcomes. Results. From April through October 2009, peramivir was requested for 42 patients and administered to 20 adults and 11 children. At hospitalization, all patients had rapidly progressing, radiographically confirmed viral pneumonia with respiratory failure, and all but 1 patient required mechanical ventilation. In most patients, including 1 person with documented oseltamivir-resistant infection, the illness had progressed despite oseltamivir treatment. Peramivir was administered for 1–14 days (median duration, 10 days). The 14-day, 28-day, and 56-day survival rates were 76.7%, 66.7%, and 59.0%, respectively. Peramivir was generally well tolerated. Conclusions. Intravenous peramivir was well tolerated and was associated with recovery in most patients hospitalized with severe 2009 H1N1 influenza viral pneumonia and treated under an eIND.

Background. A need exists for new antimicrobial agents to treat neonates, infants, and children for hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) caused by nosocomial antibiotic-resistant pathogens. Current and clear guidance on approval of new agents for all pediatric age groups is lacking. Methods. Studies on HAP and VAP in the neonatal and pediatric age groups were collected using PubMed (National Library of Medicine). Published articles were reviewed for pediatric-specific definitions of HAP and VAP, diagnostic techniques, rates of disease, risk factors, characteristics, and outcomes. Results. Definitions of HAP and VAP in neonatal and pediatric age groups vary considerably. No well-studied, sensitive, and specific microbiologic testing techniques exist. Morbidity and mortality associated with VAP in neonates, infants, and children have been documented. Conclusions. Investigation and approval of new agents for HAP and VAP in all pediatric age groups is needed. A uniform definition of HAP and VAP is required that is relevant for clinical trials and balances the risks of experimental therapy and sampling procedures for study patients with potential benefits for both the patient under investigation and the hospitalized children who may develop nosocomial pneumonia.

Guidelines for the treatment of persons with influenza virus infection were prepared by an Expert Panel of the Infectious Diseases Society of America. The evidence-based guidelines encompass diagnostic issues, treatment and chemoprophylaxis with antiviral medications, and issues related to institutional outbreak management for seasonal (interpandemic) influenza. They are intended for use by physicians in all medical specialties with direct patient care, because influenza virus infection is common in communities during influenza season and may be encountered by practitioners caring for a wide variety of patients.

There are few placebo-controlled, randomized, prospective clinical trials of antibiotic therapy for community-acquired pneumonia (CAP) in children. The reduction in mortality seen in early trials of antibacterials for treatment of bacterial CAP in adults and children was dramatic and led to the adoption of antibacterial therapy as the standard of care for CAP in both adults and children. Because of the efficacy of antibacterials for treatment of CAP in adults and the reluctance of society to place children at risk of adverse outcomes in placebo-controlled clinical trials, pediatric investigations of this type were not performed after 1940. Instead, comparative trials were subsequently conducted and reported. More recently, comparative trials using a noninferiority trial design have been used by regulatory agencies to grant approval of antibiotic therapy for pediatric CAP. We cannot reliably distinguish between pneumonia cases caused by bacterial, viral, or atypical pathogens among the relatively homogeneous population of children with CAP who are enrolled into clinical trials. Patient- or parent-reported outcomes represent an option for appropriate, defined clinical trial outcomes for pediatric CAP, because the disease in children has a relatively short and potentially self-resolving clinical course. Clinical trials that require invasive techniques for diagnosis and placebo-controlled randomized trials are not acceptable for children, who are considered to be a vulnerable population.

The Antimicrobial Availability Task Force (AATF) of the Infectious Diseases Society of America (IDSA) has viewed with concern the decreasing investment by major pharmaceutical companies in antimicrobial research and development. Although smaller companies are stepping forward to address this gap, their success is uncertain. The IDSA proposed legislative and other federal solutions to this emerging public health problem in its July 2004 policy report "Bad Bugs, No Drugs: As Antibiotic R&D Stagnates, a Public Health Crisis Brews." At this time, the legislative response cannot be predicted. To emphasize further the urgency of the problem for the benefit of legislators and policy makers and to capture the ongoing frustration our clinician colleagues experience in their frequent return to an inadequate medicine cabinet, the AATF has prepared this review to highlight pathogens that are frequently resistant to licensed antimicrobials and for which few, if any, potentially effective drugs are identifiable in the late-stage development pipeline.

Endocarditis due to Streptococcus pneumoniae is unusual in children, accounting for 3%-7% of all cases of childhood endocarditis. The US Pediatric Multicenter Pneumococcal Surveillance Group has prospectively identified patients with invasive disease at 8 children's hospitals. During the period of 1 September 1993 through 28 February 2003, a total of 11 children with pneumococcal endocarditis were seen. Seven (64%) were 3-36 months old; 8 (73%) were boys. Ten (91%) had preexisting structural heart disease; 5 had undergone previous heart surgery. Concomitant sites of infection were noted in 6 patients (55%), including 3 patients with meningitis. One patient (9%) died during hospitalization, and 5 others (45%) experienced serious complications. Only 2 patients remained hospitalized for their entire course of parenteral antibiotic therapy. Eight of 10 pneumococcal isolates tested were vaccine or vaccine-related serotypes included in the currently licensed 7-valent conjugated pneumococcal vaccine. Pneumococcal endocarditis in children is unusual but often has serious complications.

Bacterial infections in recipients of bone marrow and solid-organ transplants remain a major cause of morbidity and death. The cases of 42 children who had undergone transplantation and developed an infection with Streptococcus pneumoniae were retrospectively reviewed. Thirty-four patients had 1 episode of infection, whereas 7 had 2 episodes and 1 had 3 episodes of infection. Solid-organ recipients were more likely to have recurrent invasive disease (P

These guidelines were formulated to provide guidance for Monitoring the care of patients receiving CoPAT includes physicians on various aspects of the administration of commu- attention to venous access, monitoring by means of specific nity-based parenteral anti-infective therapy (CoPAT). Nine laboratory tests, and emphasizing the importance of administerareas are addressed. Patient evaluation and selection criteria ing the first dose of an antibiotic in a supervised setting. Antiare discussed in detail, with an emphasis on the importance of infective selection and administration issues involving CoPAT determining the need for parenteral therapy as well as assessing include observations that once-daily drug administration is conthe patient’s general medical condition and the infectious pro- venient and, in the case of aminoglycosides, has potential theracess. peutic advantages; vancomycin use should be limited to defined The section on ‘‘Key Elements for a CoPAT Program’’ situations. underscores both the team concept (the patient, nurse, pharma- While there are many reassuring retrospective studies on the cist, and physician) and the importance of assuring clear lines efficacy and safety of CoPAT, few prospective studies have of communication between members of the team. A list of been conducted to compare the risks and outcomes for patients evaluation criteria is provided to address the dilemmas facing treated as inpatients rather than outpatients. The outcome studphysicians when insurance companies or managed care organi- ies of pneumonia in cystic fibrosis patients, for which several zations designate a specific home care program that the pre- parameters were used, showed no significant differences bescribing physician may be unfamiliar with. tween inpatient and outpatient therapy. The Joint Commission The physician’s roles and responsibilities as a member of on Accreditation of Healthcare Organizations has devised a the CoPAT team are also addressed, emphasizing unique re- number of indicators for home infusion therapy, and in this sponsibilities such as establishing a diagnosis, authorizing treat- paper, a number of other parameters are recommended for ment when the final care plan is developed, determining the possible inclusion for comparative and trend analyses. appropriate site of care, and monitoring the patient’s clinical For carefully selected patients, the benefits of CoPAT outweigh the risks; these benefits include the direct cost savings that accrue to the health care system as well as the indirect and intangible benefits that accrue to the individual. It is not

TO THE EDITOR—We are grateful for the comments of Drs Tamma and Cosgrove [1] on the issue of duration of therapy, particularly as it impacts antibiotic exposure in the child and the community. Greater antibiotic exposure is associated with greater antimicrobial resistance and also adds to costs and toxicities of therapy. This particular issue prompted considerable discussion within the writing group. However, with no scientific evidence in children from randomized controlled trials or even high-quality observational studies conducted in North American centers, the extrapolated data from community-acquired pneumonia (CAP) in adults, well-reviewed by Tamma and Cosgrove, was not felt to be of sufficient relevance to make these recommendations for children. Although children may have fewer comorbid conditions than adults, our guidelines do review the many other differences, including the relative immune incompetence in preschool-aged children compared with adults, as well as the role of viral coinfections. Differences in outcomes for children compared with adults with urinary tract infections highlight the challenges of extrapolating adult treatment protocols to children [2]. However, we certainly agree with the critical importance of this issue and included it as one of our research priorities, as provided in our Table 10: “Develop clinical trial designs that can provide information on the lowest effective antimicrobial dose for the shortest duration of therapy to decrease the development of antimicrobial resistance and the risk of antimicrobial toxicity.” Although the guidelines are unable to address the duration of antibiotic therapy based on adequate evidence, they do emphasize the importance of viral infection as a cause of pneumonia in the preschool-aged child and state that “antimicrobial therapy is not routinely required for preschool-aged children with CAP, because viral pathogens are responsible for the great majority of clinical disease.” We believe that if this recommendation is followed, it will significantly decrease the use of inappropriate antimicrobials in children and is well aligned with the goals expressed by Drs Tamma and Cosgrove. We also thank Dr Esposito for her letter citing 8 concerns regarding the Executive Summary of the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America clinical practice guidelines on the management of CAP in children >3 months [3, 4]. In her review of the Executive Summary, she may have overlooked the reference (p 618) to the full-text electronic article for the guidelines that provides a detailed description of the methods, background, and, most important, the Evidence Summaries that support each recommendation. The comments and questions she raises are all addressed within the full text that is available online (doi: 10.1093/cid/cir531).

Clinical Affairs Committee: Daniel J. Sexton, Chair, Duke University Medical Center, Durham, North Carolina; Jeffery Band, William Beaumont Hospital, Royal Oak Michigan; Steven Berman, University of Hawaii, Honolulu, Hawaii; John Bradley, Children's Hospital, San Diego, California; Joseph R. Dalovisio, Ochsner Clinic, New Orleans, Louisiana; Christopher Ingram, Raleigh Infectious Disease Associates, Raleigh, North Carolina; W. Patrick Joseph, ID Medical Group, San Ramon, California; Russell M. Petrak, Metro Infectious Disease Consultants, Hinsdale, Illinois; Thomas G. Slama, Hoosier Infectious Diseases, Indianapolis, Indiana; and Barbara H. Wade, Infectious Disease Associates, Pensacola, Florida.