Seth Hetherington

ZIDOVUDINE, DIDANOSINE, OR BOTH AS THE INITIAL TREATMENT FOR SYMPTOMATIC HIV-INFECTED CHILDREN

BACKGROUND Zidovudine has been the drug of choice for the initial treatment of symptomatic children infected with the human immunodeficiency virus (HIV). This trial was designed to assess the efficacy and safety of treatment with zidovudine alone as compared with either didanosine alone or combination therapy with zidovudine plus didanosine. METHODS In this multicenter, double-blind study, symptomatic HIV-infected children 3 months through 18 years of age were stratified according to age (<30 months or > or =30 months) and randomly assigned to receive zidovudine, didanosine, or zidovudine plus didanosine. The primary end point was length of time to death or to progression of HIV disease. RESULTS Of the 831 children who could be evaluated, 92 percent had never received antiretroviral therapy and 90 percent had acquired HIV perinatally. An interim analysis (median follow-up, 23 months) showed a significantly higher risk of HIV-disease progression or death in patients receiving zidovudine alone than in those receiving combination therapy (relative risk, 0.61; 95 percent confidence interval, 0.42 to 0.88; P=0.007). The study arm with zidovudine alone was stopped and unblinded; the other two treatment arms were continued. At the end of the study, didanosine alone had an efficacy similar to that of zidovudine plus didanosine (median follow-up, 32 months) (relative risk of disease progression or death, 0.98; 95 percent confidence interval, 0.70 to 1.37; P=0.91). A significantly lower risk of anemia or neutropenia was seen in patients receiving didanosine alone (P=0.036). CONCLUSIONS In symptomatic HIV-infected children, treatment with either didanosine alone or zidovudine plus didanosine was more effective than treatment with zidovudine alone. The efficacy of didanosine alone was similar to that of the combination therapy and was associated with less hematologic toxicity.

Phase II, Randomized, Double-Blind, Multicenter Study Comparing the Safety and Pharmacokinetics of Tefibazumab to Placebo for Treatment of Staphylococcus aureus Bacteremia

ABSTRACT Tefibazumab (Aurexis), a humanized monoclonal antibody that binds to the surface-expressed adhesion protein clumping factor A, is under development as adjunctive therapy for serious Staphylococcus aureus infections. Sixty patients with documented S. aureus bacteremia (SAB) were randomized and received either tefibazumab at 20 mg/kg of body weight as a single infusion or a placebo in addition to an antibiotic(s). The primary objective of the study was determining safety and pharmacokinetics. An additional objective was to assess activity by a composite clinical end point (CCE). Baseline characteristics were evenly matched between groups. Seventy percent of infections were healthcare associated, and 57% had an SAB-related complication at baseline. There were no differences between the treatment groups in overall adverse clinical events or alterations in laboratory values. Two patients developed serious adverse events that were at least possibly related to tefibazumab; one hypersensitivity reaction was considered definitely related. The tefibazumab plasma half-life was 18 days. Mean plasma levels were <100 μg/ml by day 14. A CCE occurred in six patients (four placebo and two tefibazumab patients) and included five deaths (four placebo and one tefibazumab patient). Progression in the severity of sepsis occurred in four placebo and no tefibazumab patients. Tefibazumab was well tolerated, with a safety profile similar to those of other monoclonal antibodies. Additional trials are warranted to address the dosing range and efficacy of tefibazumab.

Oral cefixime is similar to continued intravenous antibiotics in the empirical treatment of febrile neutropenic children with cancer.

Empiric oral antibiotic therapy for febrile neutropenic cancer patients has been suggested as a means to decrease hospitalization, but the safety of this approach has not been adequately studied in children. We compared continued iv antibiotic therapy with switching treatment to orally administered cefixime in a group of selected febrile neutropenic children for whom blood cultures were sterile after 48 h of incubation. Two hundred episodes of febrile neutropenia were studied (156 patients), and 100 episodes were randomized to receive each treatment. Failure to respond to therapy was defined by documented or suspected bacterial infection, recurrent fever, or discontinuation of assigned therapy for any reason before neutropenia resolved. Rates of treatment failure were similar in the oral cefixime group (28%) and in the iv antibiotic group (27%; P=1.0). Results support the safety of oral cefixime therapy for low-risk febrile neutropenic children, a therapeutic approach that would facilitate earlier outpatient management and decrease the costs of treatment.

Recommendations from the national vaccine advisory committee: Standards for adult immunization practice

National Vaccine Advisory Committee The Advisory Committee on Immunization Practices (ACIP) makes recommendations for routine vaccination of adults in the United States.1 Standards for implementing the ACIP recommendations for adults were published by the National Vaccine Advisory Committee (NVAC) in 20032 and by the Infectious Diseases Society of America in 2009.3 In addition, NVAC published a report in 2012 outlining a pathway for improving adult immunization rates.4 While most of these documents included guidelines for immunization practice, recent changes in the practice climate for adult immunization necessitated an update of existing adult immunization standards. Some of these changes include expansion of vaccination services offered by pharmacists and other community immunization providers both during and since the 2009 H1N1 influenza pandemic; vaccination at the workplace; increased vaccination by providers who care for pregnant women; and changes in the health-care system, including the Affordable Care Act (ACA), which requires first-dollar coverage of ACIP-recommended vaccines for people with certain private insurance plans, or those who are beneficiaries of expanded Medicaid plans.5 The ACA first-dollar provision is expected to increase the number of adults who will be insured for vaccines. Other changes include expanding the inclusion of adults in state immunization information systems (IISs) (i.e., registries) and the Centers for Medicare & Medicaid Services Meaningful Use Stage 2 requirements, which mandate provider reporting of immunizations to registries, including reporting of adult vaccination in states where such reporting is allowed.6 For the purposes of this report, provider refers to any individual who provides health-care services to adult patients, including physicians, physician assistants, nurse practitioners, nurses, pharmacists, and other health-care professionals. While previous versions of the adult immunization standards have been published, recommendations for adult vaccination are published annually, and many health-care organizations have endorsed routine assessment and vaccination of adults, vaccination among adults continues to be low.7–15 Several barriers to adult vaccination include:

Clinical and laboratory characteristics of a large cohort of symptomatic, human immunodeficiency virus-infected infants and children

BackgroundA large cohort of antiretroviral therapy-naive, symptomatic, HIV-infected children were enrolled into a controlled therapeutic trial (AIDS Clinical Trials Group Protocol 152), providing an opportunity to describe their clinical and laboratory characteristics and determine age-related disti

Multicenter study to assess safety and efficacy of INH-A21, a donor-selected human staphylococcal immunoglobulin, for prevention of nosocomial infections in very low birth weight infants.

Background: Prophylactic administration of intravenous immunoglobulin has been inconsistent in reducing the risk of sepsis in very low birth weight (VLBW) infants presumably because of varying titers of organism specific IgG antibodies. INH-A21 is an intravenous immunoglobulin from donors with high titers of antistaphylococcal antibodies. This dose-ranging study explored safety and preliminary activity of INH-A21 for prevention of staphylococcal sepsis in VLBW infants. Methods: This was a multicenter, double blind, group-sequential study. Infants with birth weights 500–1250 g were randomized to receive up to 4 doses of placebo, 250 mg/kg, 500 mg/kg or 750 mg/kg INH-A21. Safety and frequencies of sepsis were compared across treatment groups. Results: All treatment groups had similar mean gestational age, birth weight, Apgar score and maternal use of antibiotics. Randomizations to 250 mg/kg (N = 94) and 500 mg/kg (N = 96) doses were terminated after interim analyses demonstrated a low probability of finding a difference when compared with placebo. Infants randomized to the INH-A21 750 mg/kg group (N = 157) had fewer episodes of Staphylococcus aureus sepsis [relative risk (RR), 0.37; 95% confidence interval (CI), 0.12–1.12; P = 0.14], candidemia (RR 0.34; 95% CI 0.09–1.22; P = 0.09) and mortality (RR 0.64; 95% CI 0.25–1.61; P = 0.27) when compared with the placebo-treated cohort (N = 158). No dose-related trends were observed for adverse events or morbidities associated with prematurity. Conclusions: INH-A21 750 mg/kg demonstrated potential to reduce sepsis caused by S. aureus, candidemia and mortality in VLBW infants. Although statistical significance was not reached, based on the magnitude of the estimated differences, the efficacy and safety of INH-A21 750 mg/kg should be evaluated in an adequately powered, well-controlled study.

A Phase I Study of Abacavir (1592U89) Alone and in Combination With Other Antiretroviral Agents in Infants and Children With Human Immunodeficiency Virus Infection

Objectives. To evaluate the pharmacokinetic features, safety, and tolerance of abacavir, given alone and in combination with other nucleoside antiretroviral agents, in symptomatic human immunodeficiency virus (HIV)-infected children. Methods. HIV-infected children discontinued prior antiretroviral therapy and were given abacavir orally, 4 mg/kg every 12 hours for 6 weeks, followed by 8 mg/kg every 12 hours for 6 weeks (n = 39); or 8 mg/kg every 12 hours for 12 weeks (n = 8). Children then were randomized to receive a second nucleoside antiretroviral agent (zidovudine, stavudine, didanosine, or lamivudine), plus abacavir. Pharmacokinetics, safety, tolerance, CD4+ lymphocyte counts, and plasma HIV RNA concentrations were evaluated. Results. At a dose of 8 mg/kg every 12 hours, area under the plasma concentration-versus-time curves and plasma half-life values were comparable with those reported for adults receiving abacavir at a dose of 300 mg twice daily. One case each of hypersensitivity reaction and peripheral neuropathy occurred during abacavir monotherapy. Three children experienced neutropenia while receiving abacavir in combination with another antiretroviral agent. Mean CD4+lymphocyte count and plasma HIV RNA concentration did not change when prior antiretroviral therapy was changed to abacavir monotherapy. Conclusions. Abacavir therapy is associated with good short-term tolerance and safety in HIV-infected children. Phase III studies are in progress to assess the antiviral activity of abacavir in children and adults.

Solid phase disruption of fluid phase equilibrium in affinity assays with ELISA

Quantitation of antibody affinity for antigen can provide important information in assessment of the human immune response. Enzyme-linked immunosorbent assay (ELISA) methods are sufficiently sensitive to permit affinity measurements of low affinity, low titer antibody. The major assumption in using this method, that the solid phase does not influence the equilibrium of the fluid phase antibody-antigen interaction, is not strictly true. Hence, conditions must be chosen to minimize such interference, which can result in spuriously low values of affinity. The degree of solid phase interference was therefore quantitated for an ELISA that measures the affinity between antibody directed against the capsular polysaccharide of Haemophilus influenzae type b, using a monovalent 3-unit oligosaccharide prepared from polysaccharide. The solid phase antigen density had the greatest effect upon disruption of the fluid phase. The concentration of antibody chosen had a measurable but modest effect on the outcome of ELISA, whereas the time of incubation of the antibody and oligosaccharide had no demonstrable effect. By choosing the conditions of the assay carefully, it was possible to minimize interference from the solid phase, so that the measured affinity of anticapsular polysaccharide antibody for monovalent antigen was similar to that obtained with the more traditional precipitation method.

Sequence and analysis of the rpoB gene of Mycobacterium smegmatis.

The rpoB gene encodes the beta subunit of the DNA-dependent RNA polymerase of bacteria. Mutations in defined areas result in resistance to rifampin. Mycobacterium smegmatis is naturally resistant to rifampin, but analysis of the rpoB gene revealed no identifiable rifampin resistance mutations. Another mechanism of resistance may be present.

Open-Label, Dose Escalation Study of the Safety and Pharmacokinetic Profile of Tefibazumab in Healthy Volunteers

ABSTRACT Tefibazumab (Aurexis) is a humanized monoclonal antibody being evaluated as adjunctive therapy for the treatment of Staphylococcus aureus infections. This open-label, dose escalation study evaluated the safety and pharmacokinetics of tefibazumab in 19 healthy volunteers aged 18 to 69 years. Each subject received a single administration of tefibazumab at a dose of 2, 5, 10, or 20 mg/kg of body weight infused over 15 min. Plasma samples for pharmacokinetic assessments were obtained before infusion as well as 1, 6, 12, and 24 h and 3, 4, 7, 21, 28, 42, and 56 days after dosing. Plasma concentrations of tefibazumab were detected 1 h after the end of the infusion, with a mean maximum concentration of drug in serum (Cmax) of 59, 127, 252, and 492 μg/ml following doses of 2, 5, 10, and 20 mg/kg, respectively. The median time to maximum concentration of drug in serum (Tmax) was 1.0 h for each dose. The mean elimination half-life (t1/2) was approximately 22 days. The volume of distribution (V) was 4.7, 6.7, 7.2, and 7.2 liters after doses of 2, 5, 10, and 20 mg/kg, respectively. Clearance (CL) was 6.0, 9.2, 10.2, and 9.9 ml/hr, respectively. At the highest dose, plasma levels of tefibazumab were >100 μg/ml for 21 days. On day 56, the mean plasma concentrations were 6.3, 10.0, 16.4, and 30.5 μg/ml for the 2, 5, 10, and 20 mg/kg doses, respectively. Tefibazumab exhibited linear kinetics across doses of 5, 10, and 20 mg/kg. No anti-tefibazumab antibodies were detected after dosing in any subject. There were no serious adverse events, and tefibazumab was well tolerated over the entire dose range.