Acute Neurological Illness in a Kidney Transplant Recipient Following Infection With Enterovirus-D68: An Emerging Infection?

We report the first case of enterovirus-D68 infection in an adult living-donor kidney transplant recipient who developed rapidly progressive bulbar weakness and acute flaccid limb paralysis following an upper respiratory infection. We present a 45-year-old gentleman who underwent pre-emptive living-donor kidney transplantation for IgA nephropathy. Eight weeks following transplantation, he developed an acute respiratory illness from enterovirus/rhinovirus that was detectable in nasopharyngeal (NP) swabs. Within 24 h of onset of respiratory symptoms, the patient developed binocular diplopia which rapidly progressed to multiple cranial nerve dysfunctions (acute bulbar syndrome) over the next 24 h. Within the next 48 h, asymmetric flaccid paralysis of the left arm and urinary retention developed. While his neurological symptoms were evolving, the Centers for Disease Control reported that the enterovirus strain from the NP swabs was, in fact, Enterovirus-D68 (EV-D68). Magnetic resonance imaging of the brain demonstrated unique gray matter and anterior horn cell changes in the midbrain and spinal cord, respectively. Constellation of these neurological symptoms and signs was suggestive for postinfectious encephalomyelitis (acute disseminated encephalomyelitis [ADEM]) from EV-D68. Treatment based on the principles of ADEM included intensive physical therapy and other supportive measures, which resulted in a steady albeit slow improvement in his left arm and bulbar weakness, while maintaining stable allograft function.

Efficacy testing of recombinant human immunodeficiency virus (HIV) gp160 as a therapeutic vaccine in early-stage HIV-1-infected volunteers. rgp160 Phase II Vaccine Investigators.

A phase II efficacy trial was conducted with recombinant human immunodeficiency virus (HIV) type 1 envelope glycoprotein gp160 (rgp160) in 608 HIV-infected, asymptomatic volunteers with CD4+ cell counts >400 cells/mm3. During a 5-year study, volunteers received a 6-shot primary series of immunizations with either rgp160 or placebo over 6 months, followed by booster immunizations every 2 months. Repeated vaccination with rgp160 was safe and persistently immunogenic. Adequate follow-up and acquisition of endpoints allowed for definitive interpretation of the trial results. There was no evidence that rgp160 has efficacy as a therapeutic vaccine in early-stage HIV infection, as measured at primary endpoints (50% decline in CD4+ cell count or disease progression to Walter Reed stage 4, 5, or 6) or secondary endpoints. A transient improvement was seen in the secondary CD4 endpoint for the vaccination compared with the placebo arm, but this did not translate into improved clinical outcome.

Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza.

BACKGROUND: Safe and effective antiviral agents are needed to prevent infection with influenza A and B virus. Oseltamivir (GS4104), which can be administered orally, is the prodrug of GS4071, a potent and selective inhibitor of influenzavirus neuraminidases. We studied the use of oseltamivir for long-term prophylaxis against influenza in two placebo-controlled, double-blind trials at different U.S. sites during the winter of 1997-1998. METHODS: We randomly assigned 1559 healthy, nonimmunized adults 18 to 65 years old to receive either oral oseltamivir (75 mg given once or twice daily, for a total daily dose of 75 or 150 mg) or placebo for six weeks during a peak period of local influenzavirus activity. The primary end point with respect to efficacy was laboratory-confirmed influenza-like illness (defined as a temperature of at least 37.2 degrees C accompanied by at least one respiratory and at least one systemic symptom). RESULTS: In the two studies combined, the risk of influenza among subjects assigned to either once-daily or twice-daily oseltamivir (1.2 percent and 1.3 percent, respectively) was lower than that among subjects assigned to placebo (4.8 percent; P<0.001 and P=0.001 for the comparison with once-daily and twice-daily oseltamivir, respectively). The protective efficacy of oseltamivir in the two active-treatment groups combined was 74 percent (95 percent confidence interval, 53 to 88 percent) at all the sites combined and 82 percent (95 percent confidence interval, 60 to 93 percent) at sites in Virginia, where the rate of influenza infection was higher than the overall rate. For culture-proved influenza, the rate of protective efficacy in the two oseltamivir groups combined was 87 percent (95 percent confidence interval, 65 to 96 percent). The rate of laboratory-confirmed influenza infection was lower with oseltamivir than with placebo (5.3 percent vs. 10.6 percent, P<0.001). Oseltamivir was well tolerated but was associated with a greater frequency of nausea (12.1 percent and 14.6 percent in the once-daily and twice-daily groups, respectively) and vomiting (2.5 percent and 2.7 percent, respectively) than was placebo (nausea, 7.1 percent; vomiting, 0.8 percent). However, the frequency of premature discontinuation of drug or placebo was similar among the three groups (3.1 to 4.0 percent). CONCLUSIONS: Oseltamivir administered daily for six weeks by the oral route is safe and effective for the prevention of influenza.

Ritonavir and saquinavir combination therapy for the treatment of HIV infection.

OBJECTIVE: To evaluate the safety and antiretroviral activity of ritonavir (Norvir) and saquinavir (Invirase) combination therapy in patients with HIV infection. DESIGN: A multicenter, randomized, open-label clinical trial. SETTING: Seven HIV research units in the USA and Canada. PATIENTS: A group of 141 adults with HIV infection, CD4 T lymphocyte counts of 100-500 x 10(6) cells/l, whether treated previously or not with reverse transcriptase inhibitor therapy, but without previous HIV protease inhibitor drug therapy. INTERVENTIONS: After discontinuation of prior therapy for 2 weeks, group I patients were randomized to receive either combination (A) ritonavir 400 mg and saquinavir 400 mg twice daily or (B) ritonavir 600 mg and saquinavir 400 mg twice daily. After an initial safety assessment of group I patients, group II patients were randomized to receive either (C) ritonavir 400 mg and saquinavir 400 mg three times daily or (D) ritonavir 600 mg and saquinavir 600 mg twice daily. Investigators were allowed to add up to two reverse transcriptase inhibitors (including at least one with which the patient had not been previously treated) to a patient's regimen after week 12 for failure to achieve or maintain an HIV RNA level < or = 200 copies/ml documented on two consecutive occasions. MEASUREMENTS: Plasma HIV RNA levels and CD4+ T-lymphocyte counts were measured at baseline, every 2 weeks for 2 months, and monthly thereafter. Safety was assessed through the reporting of adverse events, physical examinations, and the monitoring of routine laboratory tests. RESULTS: The 48 weeks of study treatment was completed by 75% (106/141) of the patients. Over 80% of the patients on treatment at week 48 had an HIV RNA level < or = 200 copies/ml. In addition, intent-to-treat and on-treatment analyses revealed comparable results. Suppression of plasma HIV RNA levels was similar for all treatment arms (mean areas under the curve minus baseline through 48 weeks were-1.9, -2.0, -1.6, -1.8 log10 copies/ml in ritonavir-saquinavir 400-400 mg twice daily, 600-400 mg twice daily, 400-400 mg three times daily, and 600-600 mg twice daily, respectively). Median CD4 T-lymphocyte count rose by 128 x 10(6) cells/l from baseline, with an interquartile range (IQR) of 82-221 x 10(6) cells/l. The most common adverse events were diarrhea, circumoral paresthesia, asthenia, and nausea. Reversible elevation of serum transaminases (> 5 x upper limit of normal) occurred in 10% (14/141) of the patients enrolled in this study and was associated with baseline abnormalities in liver function tests, baseline hepatitis B surface antigen positivity, or hepatitis C antibody positivity (relative risk, 5.0; 95% confidence interval 1.5-16.9). Most moderate or severe elevations in liver function tests occurred in patients treated with ritonavir-saquinavir 600-600 mg twice daily. CONCLUSIONS: Ritonavir 400 mg combined with saquinavir 400 mg twice daily with the selective addition of reverse transcriptase inhibitors was the best-tolerated regimen of four dose-ranging regimens and was equally as active as the higher dose combinations in HIV-positive patients without previous protease inhibitor treatment.

Medicare coverage of outpatient ambulatory intravenous antibiotic therapy: a program that pays for itself.

A number of studies have documented the safety, efficacy, and cost-effectiveness of outpatient intravenous (i.v.) antibiotic therapy for patients with infectious diseases. Nevertheless, Medicare policy prohibiting coverage of outpatient, self-administered drugs has severely limited access of Medicare patients to ambulatory i.v. therapy, thus forcing them to rely on more costly, impatient hospital care. To test the hypothesis that a new Medicare benefit providing coverage for ambulatory i.v. antibiotic therapy could significantly reduce the program's expenditures for the treatment of infectious diseases (including pneumonia, osteomyelitis, cellulitis, and endocarditis), a cost model was constructed with use of patient care information from the clinical literature as well as clinical experts, Medicare data, and other medical claims databases. The model shows cumulative 5-year savings of nearly $1.5 billion associated with the new Medicare benefit. Policy makers should consider implementing such a benefit.

Evolution of outpatient parenteral antibiotic therapy.

The future will no doubt continue to promote safe, cost-effective therapies such as outpatient intravenous therapy. It is imperative that physicians trained and knowledgeable in the administration of outpatient intravenous antimicrobial drug administration continue to assume responsibility and leadership roles.

Managed care and the infectious diseases specialist.

There is growing demand to contain health care costs and to reassess the value of medical services. The traditional hospital, academic, and research roles of the infectious disease (ID) specialist are threatened, yet there is an increasing need for expertise because of growing antimicrobial resistance and emerging pathogens. Opportunities exist to develop and expand services for the care of patients infected with human immunodeficiency virus and in infection control, epidemiology, outcomes research, outpatient intravenous therapy, and resource management. It is important for ID physicians to appreciate the principles involved in managed care and the areas in which ID services can be valuable. To be effective, physicians need to know about tools such as practice guidelines, physician profiling, outcomes monitoring, computerized information management, risk sharing, networking, and marketing, as well as related legal issues. With a positive attitude toward learning, application, and leadership, ID physicians can redefine their role and expand their services through managed care.

Outpatient parenteral antibiotic therapy.

Clinical studies have shown that outpatient administration of parenteral antibiotics is sage, cost-effective and practical. The development of new antibiotics with prolonged half-lives, such as ceftriaxone or cefotetan, has facilitated outpatient parenteral antibiotic therapy (OPAT). Good OPAT management requires coordination of physicians, nurses, pharmacists and health care administrators, and the establishment of firm guidelines. A variety of infections can be treated through OPAT, including osteomyelitis and soft tissue infections, chronic urinary tract infections, and ear, nose and throat infections.

Treatment of skin and soft-tissue infections utilizing an outpatient parenteral drug delivery device: a multicenter trial. HIAT Study Group.

The purpose of this study was to examine the safety and efficacy of outpatient intravenous antibiotic therapy for skin and soft-tissue infections and determine its effect on length of hospital stay. In this open-label, multicenter, prospective study, 130 adult patients with skin and soft-tissue infections requiring parenteral antibiotic therapy were enrolled as a subgroup. Initial therapy was delivered to hospital inpatients or in outpatient treatment centers, followed by home infusion therapy. Cefotaxime was delivered intravenously using a programmable ambulatory infusion pump. The clinical response rate was 97.5% (n = 118), while the bacteriologic response rate was 94.0% (n = 83). Only 32.2% of patients required hospitalization, and the mean duration of inpatient care for all evaluable patients was only 1.5 days. The mean duration of hospitalization for patients receiving inpatient care was 4.7 days. In conclusion, home intravenous cefotaxime therapy is safe, effective, and may reduce healthcare costs for many patients with skin and soft-tissue infections.

Treatment of serious infections with cefotaxime utilizing an outpatient drug delivery device: global analysis of a large-scale, multicenter trial. HIAT Study Group.

The primary objective of this multicenter, prospective trial was to determine the safety, efficacy, and cost effectiveness of cefotaxime delivered via an ambulatory delivery system (ADS) in the treatment of patients with a variety of bacterial infections. The secondary objective was to determine the safety and efficacy of cefotaxime/ADS treatment of infections in a diabetic subgroup. A total of 238 patients (> or = 18 years) in five infection categories were enrolled from 10 sites. All patients received cefotaxime/ADS. Both global analysis and analysis of a subpopulation with diabetes mellitus were performed. Of the 211 patients who completed the study, 201 patients (95.3%) exhibited a satisfactory or improved clinical response following cefotaxime/ADS. Bacteriologic response, evaluable in 134 of 211 patients, was satisfactory in 125 of these patients (93.3%). Within the diabetes mellitus subpopulation, a satisfactory or improved clinical response was identified in 30 of 32 patients (93.8%). In conclusion, administration of cefotaxime via ADS is a well-tolerated, safe, and clinically effective treatment of serious infection and may be less expensive than inpatient intravenous antibiotic therapy.

Outpatient parenteral antibiotic therapy. Management of serious infections. Part II: Amenable infections and models for delivery. Infusion center, office, and home.

Outpatient parenteral antibiotic therapy (OPAT) administered in an infusion center often offers the advantages but not the expense of the hospital setting. Office-based OPAT maintains the physician-patient relationship but may be impractical for the physician. Home administration is ideal for selected patients, but when it is provided by an infusion company, the physician may be sidestepped.

Home intravenous antibiotic therapy.

This article examines the development of a home intravenous program, types of outpatient intravenous programs, the criteria for patient selection, the equipment required, types of infections treated, the use of antimicrobics, clinical experience in the elderly, and financial considerations.

The infusion center: a model for outpatient parenteral antibiotic therapy.

Outpatient parenteral treatment of infectious diseases has developed from primitive beginnings to its present state as the standard of care in many areas. The large infusion center described here is headed by physicians who specialize in infectious diseases and occupies a free-standing building where the pharmacy, laboratory, physicians' offices, examination rooms, and finance departments are centralized for efficiency, flexibility, and convenience. Each patient is seen by a physician, pharmacist, and nurse; these health care professionals share data about the patient and offer 24-hour coverage of questions and emergencies. Treating a wide variety of diseases, physicians utilize their experience and the center's intercommunication system to choose drugs most suitable for outpatient use and to carry on research. Costs in the center run between 50% and 60% lower than those in the hospital. Reimbursement, although difficult in the past, has improved considerably, but some third-party payers, including Medicare, have not reimbursed for outpatient intravenous antibiotic therapy.