William J. Holloway

Efficacy Testing of Recombinant Human Immunodeficiency Virus (HIV) gp160 as a Therapeutic Vaccine in Early-Stage HIV-1-Infected Volunteers

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.

Clinical applications of a new parenteral antibiotic in the treatment of severe bacterial infections

Cephalosporins are one of the mainstays of antibiotic therapy, and third-generation cephalosporins are first-line agents for the treatment of many types of serious infections, including those of nosocomial origin. Gaps in activity of currently available third-generation cephalosporins such as cefotaxime, cefoperazone, ceftriaxone, and ceftazidime, and increasing reports of gram-negative bacilli resistance to some of these agents, especially Klebsiella pneumoniae, Pseudomonas aeruginosa, and Enterobacter spp., make it necessary to investigate new compounds. Cefepime, a fourth-generation cephalosporin with a wide range of activity against gram-positive and gram-negative bacteria, including multi-resistant strains of Enterobacteriaceae, was evaluated in comparison with ceftazidime for the treatment of serious infections in hospitalized patients. Ceftazidime is a commonly prescribed third-generation cephalosporin used for empiric treatment of serious infections such as pneumonia, urinary tract infection, and skin and skin-structure infection. This investigation was an open, randomized comparative study involving 882 patients in North America. Cefepime 2 g every 12 hours demonstrated similar efficacy to that of ceftazidime 2 g every 8 hours for the treatment of pneumonia and urinary tract infection (including cases associated with concurrent bacteremia), and skin and skin-structure infections. The bacteriologic responses were generally >85%. The most common pathogens isolated were Escherichia coll, Streptococcus pneumoniae, P. aeruginosa, K. pneumoniae, Haemophilus influenzae, Staphylococcus aureus, and Streptococcus, group B. Overall, approximately 94% of pathogens isolated in pretreatment cultures were susceptible to cefepime and ceftazidime. Cefepime and ceftazidime were well tolerated; only 3% of patients in each group discontinued therapy because of an adverse event. The most common adverse events were headache, diarrhea, nausea, vomiting, pruritus, and rash. The results of this study indicate that cefepime is a promising, effective, and safe single-agent therapy for serious infections in hospitalized patients.

Treatment of infections in hospitalized patients with ticarcillin plus clavulanic acid: A comparative study

Ninety patients at the Wilmington Medical Center were enrolled in a comparative study to evaluate the efficacy and toxicity of ticarcillin plus clavulanic acid in the treatment of a variety of infections. Forty-seven women with obstetric or gynecologic infections were randomly assigned to receive ticarcillin plus clavulanic acid or cefoxitin. Forty-three patients with gram-negative septicemia or lower respiratory tract infection were given ticarcillin plus clavulanic acid or tobramycin plus piperacillin in a randomized fashion. Of the 47 women with obstetric or gynecologic infections, 23 were randomly assigned to receive ticarcillin plus clavulanic acid, and 24 were randomly assigned to receive cefoxitin. Several patients in each group had underlying diseases such as diabetes, obesity, and hypertension. Of the 27 pathogens isolated in the group receiving ticarcillin plus clavulanic acid, 26 (96 percent) were eradicated, including all three ticarcillin-resistant pathogens. In the cefoxitin-treated group, 31 of the 33 (94 percent) pathogens were eliminated, including all four ticarcillin-resistant organisms. Three reinfections or superinfections occurred, and cefoxitin therapy failed to eliminate an enterococcus isolate from the endometrium in one patient. The clinical response in both treatment groups was excellent. Either cure or clinical improvement was achieved for all 18 sites of infection in the ticarcillin plus clavulanic acid-treated group and for all 22 sites in the cefoxitin-treated group. There were no systemic drug reactions in either treatment group. In one patient in the cefoxitin-treated group, local phlebitis developed at the infusion site. This reaction responded to local therapy. There were no local reactions among the patients receiving ticarcillin plus clavulanic acid. Of the 43 patients with gram-negative septicemia or lower respiratory tract infection, 21 were randomly assigned to receive ticarcillin plus clavulanic acid and 22 were assigned to receive tobramycin plus piperacillin. Thirty-six patients had gram-negative sepsis, and seven patients had lower respiratory tract infection. Nine of the 36 patients suspected of having gram-negative sepsis were not evaluable because no pathogen was isolated prior to treatment. Twenty-two of the 27 patients treated for septicemia had good clinical and microbiologic responses. Three of the seven patients with pneumonia were not evaluable. Of the four evaluable patients, two had pneumococcus pneumonia; one was treated with tobramycin plus piperacillin and one with ticarcillin plus clavulanic acid. In both instances, the clinical and bacteriologic responses were considered good.

The Current Status of Osteomyelitis

It appears proper to include osteomyelitis in a panel discussion on life-threatening infections in man. Although the mortality and morbidity of osteomyelitis have been greatly reduced in recent decades, if this disease is unrecognized and untreated, the mortality rate is still about 20 percent. Equally important is the fact that rapid diagnosis and treatment are necessary to prevent progression to the disabling and frequently life-long chronic osteomyelitis.

Butirosin — Pharmacodynamics and Clinical Experience

Butirosin is a new neomycin-like aminoglycoside antibiotic exhibiting marked activity against many gram-positive and gram-negative bacteria in vitro and in vivo.1,2,3 The gram-negative spectrum includes the Klebsiella-Enterobacter-Serratia groups as well as Proteus sp. and Pseudomonas sp. Butirosin appears to have less antibacterial potency than gentamicin on a weight basis, but it appears to be less nephrotoxic and considerably less ototoxic in laboratory animals than the older drug.4 These early reports suggested that this decreased toxicity might compensate for the lower potency resulting in a safe, effective compound for use in man.