Thomas R. Cate

Effects of Requiring Prior Authorization for Selected Antimicrobials: Expenditures, Susceptibilities, and Clinical Outcomes

Antimicrobial control programs are widely used to decrease drug expenditures, but effects on antimicrobial resistance and outcomes for patients are unknown. When a requirement for prior authorization for selected parenteral antimicrobial agents was initiated at our urban, county teaching hospital, total parenteral antimicrobial expenditures decreased by 32%. Susceptibilities to all beta-lactam and quinolone antibiotics increased, with dramatic increased susceptibilities in isolates recovered in intensive care units, increased susceptibilities in isolates recovered in other inpatient sites, and little change in susceptibilities in isolates recovered in outpatient sites despite no change in infection control practices. For patients with bacteremia due to gram-negative organisms, overall survival did not change with restrictions. No differences occurred in the median time from initial positive blood culture to receipt of an appropriate antibiotic or in the median time from positive blood culture to discharge from the hospital. Thus, requiring preapproval for selected parenteral agents can decrease antimicrobial expenditures and improve susceptibilities to antibiotics without compromising patient outcomes or length of hospital stay.

Efficacy of repeated annual immunization with inactivated influenza virus vaccines over a five year period

Some reports have suggested that influenza virus vaccine is less effective in persons that have received prior annual vaccination(s) than in those receiving it for the first time. This issue was addressed by evaluating the efficacy of annual influenza vaccinations over a 5 year period in healthy adults employing commercially-available, inactivated whole-virus vaccine. Influenza vaccination had minimal effects on overall respiratory illnesses during epidemic periods. However, it reduced influenza virus shedding by an average of 38.8% and conferred protection against influenza virus infection during each epidemic. Some variation in infection rates were noted between vaccine groups given one or more than one annual immunization, and between years, but no consistent pattern of differences was noted in relation to number of successive years of vaccination. These results suggest that the current recommendation for annual influenza vaccination of persons at special risk of serious disease and complications is appropriate, but that continued efforts to improve the effectiveness of our prophylactic measures against influenza are needed.

Safety and Immunogenicity of Nonadjuvanted and MF59-Adjuvanted Influenza A/H9N2 Vaccine Preparations

BACKGROUND Influenza A/H9N2 viruses can infect humans and are considered to be a pandemic threat. Effective vaccines are needed for these and other avian influenza viruses. METHODS We performed a phase I, randomized, double-blind trial to evaluate the safety and immunogenicity of a 2-dose schedule (administered on days 0 and 28) of 4 dose levels (3.75, 7.5, 15, and 30 microg of hemagglutinin) of inactivated influenza A/chicken/Hong Kong/G9/97 (H9N2) vaccine with and without MF59 adjuvant. Vaccine safety was assessed with a diary and selected blood tests. Immunogenicity was measured using serum hemagglutination inhibition (HAI) and microneutralization (MNt) antibody assays. RESULTS. Ninety-six healthy adults (age, 18-34 years) were enrolled in the study. Arm discomfort was more common in groups that received adjuvant, but adverse effects of the vaccination were generally mild. Geometric mean serum HAI and MNt antibody titers to the influenza A/chicken/Hong Kong/G9/97 (H9N2) virus strain for all vaccine groups were similar on day 0 but were significantly higher (P<.001) on both days 28 and 56 for the MF59-adjuvanted vaccine groups than for groups given nonadjuvanted vaccine. Other measures of immunogenicity were also higher in the adjuvanted vaccine groups. HAI and MNt geometric mean titers measured after the administration of a single dose of MF59-adjuvanted vaccine were similar to those measured after 2 doses of nonadjuvanted vaccine. CONCLUSIONS The combination of MF59 adjuvant with a subunit vaccine was associated with improved immune responses to an influenza A/H9N2 virus. The adjuvanted vaccine was immunogenic even after a single dose, raising the possibility that a 1-dose vaccination strategy may be attainable with the use of adjuvanted vaccine.

Dose-Related Safety and Immunogenicity of a Trivalent Baculovirus-Expressed Influenza-Virus Hemagglutinin Vaccine in Elderly Adults

BACKGROUND Influenza-virus hemagglutinin (HA) protein expressed in insect cells by recombinant baculovirus is a candidate influenza vaccine. METHODS In a randomized, double-blind trial conducted in 399 adults > or = 65 years of age, the efficacy of trivalent inactivated influenza vaccine (TIV) licensed for intramuscular injection was compared with that of trivalent baculovirus-expressed HA vaccine administered at doses of 15 microg, 45 microg, or 135 microg of each HA. RESULTS Compared with TIV, baculovirus-expressed HA vaccine was safe and induced better serum antibody responses to the H3 component when administered at doses of 45 microg or 135 microg of each HA. CONCLUSIONS Baculovirus-expressed HA is a safe and immunogenic influenza vaccine in elderly adults.

Response of latent syphilis or neurosyphilis to ceftriaxone therapy in persons infected with human immunodeficiency virus

OBJECTIVE To evaluate the effect of ceftriaxone in treating latent syphilis or asymptomatic neurosyphilis in patients infected with the human immunodeficiency virus (HIV). DESIGN Follow-up study of patients treated at two HIV-based clinics during 16 months from 1989 to 1991. PATIENTS Patients were those in whom a clinical diagnosis of latent syphilis or asymptomatic neurosyphilis was made, who received all recommended doses of antimicrobial therapy, and who returned for follow-up visits for 6 or more months. RESULTS Forty-three patients were treated with ceftriaxone, 1 to 2 g daily for 10 to 14 days. Thirteen underwent lumbar puncture before treatment; 7 (58%) had documented neurosyphilis (pleocytosis in 5, elevated protein levels in 6, VDRL reactive in cerebrospinal fluid [CSF] in 7), and 6 had documented latent syphilis (entirely normal CSF). The remaining 30 were said to have presumed latent syphilis. There was no relation between the diagnosis and the selected dosage of ceftriaxone. Response rates were similar in those who had documented neurosyphilis and documented or presumed latent syphilis. Overall, 28 patients (65%) responded to therapy, 5 (12%) were serofast, 9 (21%) had a serologic relapse, and 1 (2%) who experienced progression to symptomatic neurosyphilis was a therapeutic failure. Thirteen patients received benzathine penicillin for presumed latent syphilis; results were similar to those observed after ceftriaxone therapy, with 8 (62%) responders, 1 (8%) serofast, 2 (15%) relapses, and 2 (15%) failures. CD4 cell counts in responders were not different from those who failed to respond. CONCLUSIONS Even in the absence of neurologic symptoms, half of the HIV-infected persons who have serologic evidence of syphilis may have neurosyphilis. Although ceftriaxone achieves high serum and CSF levels, 10 to 14 days of treatment with this drug were associated with a 23% failure rate in HIV-infected patients who had latent syphilis or asymptomatic neurosyphilis. Three doses of benzathine penicillin did not have a significantly higher relapse rate and may provide appropriate therapy, at least for documented latent syphilis in persons co-infected with HIV. Studies comparing ceftriaxone with 10 to 14 doses of procaine penicillin are needed to determine the most cost-effective treatment for asymptomatic neurosyphilis or presumed latent syphilis in this group of patients.

Serum Immunoglobulin G Response to Candidate Vaccine Antigens during Experimental Human Pneumococcal Colonization

ABSTRACT The immune response to pneumococcal surface structures during colonization was examined in a model of experimental human pneumococcal carriage. Healthy uncolonized adults were given a type 23F or 6B pneumococcus, and a portion of these subjects became colonized (6 of 14 with type 23F and 6 of 8 with type 6B). Sera from colonized and uncolonized subjects were used to determine the titer of antibody specific to pneumococcal surface components under consideration in development of noncapsular polysaccharide-based vaccines. These vaccine candidates included pneumococcal surface protein A (PspA), choline binding protein A (CbpA), lipoteichoic acid, immunoglobulin A1 (IgA1) protease, pneumolysin, proteinase maturation protein A, and pneumococcal surface adhesin A. Only the two related choline binding proteins, PspA and CbpA, were immunogenic in colonized subjects as determined by a statistically significant rise in the serum IgG titer. The serum IgG response to PspA was shown previously to correlate inversely with susceptibility to carriage and was localized to a region within the N-terminal portion of PspA. This region is highly variable in amino acid sequence between pneumococcal strains. Despite the sequence diversity in the immunodominant regions of both PspA and CbpA, a significant strain-to-strain cross-reactivity in the serum IgG response following experimental human carriage was observed. These findings support the need for further investigation of the human antibody response to PspA and CbpA and the potential use of one or both of these proteins as novel vaccine antigens for the prevention of pneumococcal colonization.

Clinical manifestations and consequences of influenza

The spread of influenza virus through a community typically causes large increases in medical visits for febrile respiratory disease. Increased school absenteeism occurs early in the epidemic, and school children appear to be important for disseminating the virus. Industrial absenteeism, hospitalizations of adults and infants for pneumonia, and deaths due to pneumonia-influenza all tend to peak later in the epidemic. Although influenza infection rates are highest in persons of school age, hospitalizations and deaths occur primarily in infants and in the elderly, particularly among those with pulmonary, cardiovascular, or other debilitating disorders. Influenza viruses can be spread by aerosol or contact. The primary target cells are those of the respiratory epithelium. In healthy adults, the typical influenza syndrome includes fever, cough, and general aches for three to seven days, but lassitude, cough, and evidence of small-airways disease may persist for weeks. Laryngotracheobronchitis, pneumonia, and unexplained fever are prominent manifestations of influenza that lead to hospitalization of young children. Adults are more likely to have complications of bacterial pneumonia and worsening of chronic pulmonary disease or congestive heart failure. Less frequent complications include myositis, various neurologic disorders, and Reyes syndrome. These consequences of influenza clearly justify strenuous efforts at prevention and control.

Purified influenza A virus N2 neuraminidase vaccine is immunogenic and non-toxic in humans

The immunogenicity and toxicity of a purified influenza virus (N2) neuraminidase vaccine (NAV) were investigated in 88 human subjects aged 18-40, and compared to response to a conventional trivalent influenza vaccine, Fluogen (Parke-Davis). NAV doses ranged from 2.6 to 69.9 micrograms and were given intramuscularly. Serologic neuraminidase-inhibiting (NI) and neuraminidase-specific ELISA responses in this N2-primed population were roughly proportional to the dose administered. Maximal response was seen in 14-21 days and NI antibody titers persisted unabated for the 6-month post-vaccination follow-up period. All doses were well tolerated with respect to local and systemic reactions. NI tests performed with the putative (1975) priming N2 antigen demonstrated anamnestic response but did not reveal responses not already shown with the homologous (1992) antigen. Response to this purified, non-adjuvanted preparation encourages continuing investigation of the induction of infection-permissive immunity with influenza virus neuraminidase.

A High Dosage Influenza Vaccine Induced Significantly More Neuraminidase Antibody than Standard Vaccine among Elderly Subjects

Antibody to the neuraminidase (NA) antigen of influenza viruses has been shown to correlate with immunity to influenza in humans and animal models. In a previous report, we showed that an inactivated influenza vaccine containing 60microg of the hemagglutinin (HA) of each strain induced significantly more serum anti-HA antibody among elderly persons than did the standard vaccine containing 15microg of the HA of each component. We developed a lectin-based assay for anti-NA antibody and used it to measure anti-NA antibody responses among subjects who had participated in that study. The high dosage vaccine contained eight times as much NA activity as the standard vaccine and induced a significantly higher frequency of antibody responses and higher mean postvaccination anti-NA titers to the N1 and N2 of the A/H1N1 and A/H3N2 viruses in the vaccines than did the standard vaccine. Ensuring an increased antibody response to the NA antigen in inactivated influenza virus vaccines should increase the protection against influenza. An increased quantity of the NA antigen in the vaccine will ensure an increased response.

Improvement of Inactivated Influenza Virus Vaccines

Inactivated influenza virus vaccines (IVVs) are used for prevention of influenza and its complications. Present vaccines are immunogenic, of low reactogenicity, and protective, but protection has varied between 0% and 100%. Increasing the dose of hemagglutinin and neuraminidase antigens with purified proteins significantly increased serum and nasal antibody responses; however, trials with newer adjuvants have not shown increased serum antibody to levels comparable with those in earlier studies using oil emulsion adjuvants. IgA antibody responses in respiratory secretions were enhanced by the respiratory administration of IVVs, but IVVs by the oral route yielded varying results. IVVs appeared less effective for pandemic influenza in 1968 than in 1957. Since IVVs will be the major preventative measure for pandemic influenza in most countries, they need to be improved to provide better protection against pandemic and interpandemic influenza. Increasing the doses of hemagglutinin and neuraminidase, using adjuvants or immunomodulators, and administering IVVs by the mucosal route could improve the performance of these vaccines.