Influenza vaccines provide diminished protection but are cost-saving in older adults.

Influenza is associated with substantial morbidity and mortality in adults aged over 65 years. Although vaccination remains the most effective method of preventing influenza and its sequellae, current vaccination strategies provide less protection to older adults than to younger persons. Influenza vaccination in community-dwelling older adults is cost-effective, though there is room for improvement. Newer vaccine strategies considered for use in older adults include alternate routes of administration (intradermal or intranasal), addition of adjuvant, and novel methods of antigen presentation. Measuring cell-mediated immune response to new vaccines in addition to antibody response may correlate better with vaccine efficacy in this population. Whilst pandemic influenza A/H1N1 2009 (pH1N1) has largely spared older adults, the impact of pH1N1 vaccination has yet to be determined.

Economic impact of standardized orders for antimicrobial prophylaxis program.

OBJECTIVE: To assess the effect and economic impact of an intervention aimed at standardizing the timing of preoperative antimicrobial prophylaxis from the perspective of a major teaching hospital. DESIGN: A pre/post study design in which a random sample of 60 procedures from a 12-month period in the preintervention phase were reviewed. A comparative sample of 60 procedures during a seven-month postintervention phase was selected. For each prophylactic course, preoperative dose administration details were classified as early (>2 h prior to incision), on time (0-2 h prior), delayed (0-3 h after), or late (>3 after). To determine the economic impact of this intervention, we used a predictive decision analytic model using institutional costs and the published probabilities of inpatient surgical wound infections (SWIs) following administration of antimicrobials timed according to the above criteria. Two conditions were analyzed: (1) an interdisciplinary two-stage therapeutic interchange program involving staff education and modification of preoperative antimicrobial orders to ensure timely administration and (2) no intervention. SETTING: An 1100-bed tertiary care, university-affiliated institution. PATIENTS: 120 randomly selected procedures involving inpatients who received a preoperative antibiotic. OUTCOME MEASURES: Differences in preoperative antimicrobial timing and cost avoidance associated with the intervention. RESULTS: In the preintervention phase, 68% of prophylactic courses were on time, 22% were early, and the balance were delayed or late. The incidence of on-time prophylaxis increased to 97% during the postintervention phase (p = 0.001). Operating room staff involvement in antimicrobial administration increased from 57% to 92% (p = 0.001). Based on a setup and annual intervention cost of $9100 CAN ($1 CAN = $0.68 US), an annual inpatient SWI avoidance of 51 cases, an average infection-associated extended hospital stay of four days, and an average treatment cost of $1957 CAN per inpatient SWI, we estimated that 153 hospital days were avoided and there was an annual cost avoidance of $90 707 CAN ($1779 CAN saved per inpatient infection avoided) due to this intervention. Using sensitivity analyses, no plausible changes in the base case estimates altered the results of the economic model. CONCLUSIONS: An interdisciplinary approach to optimizing the timing of preoperative antimicrobial doses can impact positively on practice patterns and result in substantial cost avoidance. Costs incurred to implement such an intervention are small when compared with the annual cost avoidance to the institution.

Continuous intrathecal pump infusion of baclofen with antibiotic drugs for treatment of pump-associated meningitis. Case report.

Intrathecal baclofen administered by means of an implantable pump is being increasingly used for successful treatment of spasticity. Meningitis following intrathecally administered baclofen is a rare but serious complication that is difficult to treat without removal of the pump. Because success rates with intravenously administered antibiotic drugs for the treatment of meningitis have been low, intrathecal administration of antibiotic agents is often required to eradicate the pathogen. The authors report the case of a patient in whom Staphylococcus epidermidis meningitis developed after insertion of an intrathecal baclofen pump. The patient was successfully treated by intrathecal coadministration of vancomycin and baclofen.

Double-blind, randomized study of the effects of influenza vaccination on the specific antibody response and clinical course of patients with chronic fatigue syndrome.

OBJECTIVE: To determine whether influenza immunization is associated with early side effects, a deleterious impact on the illness course and depressed antibody response in patients with chronic fatigue syndrome (CFS). DESIGN: Prospective, randomized, double-blind, placebo controlled trial. CFS patients and healthy volunteers filled out a questionnaire on immunization side effects and had hemagglutination-inhibiting (HI) antibody titres measured pre- and three weeks after immunization. CFS patients completed symptom and function questionnaires before and during the six-week, postimmunization period. SETTING: Ambulatory care. POPULATION STUDIED: Convenience sample of 40 CFS patients fulfilling the Centers for Disease Control and Prevention criteria and 21 demographically matched healthy volunteers. INTERVENTIONS: CFS patients were randomly selected to receive commercially available whole virus influenza vaccine (n=19) or an injection of saline placebo (n=21). Healthy volunteers received vaccine only. MAIN RESULTS: As a group, immunized CFS patients had lower geometric mean HI antibody rises than healthy volunteers (P<0.001). However, there was no difference in the rates of fourfold titre rises, and immunization did achieve a probably protective titre (1:32 or greater) in most CFS patients. No difference could be detected between immunized and placebo CFS patients in immunization side effects, although CFS patients as a group reported four times as many side effects as healthy volunteers. Further, in the six weeks following immunization, placebo and immunized CFS patients did not demonstrate any differences in terms of functioning, symptom severity and sleep disturbance. CONCLUSIONS: In patients with CFS, influenza immunization is safe, not associated with any excess early reactions, and stimulates an immunizing response comparable with that of healthy volunteers.

Treatment of community-acquired pneumonia in the elderly: the role of cefepime, a fourth-generation cephalosporin.

In a prospective, multicentre double-blind trial, 151 patients over the age of 65 years were randomly assigned to receive either cefepime 2 g every 12 h for a minimum of 3 days and up to 14 days or ceftriaxone 1 g every 12 h for a minimum of 3 days and up to 14 days. Antibiotics were maintained until 48 h after fever had resolved; no other antibiotics were permitted. The average age in each group exceeded 77 years and significant co-morbidity was found in the majority of patients. The mean total duration of therapy was 5.8+/-2.4 days for the cefepime group and 6.7+/-2.7 days for the ceftriaxone group (P = 0.06). The clinical success rate at the end of therapy was 79.1% with cefepime and 75.4% with ceftriaxone (P = 0.62). At the end of follow-up, 91.7% of the cefepime-treated patients and 86.5% of the ceftriaxone patients had a satisfactory clinical response (P = 0.38). In 35 bacteriological evaluable patients, potential pathogens were eradicated in all but one patient receiving cefepime. Seven patients in each group died during the study period but in each case the death was unrelated to study drug. The commonest side-effect was diarrhoea (cefepime, five patients; ceftriaxone, two patients). The clinical and microbiological efficacy of cefepime is similar to that of ceftriaxone in elderly patients with community-acquired pneumonia requiring hospitalization. Cefepime is an appropriate choice for the treatment of community-acquired respiratory tract infections in the elderly.

Cost-minimization analysis of piperacillin/tazobactam versus imipenem/cilastatin for the treatment of serious infections: a Canadian hospital perspective.

BACKGROUND: In 1998 we reported the first Canadian double-blind, randomized, clinical trial involving a comparison of piperacillin/tazobactam (P/T) with imipenem/cilastatin (I/C). The present study was conducted to determine the feasibility of replacing I/C at our institution. OBJECTIVE: To describe the outcome of a pharmacoeconomic analysis of the clinical trial from the perspective of a tertiary acute-care institution. METHODS: A total of 150 consenting adults originally prescribed I/C were randomly assigned to receive either P/T 4.5 g i.v. (n = 75) or I/C 500 mg i.v. (n = 75) every six hours. Actual direct medical resources used in relation to the treatment of bacterial infections were prospectively assessed during a clinical trial; these included cost of study and ancillary antibiotics, hospitalization, diagnostic testing (radiology, laboratory assessments), and labor, as well as treatment of adverse drug reactions, antibiotic failures, and superinfections. RESULTS: While costs for successful treatment courses were similar across treatment arms, hospitalization costs for treatment course failures were higher for P/T recipients. Direct medical costs for treatment courses associated with a superinfection were also higher in the P/T arm. Overall costs for treatment failures with either study drug were at least twofold those observed for successful treatment courses. Mean total management cost per patient in the P/T group was $15,211 ($ CDN throughout) (95% CI $11,429 to $18,993), compared with $14,232 (95% CI $11,421 to $17,043) in the I/C group (p = 0.32), resulting in a mean cost difference of $979. Sensitivity analyses revealed that the superiority of I/C over P/T for successful treatment of serious infections was sensitive to changes in the cost of hospitalization and drug efficacy for either drug. CONCLUSIONS: Based on the results of the clinical trial, P/T and I/C offer similar clinical, microbiologic, and toxicity outcomes in hospitalized patients with serious infections. Under base-case conditions, our pharmacoeconomic analysis showed that I/C was a cost-effective alternative to P/T at the dosage regimens studied. However, this finding was sensitive to plausible changes in both clinical and economic parameters.

Characterization of kinetics and target proteins for binding of human complement component C3 to the surface-exposed outer membrane of Chlamydia trachomatis serovar L2.

In order to characterize the interaction of human complement with Chlamydia trachomatis, flow cytometry was used to quantitate binding of complement component C3 to elementary bodies of C. trachomatis serovar L2 preincubated in fresh serum in the presence or absence of human polyclonal chlamydial antibody. Isolation of each of the complement activation pathways revealed that C3 was activated most effectively by the alternative pathway. The degree of binding by the classical pathway was proportional to the concentration of antibody, but dual-pathway-mediated binding was not greater than antibody-independent alternative pathway binding. Electrophoresis and immunoblotting of detergent-extracted outer membrane protein-C3b complexes indicated that the chlamydial major outer membrane protein was the primary cell surface moiety binding C3b in both the presence and absence of specific antibody. Hydroxylamine cleavage of outer membrane protein-C3b complexes provided evidence that the majority of C3b is bound to the major outer membrane protein by hydroxyl ester bonds. This result was also unchanged by the presence of specific antibody. An unexpected finding was the apparent binding of anti-C3 antibody to a 40-kDa protein of the chlamydial outer membrane complex, perhaps indicating C3 mimicry on the part of the chlamydial major outer membrane protein.

Comparison of cefoxitin and ceftizoxime in a hospital therapeutic interchange program.

OBJECTIVE: To determine whether (a) ceftizoxime can replace cefoxitin in the prevention and treatment of various infections in a major teaching hospital, (b) a previously applied two-stage intervention program is an effective method of instituting a therapeutic interchange of ceftizoxime for cefoxitin and (c) the replacement of cefoxitin with ceftizoxime results in a more cost-effective therapy. DESIGN: Two-phase, open, sequential study. SETTING: Tertiary care teaching hospital. PATIENTS: One hundred patients who received cefoxitin during the 6 months immediately before the start of the interchange program (phase 1) and 100 who received ceftizoxime during the 6 months immediately after the start of the program (phase 2) were randomly selected. RESULTS: The demographic characteristics of the two patient groups were similar except for sex (p < 0.05). The cefoxitin doses were usually given every 6 hours (in 33% of the cases) or every 8 hours (in 61%), whereas the ceftizoxime doses were usually given every 12 hours (in 98%). Prescriber distribution was stable throughout the study period, the Department of General Surgery being responsible for about 70% of the orders. Prophylactic indications accounted for over 60% of the treatment courses. The proportion of prophylactic treatment courses that resulted in a successful clinical outcome did not differ between the two groups (cefoxitin 92% and ceftizoxime 91%). Of the empiric or directed treatment courses clinical success or improvement was observed in 89% of the cefoxitin and 91% of the ceftizoxime recipients. Microbiologic eradication was seen in 65% of the cefoxitin and 90% of the ceftizoxime directed treatment courses. Pathogens isolated during therapy were similar in the two treatment groups. Diarrhea was the most common adverse effect, occurring in 8% of the cefoxitin and 10% of the ceftizoxime recipients; no Clostridium difficile or C.-difficile-producing toxin was identified in these patients. The ceftizoxime therapy was 36% less expensive than the cefoxitin therapy on average, and the annual savings was estimated to be $83,123. An estimated 5615 drug doses were avoided annually, for an additional savings of $24,875 in drug administration. Therefore, the total estimated annual cost savings resulting from this two-stage interchange program was $107,998. Given the cost of $4856 to implement and maintain the program, the estimated net savings for the first year was $103,142. CONCLUSION: Ceftizoxime can replace cefoxitin in the prevention and treatment of various infections. The form of evaluation described herein is valuable when any formulary modification is being considered in a hospital.

Seroepidemiology of hepatitis C virus in Beijing, China.

To investigate the seroprevalence of hepatitis C virus (HCV) in China we tested sera from healthy individuals without hepatitis and no history of parenteral blood exposure and from patients admitted to a hepatitis hospital in Beijing. Sera were tested for anti-HCV by first-generation enzyme immunoassay; selected positives were tested with two second-generation EIAs, one utilizing recombinant antigens and the other synthetic peptides. We found anti-HCV with the following frequencies: 10 of 164 (6%) individuals with no disease; 2 of 36 (5.5%) patients with acute non-A non-B hepatitis (NANBH); 26 of 39 (67%) patients with post-transfusion NANBH; 10 of 34 (29%) patients with chronic hepatitis negative for hepatitis B surface antigen (HBsAg); 3 of 30 (10%) patients with chronic HBsAg-positive hepatitis; 0 of 19 patients with acute HBsAg-positive hepatitis. Of 24 repeat-positive sera, 19 were positive by both and 4 by one second-generation tests. We conclude that hepatitis C infection is common in China, that it contributes substantially to the incidence of post-transfusion hepatitis, and that HCV plays a significant role in both acute and chronic hepatitis. Further studies are needed to extend these observations and to define the predominant routes of transmission of HCV in China.

Rabies in China: recommendations for control.

Reviewed are the results of 15 years' experience with rabies at You-An Infectious Disease Hospital, Beijing, China. The purpose of the study was to determine whether there are any epidemiological or clinical features of rabies that are unique to China and which might be important in developing a strategy to control it. During the period under study, 64 patients with rabies were admitted to You-An Hospital. Exposure to dogs was associated with 61 cases, two involving the handling of dog carcasses that were being prepared for meals. All of the exposures occurred in rural areas, and none of the patients received adequate prophylaxis. Patients with proximal sites of exposure and with severe injuries developed rabies after short incubation periods (P less than 0.05, and P less than 0.02, respectively). Failed vaccination was also associated with a short incubation period (P less than 0.05). Haematemesis occurred in 20 patients and was associated with shorter incubation periods (P less than 0.02), facial exposure sites (P = 0.021), and severe injuries (P = 0.047). A strategy to control rabies in China should include efforts to educate the public about handling the carcasses of stray dogs, in addition to the currently recommended strategy of controlling the dog population and of vaccinating domesticated animals.

Etiology of childhood diarrhea in Beijing, China.

To determine the role of recently recognized enteropathogens in childhood diarrhea in China, 221 children with diarrhea and 108 controls seen at the Beijing Children's Hospital were studied during April and May 1989. Stools were examined for ova, parasites, and rotavirus, cultured for bacterial pathogens, and probed for enterotoxigenic Escherichia coli (ETEC), enteroinvasive E. coli (EIEC), enterohemorrhagic E. coli (EHEC), and enteropathogenic adherence factor-positive (EAF+) E. coli. Pathogens were identified in 56.5% of children with diarrhea and 43.5% of controls (P = 0.04). Detection of enteropathogens was significantly greater in patients examined within 1 week of symptom onset (65%) than in patients examined later (39%; P = 0.01). ETEC was the most frequently detected pathogen in children with diarrhea, accounting for 20% of the cases. Other agents identified in patients included the following: salmonellae, 12%; rotavirus, 7%; EIEC, 7%; EHEC, 7%; members of the Aeromonas hydrophila group, 6%; EAF+ E. coli, 5%; Ascaris lumbricoides, 3%; shigellae, 3%; campylobacters, 2%; and Vibrio spp., 0.5%. The isolation rates of salmonellae (P = 0.02), EAF+ E. coli (P = 0.04), and mixed pathogens (P = 0.05) were significantly greater for diarrhea patients than for controls. Resistance to multiple antimicrobial agents occurred in 39% of the Salmonella isolates, 22% of the Aeromonas isolates, and 17% of the Shigella isolates. Multiresistant salmonellae (P = 0.05) and shigellae were recovered from diarrheal stools only. Ciprofloxacin, cefotaxime, and imipenem were the only agents tested to which all bacterial isolates were susceptible in vitro. These results suggest that both traditional and newly recognized agents are important causes of childhood diarrhea in Beijing and that therapy may be complicated by indigenous antimicrobial resistance.

Randomized, double-blind comparison of the efficacies, costs, and vaginal flora alterations with single-dose ceftriaxone and multidose cefazolin prophylaxis in vaginal hysterectomy.

A comparison of efficacies, costs, and effects on vaginal microflora of one preoperative and three postoperative 1-g doses of cefazolin versus those of one preoperative 1-g dose of ceftriaxone was done with 65 and 73 women, respectively, undergoing elective vaginal hysterectomy. Patient infection rates were not statistically different between the cefazolin group (six events in 6 of 73 patients [8.2%]) and the ceftriaxone group (11 events in 9 of 65 patients [13.8%]). Side effects, including diarrhea, were minimal and similar between the two groups. Significant shifts in the cervicovaginal microflora of the patients occurred postoperatively, with a marked increase in enterococci and a drop in nonenterococcal streptococci. No shifts among aerobic, facultative gram-negative rods and staphylococci were observed. Among the anaerobes, a significant decrease in the number of patients harboring nonsporulating, gram-positive rods and a less striking concomitant increase in Bacteriodes species and members of the family Peptococcaceae were noted. No qualitative differences were noted between the two groups that received prophylactic therapy. Aside from enterococci, cefazolin or ceftriaxone resistance among vaginal isolates (greater than or equal to 10(3)/ml) was minimal. Selection of resistant isolates was not different between the treatment groups. We could not detect a difference between a single 1-g dose of ceftriaxone and multidose cefazolin for infection prophylaxis in patients undergoing a vaginal hysterectomy. However, the total acquisition, preparation, and administration costs were greater for the ceftriaxone regimen than they were for the cefazolin regimen. Cefazolin should therefore remain the drug of choice for infection prophylaxis in uncomplicated vaginal hysterectomies.

Randomized, double-blind, placebo-controlled, patient-initiated study of topical high- and low-dose interferon-alpha with nonoxynol-9 in the treatment of recurrent genital herpes.

To explore further topical antiviral therapy for recurrent genital herpes, 188 culture-proven patients were randomized to receive treatment with topical interferon-alpha in high-dose (10(6) IU/g with 1% nonoxynol-9 in 3.5% methylcellulose) or low-dose (10(3) IU/g with 0.1% nonoxynol-9 in 3.5% methylcellulose) treatments or placebo (3.5% methylcellulose, alone), applied three times daily for 5 days. Of these, 105 experienced prodromal symptoms within the study period and applied the medication, of whom 99 could be evaluated for efficacy. Patients were followed with daily clinical assessments and cultures until reepithelialization. The median time to negative virus culture in high-dose recipients was 2.5 days compared with 3.9 days for placebo recipients (P = .023), and a significant dose response was observed (P = .016). Antiviral effects were more prominent in men than women. High-dose recipients also had reduced median duration of symptoms to 2.7 days from 3.7 days for placebo recipients (P = .03), with a significant dose-response relationship (P = .047). Effects on duration of symptoms were more prominent in women. Times to complete reepithelialization in those who applied the drug during the prodromal phase were 5.8 days for high-dose recipients compared with 6.5 days for placebo recipients (P = .053). A multivariate ranked linear model analysis of four efficacy variables (crusting, healing, virus shedding, symptom duration) also favored the high-dose gel (P = .015). High-dose topical interferon-alpha preparation is effective for patients with recurrent genital herpes. Applied early in the course of a recurrent episode, this treatment is safe and may provide a topical alternative to other types of therapy in the future.

Cross-resistance of Pseudomonas aeruginosa to ciprofloxacin, extended-spectrum beta-lactams, and aminoglycosides and susceptibility to antibiotic combinations.

The susceptibilities of 270 clinical isolates of Pseudomonas aeruginosa from diverse sources (82 burn patients, 76 cystic fibrosis [CF] patients, and 112 other sources) to ciprofloxacin and three other quinolones, nine extended-spectrum beta-lactams, and three aminoglycosides were determined by an agar dilution method in cation-supplemented Mueller-Hinton medium. Ciprofloxacin, ceftazidime, imipenem, and aztreonam were the most active. MICs for burn isolates were consistently higher than those for other isolates for most antibiotics, whereas those for CF strains were consistently lower. Multidrug resistance to aminoglycosides and beta-lactams occurred in 21% of the burn isolates, 2.6% of the CF isolates, and 8.9% of the other isolates. Ninety percent of these strains remained susceptible to ciprofloxacin. Seven percent of the isolates were resistant to ciprofloxacin (MIC, greater than or equal to 2 micrograms/ml). Concurrent resistance to ciprofloxacin and beta-lactams or aminoglycosides was rare (1.8 to 4%). Analysis by Spearman rank correlation revealed a high degree of correlation of MICs among antibiotics within the same class, except for imipenem. An inoculum effect was observed for all antibiotics between 10(6) and 10(4) CFU (P less than 0.05), with those for piperacillin and cefoperazone being the most pronounced (16-fold and 8-fold differences, respectively), and was least apparent for the quinolones, aminoglycosides, imipenem, and aztreonam (twofold differences). Selected strains for which there were high MICs of ciprofloxacin (greater than or equal to 1 micrograms/ml) were tested against ciprofloxacin in combination with other agents in a checkerboard agar dilution assay. Synergistic (summated fractional inhibitory concentration, /= 4) was observed in only one instance (with gentamicin).

Haemophilus influenzae meningitis in Manitoba and the Keewatin District, NWT: potential for mass vaccination.

A community-based surveillance study of all central nervous system infections was carried out in Manitoba and the Keewatin District, NWT, between Apr. 1, 1981, and Mar. 31, 1984. There were 201 cases of bacterial meningitis in Manitoba over the study period, 81 (40%) caused by Haemophilus influenzae; all but one isolate tested were type b (Hib). There were nine cases of H. influenzae meningitis in the Keewatin District. The overall annual incidence rate of H. influenzae meningitis in Manitoba was 2.5/100,000; for children under 5 years the rate was 32.1/100,000. For the Keewatin District the corresponding rates were 69.6/100,000 and 530/100,000. A total of 85% and 100% of the cases of H. influenzae meningitis occurred by 24 months of age in Manitoba and the Keewatin District respectively. The age at onset was earlier in native Indian children (22 cases) and Inuit children (9 cases) than in non-native children (59 cases) (p less than 0.005); thus, vaccine prevention of Hib meningitis will likely be more difficult in native Indian and Métis children. Without evaluating the increased potential of H. influenzae vaccines to prevent nonmeningitic forms of disease, we concluded that mass childhood vaccination with polyribosylribitolphosphate (PRP) vaccine is not warranted in Manitoba or the Keewatin District. Immunogenicity studies suggest that administration of conjugated Hib vaccines such as PRP-D in infancy may prevent approximately one-third to two-thirds of cases of H. influenzae meningitis; these vaccines warrant consideration for use in mass childhood vaccination programs.

Inhibition of polymorphonuclear leukocyte chemotaxis by the mucoid exopolysaccharide of Pseudomonas aeruginosa.

We tested the effect on human polymorphonuclear leukocyte (PMN) chemotaxis of the mucoid exopolysaccharide (MEP) elaborated by Pseudomonas aeruginosa strain P1M recovered from the sputum of a patient with cystic fibrosis (CF). A dose-related inhibition of chemotaxis under agarose was observed when mucoid exopolysaccharide at concentrations of 0.5 to 5.0 mg/ml was incorporated into the agarose. Similar inhibition was observed with the closely related polysaccharide alginic acid, but not with the neutral polymer Ficoll. The exopolysaccharide did not bind or inactivate the chemoattractant substance, nor was it toxic to PMN's. Digestion with alginase did significantly abrogate the inhibitory effect of alginic acid, but not of MEP. There was no difference in chemotaxis in the presence of the exopolysaccharide preincubated with heat-inactivated pooled antisera from CF patients chronically colonized with mucoid P. aeruginosa compared to MEP alone, or MEP preincubated with heat-inactivated pooled normal human sera. Inhibition of chemotaxis may represent yet another pathogenetic property of P. aeruginosa mucoid exopolysaccharide.