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The anti-influenza A activities of amantadine and ribavirin were investigated separately and in combination. Ferret tracheal ciliated epithelium was continuously exposed to the drugs at concentrations (0.25, 0.5, and 1 mg/l) comparable to those found in human serum after oral administration. Each drug alone produced a modest delay in A/Alaska/6/77 (H3N2) induced cytopathic effect. The combination of drugs synergistically delayed cytopathic effect. At 1 mg/l of each, cytopathic effect was prevented in 75% of rings for the 28-day duration of the experiment. This effect was greater than that of 32 mg/l of amantadine or 64 mg/l of ribavirin as single antiviral drugs. Peak virus production was suppressed 4.4 log-fold by the combination of 1 mg/l of each drug. This is in contrast to amantadine alone which suppressed peak virus production by 1 log-fold and ribavirin along which at 1 mg/l suppressed peak virus production by 1.9 log-fold. At lower concentrations, the drugs were at least additive in suppression of virus production. [ABSTRACT FROM AUTHOR]

In these studies very high doses (up to 4800 CCA units in adults) of formalin inactivated influenza vaccine purified by density gradient centrifugation were given safely to more than 5000 volunteers drawn from adolescent, middle aged and elderly populations. The relative paucity of reactions, compared with those groups receiving much lower doses of formalin-inactivated vaccine produced by Sharples centrifugation, suggests that reactions are due to non-viral substances rather than to toxic properties of the viruses, and that these substances are removable. Homologous serum HI antibody responses increased with increasing vaccine dosage and there was no plateau effect at the higher dose level. In those groups studied, the appearance of neutralizing activity in post-vaccination nasal washings correlated closely with the higher vaccine doses and higher HI antibody titres. The occurrence of the ‘Hong Kong flu’ epidemic in two of the groups, including over 3000 vaccine recipients, provided a unique opportunity to study the efficacy of the various vaccines used. Only those groups receiving high doses of a Hong Kong-like antigen (A2/Aichi/2/68) enjoyed significant reduction in illness (70%). Furthermore, there was a 90% reduction in the incidence of fever in that group. These results indicate that very large doses of purified influenza vaccine can be given safely. Significant prevention and modification of disease caused by influenza via the vaccine approach is dependent on the administration of large doses of the appropriate antigen. [ABSTRACT FROM PUBLISHER]

The data from our 1968-69 influenza vaccine field trials are anlaysed and pre-challenge haemagglutinin and neuraminidase serum antibodies are evaluated as indices of protection. Prevention of flu-like disease, fever, confinement to bed, and/or seroconversion to Hong Kong was significantly related to post-vaccine A/Hong Kong/68(H3N2) haemagglutination-inhibition (HI) titres. Prevention of disease was also related, although not significantly statistically in every category, to pre-challenge A/Hong Kong/68 neuraminidase inhibition (NI) titres. The trend was the same regardless of whether the origin of the NI antibody was through A/Aichi/68 or A/Japan/62 vaccines or through pre-Hong Kong influenza infections. In summarizing the data using fever as an index of disease, the attack rate (AR) among volunteers without Hong Kong NI or HI antibody was 45%. Presence of NI antibody, in the absence of HI antibody, significantly reduced the AR to 24%. Those with both NI and HI titres experienced a still lower AR of 14%. Those with HI and NI titres both > 1: 160 ran little risk of disease, with an AR of 7%. [ABSTRACT FROM PUBLISHER]

Gram-negative bacteremias in hospitalized immunocompromised patients can, of course, lead to sepsis and shock. How can such potentially disastrous infections be managed? Among the cornerstones of management that may curb mortality and morbidity are early recognition of infection, invasive monitoring and therapeutic techniques, and careful selection of antibiotics.

During a hospital epidemic of infections with gentamicin-resistant Serratia marcescens (GRS), we studied the relation between receiving antibiotics and acquiring GRS. In a five-month period, 22 patients acquired GRS, whereas 18 patients acquired gentamicin-sensitive Serratia (GSS). When compared with patients with nosocomial GSS infection, patients with nosocomial GRS had been in the hospital (p = 0.04) and the intensive care unit (p = 0.003) longer before infection and more had received gentamicin (p = 0.001) or ampicillin (p = 0.02) before infection. To control for the influence of underlying disease, we matched all 12 ICU patients with GRS infection and 12 patients without GRS infection for underlying illness and duration of intensive care. Use of any antibiotic (p = 0.04), or a combination of gentamicin plus ampicillin or cephalosporin (p = 0.047) was more common among patients with GRS infection. The hospital had not significantly increased the use of aminoglycosides from the previous year. We conclude that for the individual patient antimicrobial therapy, especially with gentamicin or ampicillin, creates a risk for later infection by GRS that is independent of the severity of the underlying illness.

Amantadine, an oral antiviral agent, is effective in the prophylaxis and treatment of all strains of influenza A, preventing 70 to 90 percent of both experimentally induced and natural infections. Although not a substitute for vaccination, prophylactic amantadine can be particularly helpful in high-risk groups, including those with cardiovascular and pulmonary diseases and those in chronic-care settings. Adjunctive administration to previously immunized high-risk persons enhances the vaccine's efficacy. If given to nonimmunized persons who are then vaccinated during an influenza out-break, it will protect them for the two to three weeks needed for vaccine-induced immunity to develop. If given to residents of a chronic-care facility early in an outbreak, it is helpful in controlling the outbreak. Used therapeutically within 48 hours of the onset of symptoms, amantadine will shorten influenza illness by up to 50 percent, reduce fever, and hasten the resumption of normal activities. Amantadine is particularly recommended for high-risk persons in whom influenza-like symptoms develop during a confirmed or suspected outbreak of influenza A.

In a 2-year period, 9 adults were admitted to hospital with acute epiglottitis confirmed by direct laryngoscopy or lateral neck radiograph, or both. The mean age was 53 +/- 14 years, with acute epiglottitis occurring in 89% during the months of September to March. Intubation was required in 4 patients. The duration of symptoms was 7.8 +/- 2.4 hours for intubated patients versus 18.8 +/- 8.9 hours for those not intubated. For 6 patients an incorrect diagnosis was made on their first presentation. All 8 patients having laryngoscopy had typical findings, and none had respiratory obstruction precipitated by the procedure. In 5 patients blood cultures were positive, 4 for Hemophilus influenzae type b, and 1 for Streptococcus pneumoniae. In 2 patients the H influenzae was ampicillin-resistant. All patients recovered after receiving parenteral steroid therapy and appropriate antibiotics.

The effects of varying concentrations of halothane on tracheal ciliary activity were studied using a ferret tracheal organ culture technique. Using 1% and 2% halothane produced no impairment of ciliary activity, while 3% halothane caused some ciliostasis; 4% and 5% halothane produced rapid cessation of ciliary activity. Recovery was prompt and complete after exposure to 4% halothane for as long as 3 days, but after 4 days of exposure recovery was incomplete and after a week of exposure death of ciliary cells occurred.

Although N-acetyl-L-cysteine (Mucomyst) is an effective mycolytic, numerous investigations have failed to demonstrate a consistent improvement in pulmonary mechanics following its use. In order to determine whether its beneficial mucolytic activity might be counterbalanced by a deleterious direct effect on cilia, we studied its effect on the activity of ciliated epithelium in the ferret tracheal organ culture system. N-acetyl-L-cysteine consistently caused progressive time-dependent ciliostasis at concentrations clinically employed, with complete ciliary paralysis within 8 hr. The effect was only partially reversed by the removal of the drug. Control preparations retained full ciliary activity for 3 to 12 weeks. In order to determine the active site on the N-acetyl-L-cysteine molecule, we investigated the ciliostatic effects of five of its chemical analogs. Isomolar N-acetyl-L-alanine was not ciliostatic, indicating the necessity of a sulfhydryl group for activity. Ciliostasis was independent of isomeric structure, acetylation, and chain length, as evidenced by the similar ciliostatic effects of L-cysteine, D-cysteine, 2-mercaptoethylamine, and N-acetyl-L-homocysteine. We conclude that N-acetyl-L-cysteine induces partially reversible ciliostasis of tracheal epithelium via its sulfhydryl group; prolonged use of this drug may impair mucociliary clearance.

Organ cultures of ferret tracheal rings maintained in tubes for up to two months supported the growth of several strains of influenza A viruses produced by genetic recombination. These strains were developed as possible candidates for live attenuated influenza virus vaccines. By observing the effects on cilia and titrating the growth in eggs it was possible to rank these various influenza strains in order of descending virulence for the respiratory epithelium in organ culture. This rank corresponded in general to the virulence of these viruses for human volunteers. Viruses too virulent to use as vaccine strains in man regularly destroyed the ciliated epithelium of ferret trachea while strains attenuated for man usually did not. Although the ciliated respiratory epithelium of ferret was not as sensitive as that derived from human embryonic trachea, this test did identify all the tested strains too virulent for evaluation in human volunteers.

The Hong Kong/68-ts-1[E] virus, which has a 38 degrees C shutoff temperature for plaque formation, has been proposed as a donor of its two ts lesions to new variants of influenza A virus that pose an epidemic threat. To further examine whether the acquisition of the two ts-1[E] lesions will predictably attenuate new influenza A variants, the HK/68-ts-1[E] virus was mated with the A/Vic/3/75 wild-type virus. The Vic/75-ts-[E] recombinants that had the two ts-1[E] lesions also had a 38 degrees C shutoff temperature. Two Vic/75-ts-1[E] recombinants (clones 81 and 113) that had the two ts-1[E] lesions, a 38 degrees C shutoff temperature, and the Vic/75 hemagglutinin and neuraminidase glycoproteins were similar to each other and to their ts-1[E] parent in the pattern of replication and genetic stability in hamsters. These findings support the hypothesis that the acquisition of the two ts-1[E] lesions will predictably attenuate wild-type influenza A virus. Each Vic/75-ts-1[E] recombinant virus that possessed only the group 1 ts-1[E] lesion had a 39 degrees C shutoff temperature. Two of three of the Vic/75-ts-1[E] recombinants that had only the group 2 ts-1[E] lesion had a 39 degrees C shutoff temperature. This suggests that the HK/68-ts-1[E] donor virus contains two ts genes each of which by itself restricts plaque formation at 39 degrees C and above. The HK/68-ts-1[E] parent virus and its Vic/75 recombinant clones 81 and 113 were evaluated in ferret tracheal organ cultures maintained at permissive and restrictive temperatures. The Vic/75-ts-1[E] clone 81 differed from its parent and sister clone 113 in that it replicated readily and caused ciliostasis at 37 degrees C, a temperature restrictive for the replication of other ts-1[E] recombinants with a 38 degrees C shutoff temperature. The genetic basis underlying this difference was not elucidated.

Pulmonary antibacterial activity was determined by challenging halothane-exposed and control mice to radiolabeled (32P) Staphylococcus aureus produced by an aerosol generator and by determining the relative changes in viable bacterial and radioisotope counts in ground lung immediately after exposure and 4 hours later. Mice that were anesthetized for 4 hours with 1 or 2 MAC halothane and allowed to recover for 1 hour showed higher 4-hour bacterial counts when compared to controls, while radioisotope counts were the same in both groups. These data indicate that 1 and 2 MAC halothane anesthesia is associated with depressed lung bactericidal activity but that physical clearance mechanisms are not depressed.

Patients with frequent recurrences of genital herpes were treated with oral acyclovir tablets, 800 mg, or placebo once daily for two years. Confirmed recurrences for all patients were treated with acyclovir capsules, 200 mg orally five times per day, for five days. Of 46 patients enrolled, 18 of 22 acyclovir recipients and 14 of 24 placebo recipients completed two years of study. Patients receiving acyclovir experienced a mean of 0.184 recurrences/month compared with a mean of 0.977 recurrences/month for patients receiving placebo (p less than 0.0001). A total of 28 percent of acyclovir recipients and no placebo recipients remained free of recurrences for two years. The low rate of recurrences in the acyclovir group remained consistent throughout the study. No serious clinical or laboratory abnormalities associated with acyclovir were observed. The 800-mg acyclovir tablet given daily was well-tolerated and effective for two years in the management of recurrent genital herpes.

The safety and effectiveness of ticarcillin plus clavulanate potassium was evaluated in an open study of 43 patients with community-acquired lower respiratory tract infections. The mean age of the 28 patients in whom bacteriologic evaluations were possible was 55 years; at least two thirds of the patients had a history of alcoholism or chronic obstructive pulmonary disease. A pathogen was isolated from sputum samples in 23 patients; five of these 23 also had documented bacteremia. There were five additional cases of bacteremia associated with clinical signs and symptoms of pneumonia but with no organisms isolated from sputum cultures. Thirty-five pathogens were isolated from the 33 evaluable infection sites, primarily Streptococcus pneumoniae and Hemophilus influenzae. S. pneumoniae was the causative organism in all 10 cases of bacteremia. Ticarcillin plus clavulanate potassium (3 g of ticarcillin and 100 mg of clavulanic acid) was administered intravenously for a mean of six days. All 35 organisms isolated before treatment were eradicated. In one patient a superinfection with Pseudomonas aeruginosa developed after treatment with ticarcillin plus clavulanate potassium. A clinical evaluation was possible for 32 of the 33 infection sites; clinical cure was achieved at 31 sites and improvement was seen at the other site. All 43 patients were monitored for adverse reactions by both clinical observation and laboratory tests. In one patient, reversible thrombocytopenia developed that required discontinuation of ticarcillin plus clavulanate potassium. In another patient, there was a slight decrease in the potassium level during therapy. No systemic adverse reactions occurred, nor was there any instance of local effects associated with the intravenous infusion of the drug.

A live attenuated influenza vaccine candidate was not genetically stable when administered to some children who lacked antibody to surface proteins of the virus. To obtain additional biological information about these revertants, the vaccine strain, the wild-type parental strain, and isolates recovered from inoculated children during a vaccine trial were evaluated in ferret tracheal organ culture for effects on the ciliated epithelium and replication at both permissive and restrictive temperatures. The studies revealed that the vaccine strain destroyed cilia and replicated to high titer at its permissive temperature (33 degrees ) but caused minimal damage and replicated to very low titer at its restrictive temperature (37 degrees C). The wild-type parent destroyed cilia at both 33 and 37 degrees C. Isolates which were no longer temperature sensitive (ts(+)) destroyed cilia at both restrictive and permissive temperatures and grew to high titer. Isolates which retained the ts phenotype behaved as the vaccine strain in this system. The ts(+) virus recovered from volunteers behaved like the wild-type parent, which suggests that these viruses had not merely lost their ts phenotype, but had undergone reversion to wild type. Important information about the genetic stability of temperature-sensitive influenza vaccine strains recovered from volunteers can be obtained by evaluating them in ferret tracheal organ culture.

The effect of standard concentrations of lidocaine HCl and methylparaben (preservative) on the ciliary activity of ferret tracheal rings in organ culture was assessed. Pure lidocaine concentrations as low as 0.5% caused complete ciliostasis which was reversible after removal of the drug. One percent and two percent effects were not completely reversible. Pure methylparaben concentrations as low as 0.06 mg/ml paralyzed cilia; and, at concentrations of 0.5 mg/ml or higher, adverse effects were not completely reversible. When lidocaine and methylparaben were combined at the same ratio used in commercial preparations, their ciliotoxic effects were additive. These data suggest that topical respiratory anesthesia may result in prolonged ciliary paralysis.

Pyogenic meningitis became apparent on the third day of ampicillin and gentamicin therapy for Aeromonas hydrophila sepsis in a patient with severe alcoholic hepatitis. The patient responded clinically to therapy with intravenous cefotaxime sodium and gentamicin sulfate. Antibiotic therapy that provides adequate CSF concentrations should be considered in the treatment of patients with Aeromonas sepsis.

Several strains of wild-type influenza A virus were studied in the ferret tracheal organ culture system. Ciliary activity and viral replication were measured. Ciliary activity was reduced more rapidly by A/Hong Kong/45/68 (H3N2) (A/HK) and A/Victoria/3/75 (H3N2) (A/Vic) than by A/New Jersey/8/76 (Hsw1N1) (A/NJ), A/Scotland/840/74(3HN2) (A/Scot), or A/USSR/90/77 (H1N1) (A/USSR). A/HK, A/Vic, and A/Scot produced titers of virus higher than A/USSR or A/NJ during the first three days after infection. Differences in effects of the five viruses on cilia were not related to history of egg passage. The two strains that destroyed ciliary activity rapidly had caused excess mortality in the United States, whereas the three that destroyed ciliary activity more slowly had not. A relationship may exist between the properties contributing to virulence in humans and the destruction of ciliary activity in vitro in this culture system.

High (3000 CCA units) and standard low (300 CCA units) doses of the monovalent purified vaccines described in an earlier paper were evaluated in a double-blind manner in 2 adult populations for protective effectiveness against illness caused by the Hong Kong influenza virus. Epidemics in both populations occurred 4-6 weeks after single injections of vaccine were given.The attack rates among recipients of low or high doses of A2/Japan vaccines in a prison were virtually identical to those among the control groups receiving B/Massachusetts vaccines. The attack rate among those receiving 3000 CCA units of Aichi vaccine was nearly 70% less than the rate among recipients of A2/Japan or B/Mass. vaccines. Similarly, in a retirement community the attack rate among the recipients of 3000 CCA units of Aichi vaccine was 50%-70% lower than the attack rate among the recipients of the A2/Japan vaccine. In both populations, recipients of high doses of Aichi vaccine who later became ill tended to have less morbidity, fewer and lower fevers, and shorter stays in bed. Attack rates among the groups receiving low doses of Aichi vaccine were somewhat lower than rates among those receiving A2/Japan or B/Mass. vaccines, but the effect was not statistically significant. Divalent and polyvalent commercial vaccines were also without protective effect.The results indicate that optimally constituted influenza vaccines at standard dosage levels have little, if any, effectiveness and that even very large doses of vaccine do not approach the high degrees of effectiveness that have been achieved with other virus vaccines.