Evaluation of new anti-infective drugs for the treatment of acute bacterial meningitis. Infectious Diseases Society of America and the Food and Drug Administration.

Predisposing conditions for acute bacterial meningitis include prematurity, young age, management in an intensive care setting, low socioeconomic background, and crowded living conditions. Clinical findings vary with age and may be nonspecific (altered feeding behavior) or specific (Kernig and Brudzinski signs). Examination and culture of cerebrospinal fluid (CSF) are essential for diagnosis. Antigen identification in CSF, serum, or urine by latex agglutination or other techniques can be useful in the identification of the pathogen. Randomized, controlled studies with a single-, double-, or evaluator-blinded design are encouraged. Among neonates, infants, and children, CSF should be examined again 24-36 hours after initiation of therapy. Outcomes should be judged by both clinical and microbiological criteria. Assessment of microbiological outcome is paramount.

Evaluation of new anti-infective drugs for the treatment of cryptococcal meningitis. Infectious Diseases Society of America and the Food and Drug Administration.

Cryptococcus neoformans may infect persons with intact or compromised host defenses. Clinical manifestations generally correlate directly with the degree of immunosuppression. Treatment is prescribed on the basis of the severity of disease and the degree of immunosuppression. Cryptococcal meningitis is the most common clinical form of cryptococcal infection and the most amenable to study in clinical trials. The current standard of care for cryptococcal meningitis is therapy with amphotericin B. Despite clinical improvement and microbiological suppression of the organism at the completion of therapy, the microbiological outcome will be identified as presumptive persistence if treatment is continued. Patients should be observed for 1 year after completion of therapy before a final assessment is made.

Evaluation of new anti-infective drugs for the treatment of viral encephalitis. Infectious Diseases Society of America and the Food and Drug Administration.

Viral encephalitis may develop subsequent to viremia, via neuronal spread, or by arthropod vector. Diagnosis often requires invasive studies such as lumbar puncture and brain biopsy. This guideline addresses herpes simplex, rabies, and arbovirus infections of the central nervous system. Clinical trials should be designed according to the availability of approved therapeutic agents. Study designs with an active control (herpesvirus), a placebo control (arbovirus), or no control (rabies virus) are recommended. Outcome should be assessed 4-6 weeks, 4-6 months, and 11-13 months after the completion of therapy. For newborns with encephalitis, outcome should be assessed yearly through the age of 5 years. Assessment of clinical outcome is paramount.

Evaluation of new anti-infective drugs for the treatment of toxoplasma encephalitis. Infectious Diseases Society of America and the Food and Drug Administration.

Toxoplasma gondii is a protozoan that exists in three forms, all of which are potentially infectious for humans. After acute infection, cysts persist in the central nervous system and extraneural tissue. Human hosts with compromised immunity, particularly those with the acquired immunodeficiency syndrome, are vulnerable to reactivation and dissemination. The most common clinical expression of toxoplasma infection is encephalitis. The diagnosis is established by clinical presentation, computed tomography and/or magnetic resonance imaging, and detection of antibodies to T. gondii in serum of patients positive for human immunodeficiency virus. Brain biopsy may be performed. Protocols may be developed for the evaluation of new regimens for the treatment of acute encephalitis, the suppression of disease after treatment, or the prevention of reactivation before the onset of clinical disease. Assessment of clinical outcome is paramount.

Aztreonam in the treatment of gram-negative bacterial meningitis.

Aztreonam was administered to 122 patients with presumptive or confirmed gram-negative bacillary meningitis in an open, multinational study. The antibiotic was administered at a dosage of 1-2 g to adults, 50 mg/kg to children greater than 2 years old, and 30 mg/kg to infants three or four times daily. Seventy-seven patients had microbiologically confirmed gram-negative meningitis due to an aztreonam-susceptible organism and received aztreonam for at least 48 hours. Haemophilus influenzae was the most frequently recovered pathogen (40 patients), followed by Enterobacteriaceae (16 patients), Neisseria meningitidis (15 patients), and Pseudomonas species (six patients). All but four patients were microbiologically cured. Microbiologic failure was associated with either a persistent intracerebral abscess (one patient) or a foreshortened course of therapy before microbiologic reevaluation and death (at 48 hours, 48 hours, and 72 hours after initiation of treatment, respectively). These data suggest that aztreonam is effective in the treatment of gram-negative bacillary meningitis caused by susceptible organisms.

Efficacy of aztreonam in the treatment of skeletal infections due to Pseudomonas aeruginosa.

Twenty-eight patients with skeletal infections due to Pseudomonas aeruginosa were treated with aztreonam during two open, noncomparative, multicenter clinical trials. Ten patients with septic arthritis received 2 g of aztreonam three times a day (modal) for 30 days (mean). The mean follow-up period was 4 weeks. Microbiologic cure was achieved in all 10 patients; complete clinical cure, in eight; and partial clinical cure, in two. Eighteen cases of osteomyelitis were treated with 2 g of aztreonam three times a day (modal) for 40 days (mean), with a mean follow-up period of 6 months. Microbiologic cure was achieved in 17 patients. Relapse occurred 1 month after therapy in one patient. Complete clinical cure was achieved in 13 and partial clinical cure was achieved in five patients. The most common adverse reactions to aztreonam were a transient elevation in levels of hepatic enzymes and transient eosinophilia. Three superinfections and one subsequent infection occurred. These results support use of aztreonam for the treatment of skeletal infections due to P. aeruginosa.

Group A beta-hemolytic streptococcal bacteremia and intravenous substance abuse. A growing clinical problem?

Over an 18-month period, the incidence of group A beta-hemolytic streptococcal bacteremia rose from an average of 2.5 per 10,000 patient discharges to 17.9. A retrospective analysis was performed comparing patients with group A beta-hemolytic streptococcal bacteremia during this 18-month period with those who presented over the preceding 36 months. Most of the increased incidence was attributable to individuals hospitalized with a diagnosis of drug addiction who had concomitant soft-tissue infection, although the absolute number of hospitalized drug addicts did not change during this interval. No common or distinctive group A streptococcal serotypic patterns were discovered. This experience suggests that group A beta-hemolytic streptococcal bacteremia and soft-tissue infection may present in epidemic fashion among parenteral drug addicts in the absence of a common source.

Coagulopathy associated with extended-spectrum cephalosporins in patients with serious infections.

Patients enrolled in two double-blind multicenter studies were evaluated for the development of hypoprothrombinemia during treatment with cephalosporins. Patients with pneumonia or peritonitis received ceftizoxime, cefotaxime, or moxalactam. The incidence of hypoprothrombinemia was greater in patients with peritonitis (12 of 49) than in those with pneumonia (5 of 96; P less than 0.05). Overall, moxalactam was associated with a higher incidence of hypoprothrombinemia (13 of 52) than either ceftizoxime (1 of 43; P less than 0.05) or cefotaxime (3 of 50; P less than 0.05), and moxalactam patients incurred the highest average increase in prothrombin time (3.7 s) as compared with either ceftizoxime (0.5 s; P less than 0.05) or cefotaxime (0.9 s; P less than 0.05) patients. The occurrence of hypoprothrombinemia in moxalactam patients with peritonitis was not related to dosage, duration of therapy, age, sex, race, or renal or hepatic function. The degree of ileus was, however, strongly related to the development of coagulopathy in moxalactam-treated patients only.

Clinical efficacy of cefonicid in the treatment of staphylococcal infections.

Cefonicid is a parenteral cephalosporin with a half-life of 4.5 hours, which permits once-daily dosing. The efficacy of cefonicid in the treatment of established staphylococcal infections was reviewed in all patients with infections due to staphylococci who were treated with cefonicid during the US clinical development program. Two hundred evaluable cases were identified, of which 95 had other pathogens as well. Cefonicid was clinically effective in 92% of skin and soft tissue infections, 74% of bone and joint infections, 83% of respiratory tract infections, and 95% of urinary tract infections. None of the three evaluable patients with Staphylococcus aureus endocarditis responded to cefonicid. Thus, based on current evidence, cefonicid is not effective in the treatment of established staphylococcal endocarditis. However, for the treatment of staphylococcal infections at other sites, cefonicid is comparable to other cephalosporins, most of which must be administered more frequently than cefonicid and thus are less cost-effective.

Five cephalosporins: pharmacokinetics and their relation to antibacterial potency.

In a group of adult volunteers, pharmacokinetic profiles of five cephalosporins were correlated with their minimal inhibitory concentrations (MICs90) against Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Enterobacter aerogenes. Subjects received the following intravenous regimens in a randomized, crossover fashion: (1) 0.5 gm, 1 gm, or 2 gm of cefazolin; (2) 2 gm of cephalothin; (3) 1 gm of cephapirin; (4) 1 gm of cefoxitin; or (5) 0.5 gm of cefamandole. The 500-mg dose of cefazolin produced serum concentrations that exceeded those of any of the other cephalosporins at 0.5, 1, 2, 4, and 6 hours after administration. The area under the curve for this dose of cefazolin was at least twice that of any of the other antibiotics. Two hours after a 500-mg dose of cefazolin, serum levels exceeded the MIC90 for all seven groups of pathogens; at six hours, the 500-mg dose of cefazolin continued to achieve serum levels above the MIC90 against the majority of bacterial groups. In contrast, at two hours after administration none of the other cephalosporins maintained serum levels above the MIC90 for all pathogens; at six hours, the levels of cephapirin were adequate to inhibit the two streptococci, but serum levels of all other cephalosporins were inadequate to inhibit any of the pathogens. These data indicate that a 500-mg dose of cefazolin maintains serum levels above the MICs90 longer than any of the other cephalosporins tested and support the use of a 500-mg dose of cefazolin every eight hours for surgical prophylaxis and treatment of most community-acquired infections. Such a comparatively low dosage offers substantial savings to both patient and hospital.

Efficacy of ceftizoxime administered twice daily in hospitalized patients with respiratory tract infections.

The efficacy and safety of ceftizoxime administered twice daily were evaluated in 215 hospitalized patients with documented lower respiratory tract infections. The majority of patients received 1 to 2 gm of ceftizoxime intramuscularly or intravenously every 12 hours; the mean dosage was 2 gm/day, and the mean duration of therapy was 8.9 days. Clinical cure was achieved in 204 (95%) of the 215 patients with lower respiratory tract infection. One hundred and thirty-eight patients were both clinically and bacteriologically evaluable. The clinical response rates, by organism, were: Streptococcus pneumoniae, 100% (50/50); Haemophilus influenzae, 96% (25/26); gram-negative bacilli (Escherichia coli, Proteus mirabilis, Enterobacter sp, Serratia sp, Pseudomonas sp, Klebsiella sp, Citrobacter sp, and Morganella morganii), 86% (32/37); and Staphylococcus aureus, 92% (12/13). In the other 77 patients with clinical symptoms, no pathogen was isolated or insufficient follow-up data were collected to assess bacteriologic response. Adverse reactions, which were infrequent, were similar to those reported in other US trials of the drug. The findings indicate that ceftizoxime, 1 to 2 gm BID, is effective and safe in the treatment of lower respiratory tract infections in hospitalized patients. This low-dose regimen can significantly reduce the cost of cephalosporin therapy.

Comparison of immunodiffusion and crossed-immunoelectrophoresis in the diagnosis of invasive candidiasis.

A retrospective single blind study was conducted to compare the efficacy of crossed-immunoelectrophoresis using concanavalin A intermediate gel with double immunodiffusion tests in the diagnosis of invasive candidiasis. On the basis of cytoplasmic antibody detection, crossed-immunoelectrophoresis with concanavalin A differentiated reliably between Candida albicans fungemia and invasive candida infection, whereas double immunodiffusion did not. With regard to sensitivity, specificity, and predictive value crossed-immunoelectrophoresis with concanavalin A was superior to double immunodiffusion. Analysis of double immunodiffusion precipitin bands revealed fuzzy and sharp precipitin bands which corresponded to mannan (fuzzy) and cytoplasmic (sharp) antibodies in the crossed-immunoelectrophoresis with concanavalin A assay. Therefore, the finding of sharp bands in the double immunodiffusion procedure supports the diagnosis of invasive candidiasis.

Gentamicin-carbenicillin synergy among gentamicin resistant Pseudomonas aeruginosa.

Forty-five isolates of gentamicin resistant Pseudomonas aeruginosa were evaluated for gentamicin-carbenicillin synergy. Only 9 percent (4/45) showed synergy. Of nine isolates with demonstrable zones around a gentamicin disc (8 to 12 mm), none showed a synergistic response. Effective treatment of gentamicin resistant Ps. aeruginosa with gentamicin and carbenicillin should not be assumed without additional test procedures.

A cluster of Acinetobacter Pneumonia in foundry workers.

In a 3-month period, three men who had worked for 5 to 19 years as welders or grinders of steel castings in a foundry acquired pneumonia caused by Acinetobacter calcoaceticus variety anitratus serotype 7J. Two of the men died, and postmortem examination showed mixed-dust pneumoconiosis with iron particles in the lungs. A calcoaceticus variety anitratus serotype 7J was isolated from the air in the foundry but the source was not found. The prevalence of antibody titers of 64 or greater to the 7J strain was significantly higher among foundry workers (15%) than among community controls (2%) (p less than 0.01). Sampling showed that the concentrations of total and metallic particles (especially iron) and of free silica in air inhaled by welders and grinders at the foundry frequently exceeded acceptable levels. These findings suggest that chronic exposure to such particles may increase susceptibility to infection by this organism, which rarely affects healthy people.