Immunoprophylaxis against klebsiella and pseudomonas aeruginosa infections. The Federal Hyperimmune Immunoglobulin Trial Study Group.

To determine if passive immunization could decrease the incidence or severity of Klebsiella and Pseudomonas aeruginosa infections, patients admitted to intensive care units of 16 Department of Veterans Affairs and Department of Defense hospitals were randomized to receive either 100 mg/kg intravenous hyperimmune globulin (IVIG), derived from donors immunized with a 24-valent Klebsiella capsular polysaccharide plus an 8-valent P. aeruginosa O-polysaccharide-toxin A conjugate vaccine, or an albumin placebo. The overall incidence and severity of vaccine-specific Klebsiella plus Pseudomonas infections were not significantly different between the groups receiving albumin and IVIG. There was some evidence that IVIG may decrease the incidence (2.7% albumin vs. 1.2% IVIG) and severity (1.0% vs. 0.3%) of vaccine-specific Klebsiella infections, but these reductions were not statistically significant. The trial was stopped because it was statistically unlikely that IVIG would be protective against Pseudomonas infections at the dosage being used. Patients receiving IVIG had more adverse reactions (14.4% vs. 9.2%).

Anti-infective drugs in the prevention and treatment of sepsis syndrome.

Anti-infective drugs may be used to prevent or treat infectious diseases. Preventing serious infections using aerosolized drugs, selective decontamination of the intestinal tract, or devices impregnated with anti-infective materials generally has been unsuccessful. Treatment of serious infections arising from the community or hospital setting requires knowledge of the most likely pathogens responsible for the illness, the antimicrobial susceptibility of those organisms, and the proper dosing of antimicrobial therapy.

In vitro activity of sparfloxacin, ciprofloxacin, ofloxacin, and other antibiotics against bloodstream isolates of gram-positive cocci.

The in vitro activity of sparfloxacin was compared with the activities of ciprofloxacin, ofloxacin, and six other antimicrobial agents against 323 bloodstream isolates of staphylococci (both oxacillin susceptible and resistant) enterococci, and pneumococci. Sparfloxacin was more active than both ciprofloxacin and ofloxacin against all the isolates tested. Its activity (MIC for 90% of strains tested < or = 0.10 microgram/ml) against oxacillin-susceptible staphylococci was superior to that of ciprofloxacin and ofloxacin by at least fourfold. Sparfloxacin was also more potent against pneumococci. However, fluoroquinolone resistance was noted among oxacillin-resistant strains of Staphylococcus aureus and coagulase-negative staphylococci.

Quinolone therapy in intensive care unit settings.

Three fluoroquinolone antimicrobials (norfloxacin, ciprofloxacin, and ofloxacin) could be used to prevent or treat infections in intensive care unit patients. All of these fluoroquinolones are particularly active against Gram-negative, aerobic bacteria. However, the pharmacokinetic properties of each fluoroquinolone are unique. Furthermore, only ciprofloxacin and ofloxacin are available for intravenous administration. Based on current, available information: a) fluoroquinolones are not endorsed for inclusion in selective decontamination protocols; b) fluoroquinolones are endorsed for empiric therapy of suspected Gram-negative bacterial infections based on local microorganism susceptibility patterns; and c) fluoroquinolones are endorsed for treatment of microbiologically documented infections based on their distribution properties, low rate of toxicity, and rapid bactericidal effect.

In vitro activities of ramoplanin, selected glycopeptides, fluoroquinolones, and other antibiotics against clinical bloodstream isolates of gram-positive cocci.

The susceptibilities of 316 gram-positive bacteremic isolates to ramoplanin, vancomycin, and teicoplanin and seven other antibiotics were tested. Ramoplanin demonstrated MICs of < or = 0.25 microgram/ml for at least 99% of Staphylococcus aureus isolates and 100% of coagulase-negative staphylococci tested. For both oxacillin-susceptible and oxacillin-resistant S. aureus and coagulase-negative staphylococci, the activity of ramoplanin surpassed those of both vancomycin and teicoplanin. Ramoplanin and teicoplanin had comparable activities against enterococci and Streptococcus pneumoniae and were superior to vancomycin.

Prospective observational study of Klebsiella bacteremia in 230 patients: outcome for antibiotic combinations versus monotherapy.

Combination antimicrobial agent therapy has been advocated for treatment of gram-negative bacteremia, including that caused by Klebsiella spp. We performed a prospective, observational, 10-hospital collaborative study to evaluate the efficacy of antibiotic combination therapy versus that of monotherapy for 230 consecutive patients with Klebsiella bacteremia. The species involved were K. pneumoniae (82%), K. oxytoca (15%), and K. ozaenae (0.4%). Of the bacteremias, 26% were polymicrobial in nature. A total of 53% of cases were nosocomial infections. The most common portals were the urinary tract (28%), biliary tract (12%), lung (10%), and abdomen (9%). Some 49 and 51% of the patients had received monotherapy and antibiotic combination therapy (beta-lactam plus aminoglycoside), respectively; 14-day mortalities in the two groups were 20 and 18%, respectively. However, for the subgroup of patients who experienced hypotension within 72 h prior to or on the day of the positive blood culture, those patients who received combination therapy experienced significantly lower mortality (24%) than did those who received monotherapy (50%). We conclude that monotherapy with an antibiotic that is active in vitro against Klebsiella (beta-lactam or aminoglycoside) is sufficient therapy for less severely ill patients (immunocompetent, urinary tract portal, mentally alert, normal vital signs). On the other hand, for severely ill patients who experience hypotension, antibiotic combination therapy with a beta-lactam and an aminoglycoside agent is preferred.

General guidelines for the clinical evaluation of anti-infective drug products. Infectious Diseases Society of America and the Food and Drug Administration.

This document provides new general guidelines for the design and execution of studies evaluating anti-infective drugs for the prevention or treatment of infectious diseases. The first step in evaluation is the determination of in vitro microbial susceptibility. Next, studies are conducted in animals. Several animal models provide information useful in the prediction of appropriate dosing and activity in humans. If the results of these studies are favorable, staged clinical trials are then conducted. These guidelines reflect changes in the practice of medicine, dealing with topics such as the switch from parenteral to oral drug administration during a course of therapy, treatment in settings other than acute-care hospitals, and the use of alternative comparison drugs for the study of indications or dosing schedules not covered by the product label. Because further changes in practice are anticipated, the present guidelines will need to be updated and revised periodically.

An approach to evaluating antibacterial agents in the treatment of urinary tract infection.

The evaluation of antibacterial therapy for urinary tract infection (UTI) is based on the results of randomized, controlled comparative studies (preferably double-blinded) in which sufficient numbers of patients are entered into both arms to ensure statistical validity. Since the term UTI encompasses a broad array of clinical syndromes (acute uncomplicated UTI; acute uncomplicated pyelonephritis; complicated UTI; and asymptomatic bacteriuria), the design of clinical studies should include a careful definition of the clinical syndromes being studied, the course of therapy prescribed, and the microbiological characterization necessary for evaluability. End points to be considered in the evaluation of new therapies include the effect of therapy on clinical symptoms; the ability of the therapy to eradicate the original infecting organism; the incidence of reinfection posttherapy; the number of instances of primary drug resistance of the infecting inoculum; and the incidence of adverse effects with a particular regimen.

The in-vitro activity of temafloxacin, against gram-positive bacteria.

Temafloxacin, a new fluoroquinolone with enhanced activity against Gram-positive bacteria, was compared with other antibiotics. A review of the literature on the in-vitro activity of temafloxacin was also done. The susceptibility of Gram-positive cocci isolated from blood cultures was determined using a broth microdilution method. Temafloxacin MIC90s for Staphylococcus aureus (oxacillin-sensitive and -resistant) and Streptococcus pneumoniae were less than 0.12, less than 0.12 and 0.76 mg/L respectively. Temafloxacin was more active than either ciprofloxacin or ofloxacin against these organisms. A review of the literature supported these findings. Temafloxacin was the most active of the quinolones tested against a small number of S. pneumoniae with decreased sensitivity to penicillin. Temafloxacin activity was not appreciably affected by changes in pH or the presence of serum, but activity was slightly reduced in urine at pH 6.5-7.2, and at high magnesium ion concentrations. With the exception of S. pneumoniae at high concentration, no significant inoculum effect was observed.

The path to new FDA guidelines for clinical evaluation of anti-infective drugs.

This article describes the current collaborative effort of the U.S. Food and Drug Administration and the Infectious Diseases Society of America to generate new general and disease/organism-specific guidelines for the evaluation of anti-infective agents. The description includes examples of proposed changes from draft documents. If approved and implemented, the envisioned changes should enable investigators and sponsors to improve the quality of clinical trials of anti-infective drugs. The ultimate goal is to provide physicians with the best information about new drugs and thus to enhance the care of patients with infectious diseases.

The implications for Europe of revised FDA guidelines for clinical trials with anti-infective agents.

This article summarizes the current collaborative effort between the US Food und Drug Administration and the Infectious Diseases Society of America for the purpose of generating new General and Disease/Organism Specific Guidelines for the evaluation of anti-infective agents. Examples of proposed changes from draft documents are presented. The final documents may assist European colleagues in their efforts to establish a standardized new drug registration process by 1992. An area of mutual interest is the acceptability of safety and efficacy data from international clinical trials. In the interest of human and financial economies, both US and European Guidelines need to clarify the conditions, or criteria, for the conduct of valid 'off-shore' clinical trials.

Antibiotic use in the nursing home. Physician practice patterns.

Antibiotic usage patterns were studied in two nonproprietary nursing homes that included 720 intermediate care and skilled nursing home beds. Medical records of residents receiving antibiotics were reviewed every fourth month for 1 year. Of 181 antibiotic prescriptions written for indications other than prophylaxis, 41% were for presumed urinary tract infections, 35% for respiratory tract infections, and 14% for skin/soft-tissue infections. The majority of antibiotic prescriptions (54%) were made by telephone order. Cultures were obtained in 60% of suspected infections; two thirds of cultures were of the urine. Antibiotics were changed during the course of therapy in only 12% of cases. Eighty-one percent of residents treated with antibiotics improved or were cured, 9.5% were hospitalized or died, and an additional 9.5% failed to improve but remained in the nursing home. Fever was present in 48% of cases prior to treatment, but had no predictive value for patient outcome. We conclude that antibiotic treatment in the nursing home is often initiated in the absence of fever, culture information, or examination of the patient. Empiric prescription of antibiotics in this setting generally is associated with favorable clinical course.

Persistence of anti-HBs among health care personnel immunized with hepatitis B vaccine.

Health care personnel who received the hepatitis B vaccine (Heptavax-BR, MSD) were followed for persistence of hepatitis B surface antibody (anti-HBs). Response occurred in 135/146 (92.5 percent) vaccinees. Loss of anti-HBs (less than 72 RIA units; 10 S/N) occurred in 35.9 percent during the 36-month surveillance. Stepwise discriminant analysis found age and magnitude of initial antibody level, but not weight-height index, to be predictive of antibody loss over the 36 months. Twenty-four of 27 employees (88.9 percent) who lost anti-HBs responded to a fourth vaccine dose. In contrast, three of eight initial non-responders (37.5 percent) developed antibody after a fourth vaccine dose.

Pharmacokinetics of methylprednisolone sodium succinate and methylprednisolone in patients undergoing cardiopulmonary bypass.

The pharmacokinetics of methylprednisolone sodium succinate (MPHS) and methylprednisolone (MP) were determined in six patients undergoing open heart surgery with cardiopulmonary bypass. Plasma concentrations of both compounds were measured by high-performance liquid chromatography after doses of MPHS of 1.7-2.4 g. The prodrug ester MPHS yields MP with an average formation rate constant of 0.70 +/- 0.29 hr-1. Peak concentrations of MP occur around 1-2 hours after loading and additional administration of MPHS. The pharmacokinetic values of the two drugs in patients having cardiopulmonary bypass were compared to those in younger, healthy subjects. The volume of distribution of MPHS was lower in the patients, and that of MP was similar to the value in controls. Total clearances of both agents were reduced by about 5 and 2 times. The elimination half-life of MPHS was increased slightly, whereas that of MP increased more than twice in the patients. Significant alterations in clearances occurred in patients, but concentrations of MP were appreciable and prolonged MP due to the extensive formation of MP from MPHS and reduced clearance of MP.

Routine screening for syphilis is justified in patients admitted to psychiatric, alcohol, and drug rehabilitation wards of the Veterans Administration Medical Center.

Of 1515 patients admitted to psychiatric, alcohol, and drug rehabilitation services in the Veterans Administration Medical Center, Buffalo, NY, during the year 1987, who were screened by serologic tests for syphilis, 16 (1.05%) had positive rapid plasma reagin and fluorescent treponemal antibody-absorption tests for syphilis. A positive serologic test result was not suspected on clinical grounds in any of these patients. All were detected by routine screening. Of the 16 patients, 15 had charts available for review. Seven patients were treated for primary or late syphilis; four patients had received previous treatment; and four patients had no evaluation of test results and received no treatment. Routine screening of hospitalized patients who are alcohol or drug abusers is justified, but close follow-up is necessary to make screening meaningful.