[The FDA's questions].
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Anti-Inflammatory Agents, Non-Steroidal↗
Biomedical subjects
S Opal
Publications and source records attributed to S Opal.
New strategies for clinical trials in patients with sepsis and septic shock.
OBJECTIVE: The difficulty in identifying new treatment modalities that significantly reduce the mortality and morbidity rates associated with sepsis has highlighted the need to reevaluate the approach to clinical trial design. The United Kingdom Medical Research Council convened an International Working Party to address these issues. DATA SOURCES: The subject areas that were to be the focus of discussion were identified by the co-chairs, and group leaders were nominated. Preconference reading material was circulated to group members. STUDY SELECTION AND DATA EXTRACTION: Small-group discussion fed into an iterative process of feedback from plenary sessions, followed by the formulation of recommendations. Finally, each working group prepared a summary of its recommendations and these are reported herein. DATA SYNTHESIS: There were five key recommendations. First, investigators should no longer rely solely on the American College of Chest Physicians/Society of Critical Care Medicine definitions of sepsis or sepsis syndrome as the basis of trial entry. Entry criteria should be based on three principles: a) All patients should have infection; b) there should be evidence of a pathologic process that represents a biologically plausible target for the proposed intervention, for example, an abnormal circulating level of a biological marker pertinent to the study drug; and c) patients should fall into an appropriate category of severity (usually severe sepsis). Second, investigators should use a scoring system for organ dysfunctions that has been validated and that can be incorporated into all sepsis studies; agreement on the use of a single system would simplify comparisons between studies. Third, the primary outcome measure generally should be mortality rates, but under appropriate circumstances major morbidities could be considered as primary end points. Regardless of choice of the duration to primary end point, patients should be followed for > or =90 days. Fourth, sample size needs to be based on a realistic assessment of achievable effect size based on knowledge of the at-risk population. Fifth, subgroups should be few in number and should be defined a priori on the basis of variables present before randomization. CONCLUSIONS: Important changes in several aspects of trial design may improve the quality of clinical studies in sepsis and maximize the chance of identifying effective therapeutic agents.
Clinical Trials as Topic↗
Differences between American and German medical students and physicians in knowledge of infectious diseases.
Unlike in the USA and many other countries, the discipline of infectious diseases is not established as a specialty or a subspecialty in Germany. In order to assess the impact of this structural difference, the knowledge of clinical infectious diseases was compared among 64 German and 82 American physicians and medical students using a 33-question, multiple-choice questionnaire. Participants in the USA had significantly better scores, and, among them, the number of correct answers increased steadily along with clinical experience. In contrast, among the German participants only a minor increase in knowledge was observed after the first 2 years of postgraduate training. The superior knowledge of infectious diseases demonstrated by physicians and medical students in the USA is presumably due to better training in this field during medical school and residency. Additionally, repeated exposure to infectious disease consultation in daily practice is likely to provide continuous medical education. The results of this study may provide a rationale for establishing infectious diseases as a recognized medical subspecialty in Germany.
Adult↗
Roundtable I: relationships between coagulation and inflammatory processes.
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Blood Coagulation↗
A comparative trial of imipenem versus ceftazidime in the release of endotoxin and cytokine generation in patients with gram-negative urosepsis. Urosepsis Study Group.
Evidence from in vitro experiments and animal and human studies indicate that antibiotic therapy may induce the release of endotoxin from the outer membrane of Gram-negative bacteria. Antibiotics that bind preferentially to penicillin-binding protein-2 (PBP-2)--such as imipenem--are associated with little release of endotoxin, while antibiotics that preferentially bind to PBP-3--such as ceftazidime--are associated with far greater release of endotoxin. We conducted a randomized, multicenter, double-blind study comparing imipenem to ceftazidime in patients with urinary tract infections caused by Gram-negative bacilli associated with signs and symptoms of systemic inflammation. A total of 33 patients were randomized to receive either imipenem (n = 14) or ceftazidime (n = 19) for initial treatment for urosepsis. No differences in plasma endotoxin, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) or urine endotoxin, IL-6 or IL-8 levels were found between the two treatment groups within the first 8 h after antibiotic administration. We conclude that, if differences exist with respect to endotoxin release by these two antimicrobial agents, these differences are not readily demonstrable in this clinical study with carefully defined patients with Gram-negative urinary tract infections.
Adult↗
Antibiotics and nephrostomy tube care: preliminary observations. Part I. Bacteriuria.
The authors sought to establish whether bacteriuria or candiduria would develop in patients with a noninfected, obstructed renal collecting system after placement of a percutaneous nephrostomy tube. Tubes were placed in 27 sterile systems in 25 patients. Urine was cultured at 7-10-day intervals, and urinalysis was performed. Bacteriuria and pyuria were defined on the basis of laboratory values of greater than or equal to 10(4) colony-forming units per milliliter and greater than or equal to five white blood cells per high-powered field, respectively. Twenty-two systems were followed until all demonstrated multiple organisms. No clinical symptoms were related to bacteriuria.
Adult↗
Antibiotics and nephrostomy tube care: preliminary observations. Part II. Bacteremia.
Bacteriuria occurs after long-term drainage of the kidney. This study was designed to determine if the risk of bacteremia increases at the time of tube or stent change, whether bacteremia correlates with clinical infection, and if prophylactic antibiotics are effective in the prevention of bacteremia. One hundred four tube changes in 74 patients with percutaneous nephrostomy tubes and documented positive urine cultures were studied. Patients were arbitrarily divided into groups receiving and not receiving antibiotics before nephrostomy tube change. Asymptomatic bacteremia was documented in 11 of 104 tube changes (11%). Results of five blood cultures were positive in the group receiving antibiotics, and six cases of bacteremia occurred in the group not receiving antibiotics (P = .96). Routine nephrostomy/stent change can cause frequent, asymptomatic bacteremia in patients with colonization of bacteria in the urinary tract. Antibiotic prophylaxis was unsuccessful in preventing transient bacteremia, a factor that may have implications in patients with underlying valvular heart disease and other patients at risk for bacteremia.
Adult↗
Resistance trends of Neisseria gonorrhoeae in the Republic of Korea.
Penicillinase-producing Neisseria gonorrhoeae has increased in the Far East to the point that penicillin can no longer be recommended as the drug of choice, mandating a change to spectinomycin. As part of an ongoing surveillance of antibiotic susceptibilities, minimal inhibitory concentrations of penicillin, tetracycline, spectinomycin, trimethoprim-sulfamethoxazole, cefoxitin, ceftriaxone, cefotaxime, and moxalactam were determined. A disturbing, steady increase in resistance to spectinomycin was documented.
Anti-Bacterial Agents↗
Progressive increase in antibiotic resistance of gram-negative bacterial isolates. Walter Reed Hospital, 1976 to 1980: specific analysis of gentamicin, tobramycin, and amikacin resistance.
During a five-year period at Walter Reed Army Hospital, Washington, DC, the frequency of aminoglycoside resistance among clinical bacterial isolates increased from less than 1% in 1976 to 13% of all isolates in later years. This resistance was seen among frequently isolated species of gram-negative bacilli isolated from patients throughout the hospital and from all anatomical sites, including blood. The incidence of gentamicin and amikacin resistance rose with increased administration of these antibiotics; however, the incidence of tobramycin resistance increased despite its minimal usage. From 1977 to 1978 and from 1979 to 1980, there was a decrease in the conjugal transmissibility of resistance to gentamicin and tobramycin. There was no detectable transmissible amikacin resistance. These findings suggest that high priority must be given to strategies that limit the emergence and dissemination of organisms resistant to these important antibiotics.
Amikacin↗
K antigen and serum sensitivity of rough Escherichia coli.
We prepared bacterial hybrids which express both K1 and K27 antigens and examined the relative contributions of these capsules to serum resistance. Escherichia coli Hfr strain F639 (rough, K27+, serum sensitive) was conjugated with E. coli recipient strain E412 (rough, K1+, His- Trp- Strr, serum resistant). Transconjugants which inherited both the his and trp linked genes for K27 antigen synthesis were analyzed. These hybrids retained and expressed the K1 antigen since the K1 locus is nonallelic with K27 gene loci. Hybrid strains which express both K1 and K27 antigens exhibit serum resistance, but not at the level of the K1+ parental strain. An isogenic K1 derivative of a hybrid which expressed only K27 antigen was serum sensitive (greater than 99% kill, 60 min). These findings indicate that the presence of the K1 capsular antigen can protect some rough strains of E. coli from serum bactericidal activity, whereas K27 and perhaps other K antigens fail to provide such a protective effect.
Antigens↗