Development of a time-to-positivity assay as a tool in the antibiotic management of septic patients.

Optimal use of antibiotics is a key component of the management of sepsis. The purpose of this study was to develop a modification of the time-to-positivity (T(pos)) assay for use in the acute management of septic patients. Initial laboratory experiments, followed by ex-vivo validation and pilot studies, were performed with a small number of healthy human volunteers and 46 septic patients on a general intensive care unit, chosen on the basis of their antibiotic regimen. The study demonstrated that the T(pos) assay could be used as a surrogate for antimicrobial activity, and provided preliminary data to demonstrate how this approach might be used to monitor the efficacy of antibiotic therapy in septic patients. The T(pos) assay might offer a quick and convenient way to improve the efficacy of antibiotic therapy in septic patients, and further prospective large-scale studies are now warranted.

Antibiotic prophylaxis in surgery of the intervertebral disc. A comparison between gentamicin and cefuroxime.

Antibiotics are often administrated prophylactically in spinal procedures to reduce the risk of infection of the disc space. It is still not known which antibiotics are able to penetrate the intervertebral disc effectively. In a prospective, randomised, double-blind clinical study, we examined the penetration of the intervertebral discs of two commonly used antibiotics, cefuroxime and gentamicin. The patients, randomised into two groups, received either 1.5 g of cefuroxime or 5 mg/kg of gentamicin prophylactically two hours before their intervertebral discs were removed. A specimen of blood, from which serum antibiotic levels were determined, was obtained at the time of discectomy. Therapeutic levels of antibiotic were detectable in the intervertebral discs of the ten patients who received gentamicin. Only two of the ten patients (20%) who received cefuroxime had a quantifiable level of antibiotic in their discs although therapeutic serum levels of cefuroxime were found in all ten patients. Our results show that cefuroxime does not diffuse into human intervertebral discs as readily as gentamicin. It is possible that the charge due to ionisable groups on the antibiotics can influence the penetration of the antibiotics. We therefore recommend the use of gentamicin in a single prophylactic dose for all spinal procedures in order to reduce the risk of discitis.

Mind over grammar: reasoning in aphasia and development.

Research on propositional reasoning (involving 'theory of mind' understanding) in adult patients with aphasia reveals that reasoning can proceed in the absence of explicit grammatical knowledge. Conversely, evidence from studies with deaf children shows that the presence of such knowledge is not sufficient to account for reasoning. These findings are in keeping with recent research on the development of naming, categorization and imitation, indicating that children's reasoning about objects and actions is guided by inferences about others' communicative intentions. We discuss the extent to which reasoning is supported by, and tied to, language in the form of conversational awareness and experience rather than grammar.

Learning from other people's mistakes: causal understanding in learning to use a tool.

Despite considerable debate about whether nonhuman primates learn to use tools via imitation, this type of learning by children has received surprisingly little attention. The findings of two studies that go some way toward filling this gap are reported here. Study 1 showed that when 2- and 3-year-old children (N = 68) were shown a correct solution to a tool-using task (which they could not solve spontaneously), all the children in both age groups managed at least a partial solution. When children were shown an incorrect solution followed by a correct solution, 2-year-olds again produced only a partial solution. By contrast, most 3-year-olds produced a full solution. Study 2 replicated this age change in a separate sample of children (N = 100) with a different tool-using task. Study 2 also showed that 3-year-olds benefit from observing an incorrect action when it can be contrasted with a correct action: they chose the more effective of the two actions. Taken together, the two studies indicate that by 3 years of age, children do not indiscriminately imitate actions on a tool, but selectively reproduce those actions that have a desired causal effect.

Severe impairment in grammar does not preclude theory of mind.

Debates about the role of language in human thinking are increasingly prominent in the cognitive sciences. There are claims that certain forms of reasoning can only be performed through access to the resources of the language faculty. In particular, a component of social cognition involving the representation of the mental states of others ('theory of mind' reasoning) has been claimed necessarily to involve propositions of natural language. A recent case study reported a man (SA) with severe agrammatic aphasia who was unable to understand or produce language propositions in any modality of language use, but who was able to complete theory of mind tasks. We report a replication of this finding using a modified picture theory of mind task with a second patient (MR). Despite severe aphasia and impaired performance on a test of executive function, MR demonstrated retained theory of mind reasoning. These results reveal the functional autonomy of theory of mind from the capacity for propositional/grammatical language, and support its independence from executive function.

A new in-vitro model to investigate antibiotic penetration of the intervertebral disc.

We have studied the ability of a range of antibiotics to penetrate intervertebral disc tissue in vitro, using a mouse disc model. Equilibrium concentrations of antibiotics incorporated into the entire disc were determined by bioassay using a microbial growth-inhibition method. Uptake was significantly higher with positively-charged aminoglycosides compared with negatively-charged penicillins and cephalosporins. Uncharged ciprofloxacin showed an intermediate degree of uptake. Our results support the hypothesis that electrostatic interaction between charged antibiotics and negatively-charged glycosaminoglycans in the disc is an important factor in antibiotic penetration, and may explain their differential uptake.

Assay of vancomycin by fluorescence polarisation immunoassay and EMIT in patients with renal failure.

Serum with vancomycin concentrations between 5 and 15 mg/L from patients on dialysis were assayed by fluorescence polarization immunoassay (FPIA) and enzyme multiplied immunoassay technique (EMIT). The concentrations as determined by FPIA were higher than those using EMIT (mean difference 2.1 mg/L, S.D. 1.5; range -0.8-6.3) with substantial interpatient variability in the difference between the two assays. This suggests that concentrations of active vancomycin are lower than indicated by FPIA and thresholds for redosing may need to be adjusted.

An outbreak of Enterobacter cloacae associated with contamination of a blood gas machine.

Over a 3-month period, five cases of Enterobacter cloacae bacteraemia occurred on our neonatal unit. In at least three of these, isolation of the organism coincided with clinical deterioration and evidence of sepsis. In one case, the same strain was isolated from an abscess on the neonate's forearm. The isolates had identical sensitivity patterns being resistant to all beta-lactams tested except imipenem. The extended time course of the infections made cross-infection an unlikely explanation. Moreover, close questioning of the staff and observation of their practices with regard to blood culture collection, failed to reveal any likely mechanism for pseudobacteraemia. On extensive investigation of the environment to try to identify a potential source of the organism, a strain of Enterobacter cloacae, was isolated from the probe of the blood gas machine and the probe cover. No other environmental samples were found to harbour the organism. Subsequent typing procedures showed the blood gas isolate to be indistinguishable from the clinical isolates. Five neonates were successfully treated with imipenem and gentamicin. The exact mechanism whereby these bacteraemias occurred remains obscure. In one case, the baby had positive blood cultures within 2 h of being on the unit and contamination of the blood culture bottle by the doctor taking the culture was suspected. Most of the episodes, however, appeared clinically to be genuine septicaemias. When vigorous infection control procedures were instituted to prevent staff acquisition of the organism from the machine, cases on the unit ceased.

Characterisation of strains of Aeromonas spp. by phenotype and whole-cell protein fingerprint.

Sixty-eight isolates of Aeromonas spp. were examined biochemically and their cell proteins were analysed by silver-stained SDS-PAGE. Protein fingerprints did not correlate with phenotype. However, consideration of both phenotype and fingerprint showed clustering of epidemiologically related isolates. There was also evidence that similar strains could be found in infected people and water or other environmental samples.

An epidemiological study of listeriosis complicating a bone marrow transplant.

Following an unrelated-donor bone marrow transplant a six-year-old child with severe aplastic anaemia developed Listeria monocytogenes septicaemia and meningitis. Cook-chill foods consumed during his stay in hospital were found to contain strains of L. monocytogenes and other Listeria species. Whole cell protein SDS-PAGE was performed on all isolates. No food isolates were found that were identical to the patient's strain by this technique or by serotyping. The usefulness of whole cell protein SDS electrophoresis for listeria strain differentiation is discussed.

Whole-cell protein electrophoresis for typing Mycobacterium tuberculosis.

A method of discriminating between strains of Mycobacterium tuberculosis by using sodium dodecyl sulfate-polyacrylamide gel electrophoresis of whole-cell proteins combined with a sensitive silver stain is described. Thirty-five isolates of M. tuberculosis and five isolates from other species of Mycobacterium were examined, including serial isolates from the same patients and isolates from a small cluster of hospital cases. Different species of Mycobacterium were clearly distinguished, and within the species M. tuberculosis, different fingerprints were obtained, allowing discrimination of some strains from different patients. The reproducibility and discrimination of the technique are discussed.

Pseudomonas pickettii infections in a paediatric oncology unit.

Over a 3-month period, seven patients in a paediatric oncology unit developed Pseudomonas pickettii septicaemias. The outbreak was difficult to recognize since the cases occurred at widely spaced intervals and problems were experienced with the identification of the isolates. Many of the isolates were initially misidentified on the basis of a short sugar set used in the laboratory for identification of the non-fermenting Gram-negative bacilli. Moreover, the organisms had varying sensitivity patterns. The source of the organisms proved to be vials of 'sterile' distilled water which had been used for flushing the patients' indwelling Hickman lines. No further cases occurred once the use of this water was discontinued.

Effects of incorporating ampicillin, bile salts and carbohydrates in media on the recognition and selection of Aeromonas spp. from faeces.

The effects of incorporating ampicillin, some bile salts and sugars into media on the primary recognition and selection of aeromonads from faeces were examined. Most (88%) of the 101 Aeromonas strains examined had an ampicillin MIC of greater than or equal to 40 mg/L, and would be isolated on blood agar containing ampicillin 30 mg/L. The strains with an ampicillin MIC of less than 40 mg/L were all of human origin and predominantly A. caviae. Although ampicillin at 10, 20 or 30 mg/L in blood agar inhibited faecal bacteria, the ability to detect Aeromonas strains with a high ampicillin MIC was less when the lower concentrations of ampicillin were used, without any improvement in the isolation of those strains with a low ampicillin MIC. Thirty-seven strains were tested for sensitivity to several different bile salts and found to be at least as resistant to them as Escherichia coli NCTC 10418. Bile salt sensitivity was not related to the species or source of a strain. There were minor differences in sensitivity to bile salts between some strains which related to whether strains had been isolated originally in the presence of bile salt or not. The effects of the presence of E. coli, Klebsiella spp. and Enterococcus faecalis on the growth of Aeromonas strains in mixed culture on media with and without carbohydrate were examined. The colony size of some Aeromonas strains was reduced in mixed culture but colony counts were not affected with any Aeromonas strains.(ABSTRACT TRUNCATED AT 250 WORDS)

A prospective, randomized comparison of ceftazidime and ciprofloxacin as initial empiric therapy in neutropenic patients with fever.

This study developed further clinical experience in using a single agent ("monotherapy") as empirical treatment for neutropenic patients with fever, and compared the safety and toxicity of two candidate agents, ceftazidime and ciprofloxacin. A prospective, randomized, single-center efficacy and safety comparison was conducted of intravenous ciprofloxacin, 200 mg every 12 hours, and ceftazidime, 2 g every eight hours, as initial empirical therapy in neutropenic patients with fever. Regimens were modified as necessary, guided by laboratory results and/or the clinical condition. Response was evaluated at 72 hours and at the end of the neutropenia. Toxicity was evaluated by regular clinical examination and laboratory investigations. A total of 43 patients with 51 febrile neutropenic episodes were enrolled into the study and randomly assigned to one of the two regimens. Five episodes were excluded from evaluation of efficacy because of protocol violations, leaving 46 evaluable episodes (21 ciprofloxacin, 25 ceftazidime). The two groups were well matched for risk factors for infection. There were no differences between the two groups in response rates either at 72 hours or at the end of neutropenia, although in the vast majority of patients some modification of the initial therapy was required. No patients died of uncontrolled bacterial infection. Superinfection with gram-positive cocci (often streptococci) was seen primarily in bone marrow transplant recipients who had been randomly assigned to receive ciprofloxacin. This study demonstrated that, in certain circumstances, a single antibiotic can be used successfully as initial empirical therapy in febrile neutropenic patients. In this study, ceftazidime and ciprofloxacin were generally of equal efficacy, but there appeared to be an increased incidence of streptococcal superinfection in bone marrow transplant recipients who received ciprofloxacin.

Typing of Aeromonas species by protein fingerprinting: comparison of radiolabelling and silver staining for visualising proteins.

A method for typing Aeromonas species by silver staining of total soluble proteins separated by sodium dodecyl sulphate-polyacrylamide gel electrophoresis is described. There was good agreement with the results obtained by autoradiography of whole-cell proteins for isolates examined by both methods.

An open study of the safety and efficacy of enoxacin in complicated urinary tract infections.

Thirty-one patients with serious or complicated urinary tract infections were treated with oral enoxacin for between four and eight days. Twenty-five patients with microbiologically confirmed infections completed treatment with 400 mg enoxacin twice daily and at the end of treatment all urine cultures were negative. At short term follow-up, five to nine days after therapy, 21 of the 25 patients were still infection free. In total, reinfection or relapse occurred in 12 patients during the four to six weeks follow up period after termination of treatment. Significant side-effects (nausea and vomiting) occurred in only one patient.

Ceftazidime as first-line therapy for fever in acute leukaemia.

Fifty patients with acute non-lymphocytic leukaemia were treated by random allocation with either ceftazidime alone or a combination of piperacillin, netilmicin and cefotaxime for 65 febrile neutropenic episodes. Nineteen of 33 patient episodes (58%) responded to ceftazidime alone compared with 21 of 32 episodes (66%) treated with the combination. There was one infective death in a patient given the combination; rates of documented superinfection were low. The treatment groups appeared identical in terms of patient demography, underlying disease and other risk factors, though patients with a clinical site of infection responded more slowly than those without. Bacteraemia per se did not appear to influence outcome. Bactericidal serum concentrations greater than or equal to 8 X the minimum bactericidal concentration were predictive of a rapid response (within 4 days) to antibiotics. Furthermore, serum from patients treated with ceftazidime maintained adequate cidal activity against Pseudomonas aeruginosa for longer than that obtained from patients treated with the three-drug combination. Ceftazidime was shown to be a safe and effective alternative to the three-drug combination for the initial management of febrile neutropenic episodes in leukaemic patients.

Piperacillin in early neonatal infection.

Seventy infants with suspected bacterial infection in the first 48 hours of life were treated either with piperacillin and flucloxacillin or with penicillin and gentamicin. Infection was confirmed and successfully eradicated in 6 of the 35 infants receiving piperacillin and flucloxacillin. Four infants treated with penicillin and gentamicin had confirmed infection and one deteriorated initially but then recovered when treated with piperacillin. Serum piperacillin concentrations above 100 mg/l and cerebrospinal fluid piperacillin concentrations of 2.6-6 mg/l were noted for up to four hours and 7 hours respectively, even in the absence of inflamed meninges, after administration of piperacillin 100 mg/kg body weight intravenously. Median half life of piperacillin was 6.5 hours and was prolonged in renal impairment. Piperacillin is considered to be a safe and effective first line single agent treatment for early neonatal infection but because some Escherichia coli are resistant to it we recommend that a second agent be used in critically ill infants with neutropenia or meningitis.

Prophylactic cefuroxime in total joint replacement.

Cefuroxime was given during operation to 95 patients undergoing 106 total joint replacements (hip 69: knee 37). Two regimes were used. Either 1 g was given intravenously with induction of anaesthesia and then two intramuscular injections of 1 g 6 and 12 h later, or 1.5 g was given intravenously with induction and two injections of 750 mg each intramuscularly 6 and 12 h later. The concentrations of cefuroxime in bone, capsule and blood were measured in 77 patients. The assays were carried out independently in two laboratories. In most instances concentrations in the bone were above the MICs for likely pathogens, even after allowing for any contaminating blood. Concentrations in synovial capsule were generally higher than in bone. After a follow-up period of 2 years, two patients developed deep infections. The overall infection rates are comparable with the best results reported in the literature using other prophylactic antibiotics or with ultra-clean air systems.