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PubMed1989

Central pattern-generating neurons and the search for general principles.

This paper selectively reviews cellular-level studies of neurons and neural networks that function to generate rhythmic physiological and behavioral events. Studies of biological rhythms during the last 75 years have modified Sherrington's concept of nervous tissue as primarily reflexive to include the fact that some neuronal activity is also endogenously rhythmic. As a functional group, neurons that initiate and maintain physiological or behavioral rhythms are referred to as central pattern generators. Comparative studies reveal a disorienting variety of biological rhythms and underlying central pattern generator control mechanisms. This paper outlines the taxonomic diversity of biological rhythms, the strengths and limitations of various models for studying central pattern generators, and the ongoing search for general principles of rhythm generation. Studies of rhythmic phenomena displayed by intact, unanesthetized mammals have been greatly enriched by data and concepts derived from invertebrate central pattern generators. This multidisciplinary influence is illustrated by reviewing recent work that aims to localize and characterize the cellular bases of circadian rhythms, reproductive rhythms, and rhythmic changes in motor control related to the sleep cycle. The paper concludes by describing studies that aim to derive a cellular-level account for oscillator interaction, sensory feedback, and the homeostatic modulation of biological rhythms.

Animals↗
PubMed1997

The inhibitory effects of local anesthetics on superoxide generation of neutrophils correlate with their partition coefficients.

Lidocaine and tetracaine suppress superoxide anion (O2-) generation of neutrophils. We examined the effects of eight local anesthetics on O2- generation in human neutrophils and searched for a potential relationship between the biological activities and the physicochemical properties of presently available eight local anesthetics. Human neutrophils incubated with local anesthetic and a Cypridina luciferin analog as a O2(-)-specific chemiluminescence probe were stimulated by phorbol ester. The chemiluminescence development based on O2- generation was monitored by a luminometer. All of the tested local anesthetics suppressed O2- generation in a concentration-dependent manner. The concentration of each of eight local anesthetics that produced 50% inhibition of peak chemiluminescence (IC50) had a rank order of dibucaine < tetracaine < bupivacaine < ropivacaine < procaine < mepivacaine < lidocaine = prilocaine. A linear relationship was obtained between IC50 values and the values of logarithm of partition coefficient (log P) of eight local anesthetics; log (IC50 in molarity) = -1.252 - 0.514 x log P, r2 = 0.891, P < 0.001. Unlike with staurosporine, which inhibits protein kinase C (PKC), no effect was observed on the O2- generation in the presence of tetrodotoxin (TTX), veratridine (VTD), or amiloride. These results suggest that the inhibitory effects of local anesthetics on O2- generation of neutrophils are predicted by physicochemical properties of the drugs, especially partition coefficients.

Amiloride↗
PubMed1996

Inhibition of thrombin generation by heparin and LMW heparins: a comparison of chromogenic and clotting methods.

Inhibition of thrombin generation by heparin and low-molecular-weight (LMW) heparins is an important parameter which relates to their anticoagulant actions in vivo. Previous studies in our laboratory used a clotting assay for assessment of thrombin generation but other published studies have used a chromogenic method. We have therefore measured the inhibition of thrombin generation by unfractionated heparin (UFH) and LMW heparins by a modified chromogenic method using microtitre plates and compared the results with the clotting method. The degree of inhibition of thrombin generation when calculated from both peak thrombin concentrations and areas under the curve in the chromogenic assay was the same. When the activities of each heparin were expressed as EC80, i.e. concentrations required for 80% inhibition of thrombin generation, the EC80 were higher in the chromogenic assay than in the clotting system. However when the potencies of the LMW heparins were expressed as percentages of that of the UFH standard by parallel line analysis, the differences between clotting and chromogenic assay results were small and not statistically significant (P > 0.05). This study demonstrates the feasibility of measuring inhibition of thrombin generation by a modified chromogenic method using microtitre plates, and shows that the results with this method are similar to those obtained with the clotting method.

Anticoagulants↗
PubMed1998

Comparative effects of synthetic pentasaccharide, low-molecular-weight heparin, unfractionated heparin and recombinant hirudin on the generation of factor VIIa and prothrombin activation after coagulation of human plasma.

We studied the effect of synthetic pentasaccharide, a low-molecular-weight heparin (enoxaparin), unfractionated heparin and recombinant hirudin on the generation of factor VIIa (FVIIa) and prothrombin activation after in-vitro clotting of human platelet-poor plasma. FVIIa was measured with a new clotting assay that uses recombinant tissue factor truncated to interact only with FVIIa. Residual prothrombin was measured using the conventional clotting assay. FVIIa and residual FII were measured in the liquid - called pseudo-serum (psi-serum) - obtained 1 h after clotting of normal platelet-poor plasma. A kinetic study of the generation of FVIIa was also performed. Coagulation was initiated by triggering the extrinsic, the intrinsic and both associated clotting pathways. Levels of FVIIa in the psi-sera (55+/-15, 258+/-18, and 164+/-18 ng/ml, in the extrinsic, intrinsic and intrinsic + thromboplastin psi-serum respectively; values are means+/-SEM) were significantly increased compared with those in the platelet-poor plasma (3 ng/ml). Pentasaccharide, low-molecular-weight heparin and unfractionated heparin inhibited the generation of factor VIIa or its activity, or both, in a dose-dependent manner in all the experimental systems (60-90% inhibition). A kinetic study revealed that the inhibition of the generation of FVIIa by pentasaccharide and heparins starts 1 min after triggering either the extrinsic or the intrinsic clotting pathway. The downregulation of FVIIa by heparins was effected mainly by their anti-Xa activity, but also by their inhibitory effect on the generation of prothrombinase. Pentasaccharide, enoxaparin and unfractionated heparin significantly inhibited prothrombin activation in both extrinsic and intrinsic experimental system. Hirudin had no inhibitory effect either on the generation of FVIIa or on prothrombin activation in any experimental system.

Blood Coagulation↗
PubMed2004

Comparison of the effect of fondaparinux and enoxaparin on thrombin generation during in-vitro clotting of whole blood and platelet-rich plasma.

Fondaparinux, a selective antithrombin-dependent inhibitor of activated factor X (FXa), is effective in the prevention and treatment of deep vein thrombosis and seems to be superior to enoxaparin. However, the exact mechanism of fondaparinux antithrombotic action is still unclear. We compared the effect of clinically relevant concentrations of fondaparinux and enoxaparin on the initiation and propagation phase of prothrombin activation and on the endogenous thrombin potential (ETP). Coagulation was triggered either in whole blood or in platelet-rich plasma (PRP) by recalcification in the presence of diluted thromboplastin. Prothrombin activation in whole blood was assessed with an original method by measuring the kinetics of prothrombin F1+2 formation using an enzyme-linked immunosorbent assay. We also assessed the maximum concentration of thrombin (Cmax) and the ETP in PRP using the Thrombogram-Thrombinoscope assay. Concentrations of fondaparinux achieved in prophylaxis (0.11-0.28 anti-FXa IU/ml) prolonged the initiation phase and reduced the velocity of the propagation phase of F1+2 formation. Concentrations of enoxaparin achieved in prophylaxis (0.1-0.25 anti-FXa IU/ml) did not significantly modify these parameters. Concentrations of fondaparinux equal to or higher than 0.57 anti-FXa IU/ml significantly reduced the Cmax of F1+2 or thrombin as well as the ETP. At fondaparinux concentrations equal to or higher than 0.91 anti-FXa IU/ml, a maximum 60% inhibition of thrombin generation was observed. In the presence of enoxaparin concentrations equal to or higher than 0.8 anti-FXa IU/ml, the inhibition of thrombin generation was higher than 80%. Fondaparinux prolonged the initiation phase, decreased the velocity of the propagation phase of thrombin generation and partially reduced the total amount of generated thrombin. The inhibitory effect of fondaparinux on the initiation and propagation phase of thrombin generation seems to be responsible for its antithrombotic action. The more profound inhibition of thrombin generation induced by enoxaparin is due to its supplementary anti-activated factor II activity.

Anticoagulants↗
PubMed2005

Thrombomodulin accelerates activated protein C production and inhibits thrombin generation in the plasma of disseminated intravascular coagulation patients.

Thrombomodulin (TM) has been under development as a medicine for disseminated intravascular coagulation (DIC), and is expected to exhibit strong anticoagulant activity by inhibiting thrombin generation via the acceleration of protein C activation. In the present study, we examined the pharmacological action of TM in plasma obtained from DIC patients. TM was found to inhibit thrombin generation and accelerate activated protein C (APC) production at 0.3-30 TM units/ml in plasma obtained from DIC patients irrespective of their underlying disorders. In addition, there was a positive correlation between the inhibition of thrombin generation and the amount of APC produced. Thrombin generation was inhibited by over 50% when the plasma level of APC was increased by more than 0.2 microg/ml. These results indicate that TM inhibits thrombin generation in plasma obtained from DIC patients by accelerating APC production. Moreover, the results imply that the thrombin generation test may be a good method to speculate the efficacy of TM on every patient before the administration of TM.

Disseminated Intravascular Coagulation↗
PubMed1988

A new second-generation anti-HIV-1 enzyme immunoassay using recombinant envelope and core proteins.

In a multicenter collaborative study a new second-generation HIV-1 antibody enzyme immunoassay (Abbott recombinant HIV-1 EIA) using Escherichia coli-expressed recombinant p24 and p41 proteins as solid-phase antigens was compared with the first-generation H9 cell-line-based Abbott HIV-1 EIA. The results of the confirmatory assays (Western blot, immunofluorescence), combined with clinical information, were used as the reference standard for the detection of HIV-1 antibodies in 10,676 random blood donor serum specimens, in a panel of 840 specimens from symptomatic and asymptomatic patients and a total of 63 serial blood specimens from 23 people at risk. With fresh blood donor sera, the specificity of the first-generation assay ranged between 99.54 and 99.76% (95% confidence limits, CL) compared with 99.81-99.95% (95% CL) for the second-generation EIA. With panel specimens the recombinant HIV-1 EIA achieved an overall sensitivity of 100% and a specificity range of 98.3-99.7% (95% CL); the corresponding sensitivity and specificity ranges observed for the first-generation EIA were 98.0-99.5% (95% CL) and 94.3-96.8% (95% CL), respectively. The improved sensitivity for the second-generation assay was confirmed by testing serial samples from seroconverting patients. The use of recombinant proteins eliminated non-specific reactions due to class II human leukocyte antigen (HLA)-directed antibodies.

Blood Donors↗
PubMedDate not supplied

Cardiopulmonary bypass pumps and thrombin generation: what goes around comes around.

Thrombin generation and subsequent fibrin deposition occur during cardiopulmonary bypass (CPB) using roller pumps (RPs) despite the administration of high dose heparin. The authors attempted to determine if less thrombin is generated and less fibrin is deposited during CPB using a centrifugal pump (CP). In Part 1 of the experiment, 12 pigs receiving 400 U/kg heparin underwent CPB, including hypothermia, cardioplegia, and aortic cross-clamping, using a CP or RP. Blood samples were collected throughout CPB to measure thrombin generation. At the end of CPB, the amount of fibrin deposited onto each filter was assessed spectrophotometrically. In Part 2, blood samples and arterial in-line filters were obtained from 20 patients undergoing CPB, using either RP or CP, and studied as described previously. The Part 1 results showed that thrombin generation and fibrin deposition in CP pigs were <50% of those seen in the RP pigs (p < 0.01 and p < 0.01, respectively). In Part 2, thrombin generation was significantly attenuated both during and after CPB in the CP patients (p < 0.01 and p < 0.01, respectively). However, there was no significant difference in fibrin deposition between the two types of pumps after their use in the patients undergoing cardiopulmonary bypass. It is concluded that there is less thrombin generation and subsequent fibrin deposition during CPB when using a CP instead of RP in a defined experimental in vivo situation, suggesting that there is less hypercoagulability during CPB when using a CP instead of an RP. However, a large study in more patients undergoing CPB for longer pump runs is required to determine the relevance of these observations on subsequent clinical endpoints.

Animals↗
PubMed1996

Auditory brain stem response generation by parallel pathways: differential maturation of axonal conduction time and synaptic transmission.

In attempting to correlate developmental anatomical data with electrophysiological data on maturation of the auditory brain stem response (ABR), a model of ABR generation was necessary to match neuroanatomical structures to ABR components. This model has been developed by reviewing quantitative studies of human brain stem nuclei, results of intrasurgical recordings, studies of correlation of pathology with ABR waveform alterations, and findings from direct stimulation of the human cochlear nuclei through a brain stem implant device. Based on this material, it was assumed that waves I and II are generated peripherally in the auditory nerve and that waves III, IV, and V are generated centrally, i.e., by brain stem structures. It was further assumed that wave III is generated by axons emerging from the cochlear nuclei in the ventral acoustic stria and that waves IV and V reflect activity in parallel subpopulations of these ascending axons at a higher brain stem level. Beyond the cochlear nucleus, the largest component of the brain stem auditory pathway consists of axons projecting without interruption from the cochlear nuclei to the contralateral lateral lemniscus and inferior colliculus. In the proposed model of ABR generation, the III-IV interwave interval is assumed to reflect only axonal conduction in this asynaptic pathway. Electrophysiological data from infants indicate that the III-IV interwave interval becomes adult-like by the time of term birth. The second largest component of the brain stem auditory pathway is the bilateral projection through the medial olivary nucleus. The model assumes that activity in this monosynaptic pathway, consisting of axonal conduction time plus one synaptic delay, is reflected in the III-V interwave interval. If both of the preceding assumptions are true, the IV-V interwave interval represents the difference between the two pathways, i.e., the time of transmission across one synapse. The electrophysiological ABR data indicates that the IV-V interval does not mature until one year of age. It is also possible to apply this model to the peripherally generated portion of the ABR. The I-II interwave interval, assumed to solely represent conduction in VIIIth nerve axons, is adult-like before the time of term birth. The II-III interval, presumed to contain a synapse in the cochlear nuclear complex, does not reach an adult level until between 1 and 2 yr postnatal age.

Axons↗
PubMed1990

Effects of stress on gastric mucosal prostaglandin generation in intact, adrenalectomized, and sham-operated rats.

UNLABELLED: To study the effects of (a) cold restraint stress and (b) adrenalectomy in association with cold restraint stress on gastric mucosal ulceration and prostaglandin generation, we performed two experiments. In the first, 40 rats were divided into four groups of 10 rats each: (a) unstressed and (b) stressed for 0.5 h, (c) stressed for 2 h, and (d) stressed for 4 h. In the second experiment, another 80 rats were divided into four groups of 20 rats each: (a) adrenalectomy plus cold restraint stress for 2 h, (b) adrenalectomy plus no stress, (c) sham operated plus 2 h of stress, and (d) sham operated plus no stress. In both experiments we recorded an ulcer index and measured mucosal generation of prostaglandin E2 (PGE2) and prostaglandin I2 (6-keto-PGF1a). IN CONCLUSION: (a) Cold restraint stress is associated with a time-dependent decrease in gastric mucosal PGE2 generation, but no change in 6-keto-PGF1a generation, and an increase in mucosal injury that is maximal by 2 h. (b) Adrenalectomy augments the effects of stress on mucosal injury but has no effect on prostaglandin generation; thus, the ulcerogenic effect of adrenalectomy appears to be independent of an effect on prostaglandin generation.

6-Ketoprostaglandin F1 alpha↗
PubMed1985

Determinants of physician utilization among Mexican-Americans. A three-generations study.

Determinants of physician utilization were examined using a three-generational sample of Mexican-Americans in San Antonio. A typical version of Andersen's causal behavioral model was moderately successful in predicting physician utilization in the middle and older generations and less successful in the younger generation. Consistent with the literature, need factors (health indicators) tended to affect utilization most directly. The authors also examined whether acculturation into the larger society positively influenced utilization regardless of need, as the literature suggested. While three separate measures of acculturation had no independent effects on physician utilization, acculturation did affect utilization indirectly via the need variables in the middle generation, although these effects were not consistently in the direction of greater utilization. Generational differences in determinants of physician utilization are discussed particularly in relation to the model's greater relevance for the middle and older generations.

Acculturation↗
PubMed1991

The validity of proxy-generated scores as measures of patient health status.

This study examines the validity of proxy assessments as substitutes for patient assessments of patient physical and psychosocial health status. Data were obtained from 275 patient-proxy pairs who were enrolled in a national study of Adult Day Health Care. Patients and proxies (informal caregivers such as spouses) were asked to complete the Sickness Impact Profile (SIP) based on the patients health status. Findings showed that patient-generated and proxy-generated physical scores were highly correlated, although proxies rated patients as slightly more impaired than the patient's rated themselves. The correlation between psychosocial scores was not high enough to consider proxy responses as valid substitutes for patient responses. We explored these differences in response by comparing regression equations predicting patient-generated and proxy-generated physical and psychosocial SIP dimension scores. Variance in the patient-generated psychosocial score was explained by physical function, psychological distress, cognitive status and patient age. Proxy-generated psychosocial scores were primarily explained by the caregiver's psychological distress and perceived burden. These findings point out the importance of considering the source of patient health status estimates when interpreting the results of research studies.

Activities of Daily Living↗
PubMedDate not supplied

Generational diversity: teaching and learning approaches.

Nursing students represent multiple generations--Baby Boomers, Generation X, and now the Millennials. Each generation has its own set of values, ideas, ethics, beliefs, and learning styles. The authors describe the context, characteristics, and learning styles of each generation and provide suggestions for enhanced teaching and learning across multiple generations. Using generational diversity as a teaching tool in the classroom is also discussed.

Age Factors↗
PubMed1999

The effect of having myopic parents: an analysis of myopia in three generations.

PURPOSE: The etiology of myopia has been attributed to both genetic and environmental factors. The purpose of this paper is to attempt to distinguish between genetic and environmental factors in three generations of subjects from three locations. METHODS: Noncycloplegic autorefraction and distance visual acuity were measured in 3131 Chinese children 7 to 17 years old from Hong Kong, Tianjin, and Ban Chau. Data on the refractive status of the parents and grandparents were collected using questionnaires. Myopia was defined operationally as spherical equivalent refractive error (SER) of at least -1.00 D and uncorrected vision worse than logMAR 0.18 (6/9). RESULTS: The odds of having myopia for the grandparents', parents', and children's generations were 0.06, 0.26, and 0.35, respectively. Having myopic parents increased the odds ratio for having myopia (odds ratio 1.85 for children's generation and 6.71 for parents' generation), showing a genetic influence. However, the odds of having myopia also increased in offspring of nonmyopic parents between generation 2 and 3, suggesting an environmental influence. Results of prevalence and odds ratios from the three locations also demonstrated an environmental effect on development of myopia. CONCLUSION: We propose that myopic development in Chinese follows a multifactorial and polygenic model in which the genetic input has remained constant while the environmental influence has increased over the last three generations.

Adolescent↗
PubMedDate not supplied

Treatment of gonorrhea with first- and second-generation cephalosporins and other new beta-lactam antibiotics.

Aqueous procaine penicillin, ampicillin, and amoxicillin have been used successfully in treatment of gonococcal infections for many years. Many of the new beta-lactam antimicrobial agents subsequently have proved effective for treating these infections as well. First-generation cephalosporins are less active (by weight) than second-generation cephalosporins, which, in turn, are less active than third-generation drugs. Single-dose therapy of uncomplicated mucosal gonococcal infections with first-generation cephalosporins has resulted in generally unacceptably low cure rates of less than 90% in most studies, whereas parenterally and orally administered second-generation cephalosporins show good clinical efficacy. Both second- and third-generation cephalosporins are active against beta-lactamase-producing Neisseria gonorrhoeae. The extended-spectrum and ureido-penicillins are active in vitro against non-beta-lactamase-producing N. gonorrhoeae and have parallel activity in vivo. Single doses of aztreonam, the first monobactam studied in humans, have also shown excellent clinical efficacy.

Anti-Bacterial Agents↗
PubMed2000

Ex vivo generation of effective Epstein-Barr virus (EBV)-specific CD8+ cytotoxic T lymphocytes from the peripheral blood of immunocompetent Epstein Barr virus-seronegative individuals.

BACKGROUND: Although readily accomplished from immunocompetent Epstein-Barr virus- (EBV) seropositive individuals, the effective ex vivo generation of EBV-specific cytotoxic T lymphocytes (CTL) from the peripheral blood mononuclear cells (PBMC) of EBV-seronegative subjects has proven to be a challenge. The focus of our study was to ascertain optimized culture conditions required for the ex vivo generation of EBV-reactive autologous CTL from the PBMC of EBV-seronegative volunteers. METHOD: Freshly isolated PBMC obtained from immunocompetent EBV-seronegative and -seropositive individuals were used to generate EBV-specific autologous CTL lines using both conventional and a novel, modified ex vivo culture technique. RESULTS: In contrast to responses observed in EBV-seropositives after two to three rounds of ex vivo stimulation, gamma-irradiated autologous lymphoblastoid cell lines (LCL) were incapable of eliciting an effective anti-EBV cytotoxic response when freshly-isolated PBMC from EBV-seronegative individuals were used as responders. Under these culture conditions, CD4+ T cells with preferential expression of the Th2-type cytokine IL-4 were predominantly expanded in the PBMC obtained from EBV-seronegative individuals. However, the addition of recombinant human (rh) IL-12 during the primary phase of ex vivo stimulation resulted in augmentation of EBV-specific cytolysis of autologous LCL by CD8+ T cells. Furthermore, there was down-regulation in the secretion of IL-4 and up-regulation in that of the Th1-type cytokine IFN-gamma by responder CD4+ and CD8+ T cells. CONCLUSIONS: Taken together these data suggest that the addition of rhIL-12 during the primary phase of ex vivo stimulation of freshly isolated PBMC from EBV-seronegative individuals results in skewing of the immune response predominantly towards a CD4+ Th1-type (IFN-gamma) with the generation of an efficacious CTL-mediated anti-EBV reactivity. This novel ex vivo approach for generating effective autologous EBV-specific CTL could be adopted to treat refractory post-transplant lymphoproliferative disorders, which may be encountered in EBV-seropositive-->EBV-seronegative organ transplant recipients. Additionally, these ex vivo generated anti-EBV T cells could also be infused perioperatively to enhance prophylactically immunity against EBV infection in high-risk EBV-seronegative organ allograft recipients.

Antibodies, Viral↗
PubMed1994

Increased surface expression of CD11b/c and CD18 appears to be dissociated from anti-CD11b/c monoclonal antibody stimulated O2- anion generation in in vivo Escherichia coli lipopolysaccharide and tumor necrosis factor-alpha-treated rat neutrophils.

The purpose of this investigation was to determine the effect of anti-rat CD11b/c monoclonal antibody (MAb) on in vitro superoxide anion (O2-) generation in in vivo Escherichia coli lipopolysaccharide (LPS) and tumor necrosis-alpha (TNF)-treated rat polymorphonuclear leukocytes (PMN). After a continuous infusion of a nonlethal dose of E. coli LPS (.5 mg/kg) or TNF (6.0 x 10(5) units) into rats, PMN were recovered by centrifugal elutriation and discontinuous density gradient centrifugation from the liver (LPS-treated) and whole blood (LPS- and TNF-treated) and compared for CD11b/c, CD11a, and CD18 upregulation and their capacity for basal and agonist-stimulated O2- production. Immunofluorescence flow cytometry studies of rat whole blood PMN demonstrated that, upon LPS infusion, there was a time-dependent upregulation of CD11b/c and CD18, but not of CD11a. Similarly, TNF infusion upregulated CD11b/c although to a lesser degree. Stimulation of LPS- and TNF-treated PMN with phorbol 12-myristate 13-acetate (PMA), opsonized zymosan (OPZ), and anti-rat CD11b/c MAb triggered O2- generation. Although total O2- generated by OPZ and anti-rat CD11b/c MAb was less than that generated by PMA stimulation, the in vivo LPS- and TNF-induced beta 2 integrin upregulation did not result in a statistically significant enhancement of O2- generation with respect to normal saline-treated PMN. Our results do not appear to support the hypothesis that enhanced expression of CD11b/c or CD18 might be associated with enhanced in vitro anti-CD11b/c MAb-triggered O2- generation in LPS- and TNF-treated PMN in vivo.

Animals↗
PubMed2003

Restriction of third-generation cephalosporin use decreases infection-related mortality.

OBJECTIVE: To determine the effect of restriction of third-generation cephalosporin use on antibiotic resistance and the outcome of patients with infection. DESIGN: A prospective, before-after comparative study. SETTING: A general intensive care unit with 14 beds at a university-affiliated teaching hospital. PATIENTS: All patients admitted to the intensive care unit within 2 yrs. INTERVENTIONS: A new antibiotic treatment strategy was implemented during phase II. All patients with confirmed or suspected Gram-negative bacterial infections were treated mainly with antibiotics other than third-generation cephalosporins. MEASUREMENTS AND MAIN RESULTS: Antibiotic resistance among common Gram-negative bacilli and infection-related hospital mortality during phase I were compared with phase II. A 26.6% reduction in third-generation cephalosporin use (from 168.2 +/- 48.0 to 123.5 +/- 39.3 g/month, p =.021), accompanied by a 277.7% increase in cefepime use (from 10.3 +/- 19.2 to 38.9 +/- 31.7 g/month, p =.014) occurred in phase II compared with phase I. This was accompanied by a significant decrease in reduced susceptibility of Gram-negative bacilli to third-generation cephalosporins (p <.05), mainly because of the improved susceptibility of Escherichia coli and Klebsiella species (p <.05). Infection-related hospital mortality was significantly lower in phase II (19.3% vs. 36.3%, p =.014). Multiple logistic regression analysis demonstrated lower respiratory tract infection, the status of immunocompromise, and continuous veno-venous hemofiltration as independent risk factors for infection-related hospital mortality (p <.05), whereas infection with E. coli or Klebsiella species (p =.039) and restriction of third-generation cephalosporin use (p =.025) were associated with a significantly lower mortality rate. CONCLUSIONS: Restriction of third-generation cephalosporin use may improve the antibiotic susceptibility and reduce infection-related hospital mortality in critically ill patients.

APACHE↗