James C. Hurley

Treatment Outcomes for Serious Infections Caused by Methicillin-Resistant Staphylococcus aureus with Reduced Vancomycin Susceptibility

Although infections caused by methicillin-resistant Staphylococcus aureus with reduced vancomycin susceptibility (SA-RVS) have been reported from a number of countries, including Australia, the optimal therapy is unknown. We reviewed the clinical features, therapy, and outcome of 25 patients with serious infections due to SA-RVS in Australia and New Zealand. Eight patients had endocarditis, 9 had bacteremia associated with deep-seated infection, 6 had osteomyelitis or septic arthritis, and 2 had empyema. All patients had received vancomycin before the isolation of SA-RVS, and glycopeptide treatment had failed for 19 patients (76%). Twenty-one patients subsequently received active treatment, which was effective for 16 patients (76%). Eighteen patients received linezolid, which was effective in 14 (78%), including 4 patients with endocarditis. Twelve patients received a combination of rifampicin and fusidic acid. Surgical intervention was required for 15 patients (60%). Antibiotic therapy, especially linezolid with or without rifampicin and fusidic acid, in conjunction with surgical debulking is effective therapy for the majority of patients with serious infections (including endocarditis) caused by SA-RVS.

Endotoxemia: methods of detection and clinical correlates.

As an assay for endotoxin, the Limulus amebocyte lysate assay has several desirable properties: sensitivity, specificity, and potential for adaptation to a quantitative format. Several modifications have been developed to enhance its potential for clinical application. The modifications that allow quantitative measurement of endotoxin and also improve its application to blood samples are described in this review. In fluids other than blood, the detection of endotoxin with the Limulus amebocyte lysate assay can be used as an aid to identify the presence of gram-negative bacteria, and the assay has established utility. With blood, however, there are a range of factors that interfere with the detection of endotoxemia and there are disparate views with respect to the diagnostic and prognostic significance of the test results. In general, the clinical significance of the finding of endotoxemia broadly parallels the frequency and importance of gram-negative sepsis in the patient groups studied and a decline in endotoxin levels accompanies clinical improvement. However, with therapies designed to reduce levels of endotoxin, or to antagonize its effects, it is unclear whether clinical improvement occurs as a consequence of changes in the levels of endotoxemia.

Prophylaxis with enteral antibiotics in ventilated patients: selective decontamination or selective cross-infection?

Selective decontamination of the digestive tract (SDD) has been evaluated as a method to prevent colonization and infection in ventilated patients in 40 trials. On the basis of an assumption that cross-infection would be reduced as a consequence of SDD and that this would distort the results of SDD studies that used concurrent controls, 14 studies used historic controls. To test this assumption, three observations from the two types of studies were compared. (i) The differences between observed and expected event rates for each study were used to perform a meta-analysis. This revealed that the summary odds ratios for bacteremia and respiratory infection were marked by significant heterogeneity (P > 0.95) and inconsistencies between those derived from studies with concurrent versus studies with historic controls. (ii) Where the data were available, the rates of acquisition of colonization in control groups were higher in studies with concurrent controls than in studies with historic controls. (iii) At least four studies with concurrent controls have shown a pattern of pathogenic isolates consistent with cross-infection between groups. These results are contrary to the initial assumption and suggest the possibility that SDD represents a major cross-infection hazard.

Antibiotic-induced release of endotoxin. A therapeutic paradox.

SummaryThere is clear experimental evidence that antibiotics increase the bioavailability of endotoxin from Gram-negative bacteria. In this review, data for 2 variables, level of endotoxin and level of bacteria, at the time point closest to 2 hours post-antibiotic exposure were abstracted as a change from baseline readings from each available study, to enable presentation in a graphical overview. This overview indicates that the phenomenon is not limited to β-lactam agents nor is it apparent only for the more rapidly bactericidal agents. However, evidence that this phenomenon is of clinical importance is scant.With the Jarisch-Herxheimer reaction (JHR), there is clear evidence for an acute deterioration with the initiation of antibiotic therapy and yet uncertainty as to the nature of the bacterial mediator(s) of this reaction. There is no evidence to support the commonly stated concern that therapy with antibiotics with a more rapid bactericidal action may result in the sudden lysis of bacteria with the release of cell wall components and cause a deterioration that might be avoidable through the use of antibiotics with a slower time course of action.

Quantitative limulus lysate assay for endotoxin and the effect of plasma

The effects of plasma and chromogenic substrate on the kinetics of the endotoxin-activated Limulus amoebocyte lysate (LAL) assay were determined. A linear correlation was observed between the rate of development of turbidity (optical density 405) with the LAL reagent and the concentration of endotoxin over a four log ten-fold range. Like chromogenic substrate, the addition of dilution and heat treated plasma to the reaction resulted in an increase in optical density proportional to the concentration of plasma present. The presence of the treated plasma also resulted in an accelerated increase in optical density with comparable results when testing plasma at different concentrations and, additionally, serum. This accelerated increase in optical density may not be recognised in assays that monitor the progress of the reaction at a single time point and may confound assays of plasma samples that use chromogenic substrate. Plasma obtained from endotoxin sensitive and resistant strains of mice showed similar effects. The use of kinetic methodology means that a quantitative assay for endotoxin in plasma can be achieved, its variability comparable with that seen with semiquantitative serial dilution but with greater economy of the LAL reagent.

Antibiotic-induced release of endotoxin in chronically bacteriuric patients.

A novel in vivo model for the study of antibiotic-induced release of endotoxin from gram-negative bacteria is described. The model uses the chronically colonized urinary tracts of patients whose spinal cords have been injured. At baseline, the organisms were present in the range of 1 x 10(3) to 2 x 10(7) CFU/ml, and the concentration of endotoxin ranged from 2 x 10(-1) to 1 x 10(3) ng/ml in 44 studies. In 10 control studies, the concentration of endotoxin and the numbers of viable gram-negative bacteria over time changed by an average of less than 0.15 log10 units from the baseline values. At 2 h after antibiotic administration, the average decrease in CFU was 0.93 log10 units, and because antibiotics cause the release of endotoxin, an average increase in endotoxin concentration of 0.59 log10 units was noted in 21 studies with susceptible bacteria. Similar changes in response to antibiotic exposure were seen in studies with susceptible Pseudomonas bacteria in comparison with those seen in studies with susceptible members of the family Enterobacteriaceae. These results provide evidence that this novel model may be useful for comparing the effects of antibiotics with different modes of action, both as single agents and in combination, on the concentration of endotoxin in relation to changes in the numbers of bacteria, under conditions of bacterial replication and antibiotic exposure more closely resembling those found in vivo than is possible in other models.

Paracetamol overdose and hepatotoxicity at a regional australian hospital : a 4-year experience

Abstract

Reappraisal of the role of endotoxin in the sepsis syndrome

There is strong evidence to implicate endotoxin released from gram negative bacteria in the pathogenesis of the sepsis syndrome and related conditions, but equally compelling data bring the role of endotoxin into doubt. Reappraisal of endotoxin and its release from gram negative bacteria suggests that it is not directly responsible for the complications of sepsis syndrome. Rather, release of endotoxin is a marker for the transition of gram negative organisms to cell-wall-deficient forms (L-forms) that may persist undetected despite antibiotic therapy directed against the parental form. This transition has two consequences in compromised patients: L-forms cause organ failure, and they serve as a sanctuary from which cell-wall-intact revertants may arise.

Profound effect of study design factors on ventilator-associated pneumonia incidence of prevention studies: benchmarking the literature experience

BACKGROUND The ventilator-associated pneumonia incident proportion (VAP-IP) is highly variable among control groups of studies of methods for its prevention. The objective here is to develop and validate a literature-derived benchmark against which these groups can be profiled. METHODS A literature search yielded 95 cohort groups and control and intervention groups of 150 studies of either non-antimicrobial or antimicrobial methods of VAP prevention. The 95 cohort groups comprise a benchmark set (30 groups), from which the reference funnel plot (RFP) was derived, and a search set (65 groups), against which the benchmark was validated. The VAP-IP data of the benchmark set were found in five published systematic reviews, whereas the VAP-IP data of the search set were abstracted directly from the literature. FINDINGS Among the 95 cohort groups, the VAP-IP of groups with size >399 was significantly lower than the VAP-IP of smaller groups. Compared with the RFP, 15 of 51 (29%) control groups from studies of antimicrobial methods of VAP prevention with concurrent design were high outlier versus 2 of 110 (2%) control groups from other types of study design (P < 0.001). There were only 22 (14%) outlier groups, all low outlier, among the 162 intervention groups. CONCLUSIONS Study design factors such as concurrency and study size have potentially greater influence on the VAP-IP than do the VAP prevention methods under study. The outlier status of control groups were inapparent in the individual studies and the meta-analyses and yet would have confounded the estimates of treatment effect.

Concordance of endotoxemia with gram-negative bacteremia : A meta-analysis using receiver operating characteristic curves

OBJECTIVE To apply meta-analysis to compare the concordance between the results of 2 types of limulus amebocyte lysate (LAL) assay, gelation (GLAL) and chromogenic (CLAL), with the detection of gram-negative bacteremia in patients with suspected bacteremia. DESIGN Meta-analysis using receiver operating characteristic-based analytical method. DATA SOURCES MEDLINE literature search and manual reviews of article bibliographies together with direct approaches to authors of potentially eligible studies. STUDY SELECTION The studies that were selected had all included at least 10 patients, of whom at least 2 patients were diagnosed with gram-negative bacteremia, and all had data available for extraction into a contingency table format. RESULTS Fifty-six studies (28 GLAL and 28 CLAL studies) met the inclusion criteria. Studies were stratified by type of test (GLAL vs CLAL). Each analysis was repeated with smaller studies excluded. There was no difference between the 2 types of LAL assays. Among the CLAL studies, there was no difference between studies that did versus those that did not use the sepsis syndrome criteria as a basis for patient inclusion. Among 45 studies for which data on the proportion of non-Enterobacteriaceae were available, there was a trend toward higher concordance as this proportion increased. CONCLUSIONS The concordance between the LAL test and the detection of gram-negative bacteremia in patients with suspected bacteremia is no higher with the CLAL assay than with the original GLAL version. However, the concordance is higher among studies with a higher proportion of non-Enterobacteriaceae among the gram-negative bacteremia isolates.