Selective digestive and oropharyngeal decontamination in medical and surgical ICU patients: individual patient data meta-analysis.

OBJECTIVES: Selective digestive decontamination (SDD) and selective oropharyngeal decontamination (SOD) improved intensive care unit (ICU), hospital and 28-day survival in ICUs with low levels of antibiotic resistance. Yet it is unclear whether the effect differs between medical and surgical ICU patients. METHODS: In an individual patient data meta-analysis, we systematically searched PubMed and included all randomized controlled studies published since 2000. We performed a two-stage meta-analysis with separate logistic regression models per study and per outcome (hospital survival and ICU survival) and subsequent pooling of main and interaction effects. RESULTS: Six studies, all performed in countries with low levels of antibiotic resistance, yielded 16 528 hospital admissions and 17 884 ICU admissions for complete case analysis. Compared to standard care or placebo, the pooled adjusted odds ratios for hospital mortality was 0.82 (95% confidence interval (CI) 0.72-0.93) for SDD and 0.84 (95% CI 0.73-0.97) for SOD. Compared to SOD, the adjusted odds ratio for hospital mortality was 0.90 (95% CI 0.82-0.97) for SDD. The effects on hospital mortality were not modified by type of ICU admission (p values for interaction terms were 0.66 for SDD and control, 0.87 for SOD and control and 0.47 for SDD and SOD). Similar results were found for ICU mortality. CONCLUSIONS: In ICUs with low levels of antibiotic resistance, the effectiveness of SDD and SOD was not modified by type of ICU admission. SDD and SOD improved hospital and ICU survival compared to standard care in both patient populations, with SDD being more effective than SOD.

Cost-effectiveness of linezolid vs vancomycin in suspected methicillin-resistant Staphylococcus aureus nosocomial pneumonia in Germany.

BACKGROUND: The oxazolidinone antibiotic linezolid has demonstrated efficacy in treating infections caused by methicillin-resistant Staphylococcus aureus (MRSA). In a retrospective analysis of two prospective randomized clinical trials in patients with nosocomial pneumonia (NP), initial therapy with linezolid produced significantly better clinical cure and survival rates than vancomycin in the subset of patients with documented MRSA infection. This study was designed to evaluate the economic impact of these clinical outcomes from the perspective of the German health care system to determine the use of these regimens in the light of limited resources and rising costs. METHODS: A decision-analytic model using clinical trial data was developed to examine the costs and outcomes of treatment with linezolid or vancomycin in hospitalized patients with NP caused by suspected MRSA. The model followed an average patient from initiation of empiric treatment until treatment success, death, or second-line treatment failure. Local treatment patterns and resource use were obtained from a Delphi panel. Costs were taken from published sources. Outcomes included total cost per patient, cost per additional cure, cost per death avoided, and cost per life-year gained. RESULTS: The model calculated that linezolid was associated with an 8.7% higher cure rate compared with vancomycin (73.6% vs 64.9%, respectively). Average total costs per episode for linezolid- and vancomycin-treated patients were 12,829 and 12,409, respectively. Death rates were 13.2% lower with linezolid than with vancomycin (20.7% vs 33.9%), resulting in an average of 2.3 life-years gained per linezolid-treated patient in a 65-year-old cohort (14.0 life-years vs 11.7 life-years). With linezolid, incremental costs per death avoided and per patient cured were 3,171 and 4,813, respectively. The base case estimated a similar mean length of stay for both drugs (11.2 vs 10.8 days). One-way sensitivity analyses did not change the overall results. CONCLUSION: The model estimated a higher clinical cure (+8.7%) and survival (+13.2%) for linezolid compared with vancomycin at an incremental cost of 420 per treatment episode. The cost-benefit profile suggests that linezolid could be considered a cost-effective alternative to vancomycin in the treatment of patients with NP caused by suspected MRSA in Germany.

Audit of motor weakness and premature catheter dislodgement after epidural analgesia in major abdominal surgery.

In a quality improvement audit on epidural analgesia in 300 patients after major abdominal surgery, we identified postoperative lower leg weakness and premature catheter dislodgement as the most frequent causes of premature discontinuation of postoperative epidural infusion. Lower limb motor weakness occurred in more than half of the patients with lumbar epidural analgesia. In a second period monitoring 177 patients, lumbar catheter insertion was abandoned in favour of exclusive thoracic placement for epidural catheters. Additionally, to prevent outward movement, the catheters were inserted deeper into the epidural space (mean (SD) 5.2 (1.5) cm in Period Two vs 4.6 (1.3) cm in Period One). Lower leg motor weakness declined from 14.7% to 5.1% (odds ratio 0.35; 95% confidence interval 0.16-0.74) between the two periods. Similarly, the frequency of premature catheter dislodgement was reduced from 14.5% to 5.7% (odds ratio 0.35; 95% confidence interval 0.17-0.72). With a stepwise logistic regression model we demonstrated that the odds of premature catheter dislodgement was reduced by 43% for each centimetre of additional catheter advancement in Period Two. We conclude that careful audit of specific complications can usefully guide changes in practice that improve success of epidural analgesia regimens.

Monocyte phagocytosis of viable Staphylococcus aureus is impaired by barbiturates, but not by propofol.

BACKGROUND: Barbiturates and propofol are used for deep sedation of patients with elevated intracranial pressure refractory to standard therapeutic regimens. Such patients often suffer from bacterial infections, which are most commonly caused by Staphylococcus aureus. Various interactions of anesthetics with components of the host defense have been documented, but very little is known about the influence on monocytes, which are a first-line defense against bacterial invasion. Therefore, we studied the effects of thiopental, methohexital, and propofol on monocyte phagocytosis using an in vitro whole blood model of viable S. aureus. MATERIALS AND METHODS: Whole blood samples were preincubated with different concentrations of thiopental, methohexital, and propofol. Phagocytosis was stopped at different time points after addition of viable S. aureus. Monocytes then were stained with monoclonal antibodies for flow cytometric analysis of monocyte recruitment (ratio of ingesting monocytes). Furthermore, the fluorescence intensity of ingested bacteria served as semiquantitative measurement of phagocytosis activity. RESULTS: Both barbiturates inhibited monocyte recruitment and phagocytosis activity concentration-dependently, whereas propofol did not affect any of the investigated parameters. At concentrations of 7.6 x10(-3) M thiopental or 1.1 x 10(-3) M methohexital and greater, monocyte recruitment and phagocytosis activity were significantly inhibited. The calculated half-maximum inhibitory concentration (IC50) of thiopental was 8.4 x 10(-3) M for monocyte recruitment and 8.6 x 10(-3) M for phagocytosis activity. The corresponding values for methohexital were 4.1 x 10(-3) M and 1.1 x 10(-3) M, respectively. CONCLUSION: The two barbiturates induce concentration-dependent inhibition of monocyte phagocytosis, whereas propofol is without effect. In combination with previously described effects on granulocyte function, these findings suggest that defense against bacterial infection might be reduced by barbiturates.

Elimination of linezolid by an in vitro extracorporeal circuit model.

Linezolid is an oxazolidinone antibiotic with activity against important grampositive aerobic bacteria, including nosocomial pathogens. It is not known whether dosage adjustments are necessary in patients treated with continuous renal replacement therapies. This in vitro study was conducted to investigate the elimination of linezolid in an in vitro continuous hemo(dia)filtration model using different filter materials (polysulfone, polyacrylonitrile, polyamide), surface areas, and different modes of renal replacement therapies. Linezolid was measured using HPLC with UV-detection. No adsorption of linezolid to any of the tested membranes was detected. Recovery of linezolid in the ultrafiltrate was 98.2 +/- 10.5% in the filtration mode. During dialysis, recovery was significantly less (87.6 +/- 16.1%; p = 0.02). Linezolid elimination was not altered by filter size, when polysulfone filters with surface areas of 0.7 m2 and 1.3 m2 were tested. In conclusion, the dosage recommendations for linezolid are independent of the filter materials. However, the elimination is significantly higher during hemofiltration compared to dialysis.

[Detection and identification of the pathogenic cause of a brain abscess by molecular genetic methods]. / Erregerdetektion und -identifikation bei einem Hirnabszess durch molekulargenetische Methoden.

Brain abscesses are life-threatening and detection and identification of the causative pathogens are crucial for substantiating the diagnosis and for selecting the optimal antibiotic regimen. In approximately 20% of the patients microbiological cultures of abscess material remain sterile. The polymerase chain reaction (PCR) provides a methodological alternative, but data about the use of broad spectrum PCR assays to detect the causative pathogens in brain abscesses are rare. We report on the case of a 65-years-old patient with a brain abscess caused by Fusobacterium spp., which was only diagnosed by broad spectrum PCR. To our knowledge this is the second report about a brain abscess, where Fusobacterium spp. was identified only by broad spectrum PCR and subsequent DNA sequencing.

Spinal epidural abscess--a rare complication after epidural analgesia for labour and delivery.

We report a case of spinal epidural abscess formation after short-term epidural catheter placement for analgesia during labour and delivery. The patient was previously healthy and did not have any predisposing factors. Increasing back pain was the only complaint. A contrast-enhanced CT study on day 5 was inconclusive. Magnetic resonance imaging was performed and showed a large triangular-shaped abscess with adjacent inflammation of the paravertebral muscles. One day later, the patient developed a sensory deficit in the left lower limb. The neurological deficit completely resolved after surgical decompression and debridement, which was followed by antibiotic treatment.

Influence of underlying disease on the outcome of critically ill patients with acute renal failure.

BACKGROUND AND OBJECTIVE: The development of acute renal failure (ARF) in critically ill patients is associated with an increase in hospital mortality. Recently, it was shown that starting renal replacement therapy early and using high-filtrate flow rates can improve the outcome, but this could not be confirmed in later investigations. Studying selected patient subgroups could provide a useful basis for patient selection in future trials evaluating the outcome of renal replacement therapies. We, therefore, investigated the impact of the underlying disease on the outcome of patients with ARF. METHODS: We retrospectively analysed 306 patients with ARF who were treated with renal replacement therapy. Patients were classified according to six initial diagnosis groups: haemorrhagic shock, post-cardiac surgery, post-liver transplantation, trauma, severe sepsis and miscellaneous. Univariate and multivariate multiple logistic regression analysis was used to determine which factors influenced the outcome. RESULTS: Underlying disease proved to be the only independent risk factor for mortality that was present at intensive care unit (ICU) admission (P = 0.047). Patients with severe sepsis had a significantly higher mortality rate (68%) than ARF patients as a whole (51%) (P = 0.02). Length of stay in the ICU, the use of catecholamines, the delay before ARF onset, and the correlation between APACHE II score and ICU length of stay proved to be additional independent predictors of outcome. CONCLUSIONS: Patient selection and subgroup definition according to the underlying disease could augment the usefulness of future trials evaluating the outcome of ARF.

[Calibration of a room air gas monitor with certified reference gases]. / Kalibrierung eines Raumluft-Gasmonitors mit zertifizierten Prüfgasen.

Photo-acoustic infrared spectrometry is considered to be the gold standard for on-line measurement of anesthetic waste gas in room air. For maintenance of the precision of the measurements, the manufacturer recommends calibration of the gas monitor monitor every 3-12 months. We investigated whether the use of reference gases with analysis certificate could serve as a feasible alternative to commercial recalibration. We connected a multi-gas monitor type1302 (Bruel & Kjaer, Naerum, Denmark) to compressed air bottles containing reference gases with analysis certificate. Using a T-piece with a flow-meter, we avoided the entry of room air during the calibration phase. Highly purified nitrogen was used for zero calibration. The reference concentrations for desflurane, enflurane, halothane, isoflurane, and sevoflurane ranged from 41.6-51.1 ml/m(3) (ppm) in synthetic air. Since there is an overlap of the infrared absorption spectra of volatile anesthetics with alcohol used in operating rooms, we performed a cross-compensation with iso-propanol (107.0 ppm). A two-point calibration was performed for N(2)O (96.2 and 979.0 ppm), followed by cross-compensation with CO(2). Nafion tubes were used in order to avoid erroneous measurements due to molecular relaxation phenomena. The deviation of the measurement values ranged initially from 0-2.0% and increased to up to 4.9% after 18 months. For N(2)O, the corresponding values were 4.2% and 2.7%, respectively. Thus, our calibration procedure using certified reference gases yielded precise measurements with low deterioration over 18 months. It seems to be advantageous that the precision can be determined whenever deemed necessary. This allows for an individual decision, when the gas monitor needs to be calibrated again. The costs for reference gases and working time as well as logistic aspects such as storage and expiration dates must be individually balanced against the costs for commercial recalibration.

[Selective digestive tract decontamination in intensive care medicine. Fundamentals and current evaluation]. / Selektive Darmdekontamination in der Intensivmedizin. Grundlagen und aktuelle Bewertung.

Selective digestive tract decontamination (SDD) is a method where topical non-absorbable antibiotics are applied to the oropharynx and stomach which primarily is aimed at the prevention of ventilator-associated pneumonia. The rationale for SDD is that ventilator associated pneumonia usually originates from the patients'own oropharyngeal microflora. SDD is also used for the prevention of gut-derived infections in acute necrotizing pancreatitis and in liver transplantation. Despite numerous clinical trials and several meta-analyses, SDD is still a controversial topic. It is now commonly accepted that the incidence of pneumonia is reduced,however, the concept of using topical antibiotics has its inherent limitations and the best results have been obtained by combination with a short course of intravenous antibiotics. Several issues surrounding the notorious difficulties in establishing the diagnosis of ventilator-associated pneumonia especially in the presence of antibiotics are an on-going matter of debate.Furthermore, pneumonia is the leading cause of death from nosocomial infections and its prevention was not adequately followed by reduced mortality in most individual trials, however, a benefit was suggested by recalculation of data in meta-analyses. Patients are not well defined by their need for ICU admission and mechanical ventilation and the attributable mortality of infections depends more on the type and severity of the underlying diseases. Recently published trials substantially improved our understanding as to which patients may derive most benefit from SDD.Currently, it seems that an improved survival can be achieved in surgical and trauma patients with severe but salvageable diseases, which might be classified e.g.by calculation of APACHE-II scores on admission.However, the most important drawback of SDD is the development of resistance and an increased selection pressure towards Gram-positive pathogens, especially in institutions with endemic multi-resistant microorganisms.Thus, it appears that "selective" must not only be interpreted as selective suppression of pathogenic bacteria but rather as selection of appropriate groups of patients with respect to underlying diseases and severity of illness. Furthermore, it means selection of ICUs where the endemic resistance patterns might allow the use of SDD at a relatively low risk for selection of resistant microorganisms, which is still the major concern associated with SDD.

[New treatment option for gram-positive infections in critically ill patients - overview over linezolid]. / Neue Therapieoption für Intensivpatienten mit Infektionen durch Gram-positive Bakterien - Uberblick über Linezolid.

INTRODUCTION: During the last decade, there has been an emergence of multiresistant Gram-positive bacteria in intensive care units. Oxazolidinones are a new class of antibiotics without cross-resistance to other antimicrobial agents, and linezolid was recently introduced as first oxazolidinone on the German market. In this overview, we summarize important data and discuss possible indications for linezolid in the treatment of infections in critically ill patients. ANTIMICROBIAL ACTIVITY AND PHARMACOLOGY: The antimicrobial spectrum comprises mainly Gram-positive bacteria, especially Staphylococcus aureus (including MRSA), coagulase-negative staphylococci, enterococci, and streptococci. Linezolid is mostly bacteriostatic and inhibits the bacterial protein synthesis at an early stage. Adults may receive 600 mg b.i.d. intravenously or p. o. About 30 % of the dose are excreted by the kidneys as mother compound and 50 % as metabolites. Dosage reductions are not necessary, even in severe renal impairment, but about one third of the dose is eliminated during dialysis. Overall, linezolid is well tolerated, but approximately 5 % of the patients may suffer from diarrhea or nausea and there have been a few reports about reversible myelosuppressive side effects. CLINICAL STUDIES: Linezolid has been compared to vancomycin for treatment of Gram-positive nosocomial pneumonia, and the clinical cure rates were 66.4 % and 68.1 %, respectively. Linezolid is highly active and bactericidal against pneumococci. The clinical cure rates for treatment of skin and soft tissue infections were 88.1 % with linezolid and 86.1 % with penicillinase-stable penicillins. MRSA were excluded in this study, but it may be assumed from data in vitro that linezolid is equally effective against these bacteria. Data for the treatment of catheter-associated and other forms of bacteremias are mainly derived from the compassionate-use-program, where linezolid has been used in complicated cases, mainly after failure of standard therapy. The majority of infections was caused by multiresistant Enterococcus faecium and the clinical cure rates were approximately 80 %. COMMENT: The currently available data suggest that linezolid will serve as useful agent in the treatment of severe infections caused by multiresistant staphylococci and enterococci. Further studies are necessary to define the role of linezolid as first-line agent, e. g. in the treatment of central venous catheter infections. In light of the severe prognosis of pneumonias caused by MRSA, studies on the combination of linezolid and vancomycin are warranted. Despite the low level of resistance, it seems prudent not to use linezolid as first line agent in the treatment of uncomplicated infections, as long as effective standard antibiotics are available.

Prophylactic and therapeutic efficacy of antibodies to a capsular polysaccharide shared among vancomycin-sensitive and -resistant enterococci.

Enterococci are important nosocomial pathogens that are increasingly difficult to treat due to intrinsic and acquired resistance to antibiotics, including vancomycin. A recently described capsular polysaccharide (CP) isolated from Enterococcus faecalis 12030 was used to evaluate the potential efficacy of active or passive immunotherapy regimens as adjunctive treatments. Evaluation of protective efficacy was carried out in immunocompetent mice challenged intravenously (i.v.) with live enterococci. In nonimmune mice, i.v. inoculations resulted in high levels of bacteria in kidneys, spleens, and livers 5 days after challenge. Mice immunized with four 10-microg doses of CP antigen/mouse were protected against challenge with the homologous E. faecalis strain. High-titer opsonic immunoglobulin G was also induced by immunizing rabbits with the purified CP, and passive transfer of this antiserum to mice produced significantly lower bacterial counts in organs than did normal rabbit serum or sterile saline. Antibodies to the polysaccharide isolated from E. faecalis 12030 were protective against Enterococcus faecalis OG1RF and against two serologically related, vancomycin-resistant Enterococcus faecium clinical isolates. Antibodies to this CP antigen were also effective as a therapeutic reagent in mice when passive therapy was initiated 48 h after live bacterial challenge. These data indicate that CP antigens from enterococci are potential targets of protective antibodies and that these antibodies may be useful for prophylaxis and treatment of enterococcal infections.

Elimination of meropenem by continuous hemo(dia) filtration: an in vitro one-compartment model.

Meropenem is a carbapenem antibiotic with a wide spectrum of activity against most gram positive and gram negative bacteria including anaerobes. Dose adjustments are necessary during continuous renal replacement therapies of acute renal failure. This in vitro study was conducted to investigate the influence of different filter materials, surface areas (AN-69 0.6 m2 and 0.9 m2, polysulfone 0.75 m2, polyamide 0.6 m2), and increasing flow rates (from 3.3 - 26.7 ml/min) on the elimination of meropenem in an in vitro continuous hemo(dia)filtration model. Meropenem was measured using HPLC with UV-detection. While the clearance increased proportionally to increasing dialysate flow rates in filters with a surface area of 0.9 m2, a peak clearance was reached in the small filters at flow rates of 10.0 ml/min (polyamide 0.6 m2) and 18.3 ml/min (AN-69 0.6 m2), when tested under the same conditions. This indicated incomplete dialysate saturation due to the diminished time available for meropenem to equilibrate with the dialysate solution. No adsorption to either of the tested membranes was detected. Dosage recommendations derived from clinical studies might be appropriate when different filter materials, but similar operational settings of the continuous replacement therapy, are applied. Reduction of the recommended dose might be necessary, when renal replacement therapies with lower flow rates and/or filters with smaller surface areas are carried out.

Isolation and chemical characterization of a capsular polysaccharide antigen shared by clinical isolates of Enterococcus faecalis and vancomycin-resistant Enterococcus faecium.

Enterococci are a common cause of serious infections, especially in newborns, severely immunocompromised patients, and patients requiring intensive care. To characterize enterococcal surface antigens that are targets of opsonic antibodies, rabbits were immunized with various gentamicin-killed Enterococcus faecalis strains, and immune sera were tested in an opsonophagocytic assay against a selection of clinical isolates. Serum raised against one strain killed the homologous strain (12030) at a dilution of 1:5,120 and mediated opsonic killing of 33% of all strains tested. In addition, this serum killed two (28%) of seven vancomycin-resistant Enterococcus faecium strains. Adsorption of sera with the homologous strain eliminated killing activity. The adsorbing antigens were resistant to treatment with proteinase K and to boiling for 1 h, but were susceptible to treatment with sodium periodate, indicating that the antigen inducing opsonic activity is a polysaccharide. Antibodies in immune rabbit sera reacted with a capsule-like structure visualized by electron microscopy both on the homologous E. faecalis strain and on a vancomycin-resistant E. faecium strain. The capsular polysaccharides from E. faecalis 12030 and E. faecium 838970 were purified, and chemical and structural analyses indicated they were identical glycerol teichoic acid-like molecules with a carbohydrate backbone structure of 6-alpha-D-glucose-1-2 glycerol-3-PO4 with substitution on carbon 2 of the glucose with an alpha-2-1-D-glucose residue. The purified antigen adsorbed opsonic killing activity from immune rabbit sera and elicited high titers of antibodies (when used to immunize rabbits) that both mediated opsonic killing of bacteria and bound to a capsule-like structure visualized by electron microscopy. These results indicate that approximately one-third of a sample of 15 E. faecalis strains and 7 vancomycin-resistant E. faecium strains possess shared capsular polysaccharides that are targets of opsonophagocytic antibodies and therefore are potential vaccine candidates.

Elimination of fecal Enterobacteriaceae by intravenous ciprofloxacin is not inhibited by concomitant sucralfate--a microbiological and pharmacokinetic study in patients.

Intravenously administered ciprofloxacin is partially secreted into the intestinal lumen and thereby eliminates fecal Enterobacteriaceae. Sucralfate inhibits the antimicrobial activity of ciprofloxacin by chelate binding. In a prospective study, we investigated the impact of intravenous ciprofloxacin on the intestinal microflora during oral administration of sucralfate. A total of 45 stool specimens were analyzed in 20 hospitalized patients who were treated with 200 mg of ciprofloxacin i.v. bid. Ten patients concomitantly received 1 g sucralfate p.o. tid (group A). After more than 3 days of i.v. ciprofloxacin, the mean fecal ciprofloxacin concentration was 185.3 +/- 158.7 micrograms/g in patients of group A and 108.7 +/- 76.9 micrograms/g in patients without concurrent sucralfate (group B). There was no significant difference in mean fecal ciprofloxacin levels between both groups (Wilcoxon's test). Enterobacteriaceae were below the threshold of detection (10(2) cfu/g) in all patients of group B after 3 days of treatment whereas small numbers were found in only 2 samples of patients of group A (10(4) cfu/g). Intravenous ciprofloxacin eliminates or largely reduces intestinal Enterobacteriaceae irrespective of concurrent administration of sucralfate.