Stefanie Swoboda

Tigecycline for the treatment of patients with severe sepsis or septic shock: a drug use evaluation in a surgical intensive care unit

OBJECTIVES Adequate antimicrobial therapy is crucial for the survival of critically ill patients with severe nosocomial infections. Tigecycline, the first available agent in the new class of glycylcyclines, is active against multiresistant gram-positive and gram-negative bacteria. The aim of this observational, retrospective evaluation was to assess tigecycline use patterns in a surgical intensive care unit (SICU) of a tertiary care centre. METHODS Data from 70 patients receiving tigecycline in the SICU were analysed. We reviewed tigecycline use in terms of demographic data and co-morbidities, disease severity, clinical indication, microbiology, therapy regimens and mortality. A logistic regression analysis was performed to identify prognostic factors for mortality. RESULTS The majority of patients had co-morbidities such as cancer (51%) or renal replacement therapy (57%). The mean Acute Physiology and Chronic Health Evaluation (APACHE) II score of patients at admission was 27. Intra-abdominal infection was most frequently diagnosed (50% of patients); intra-abdominal infection and pneumonia were diagnosed in 14%. Methicillin-resistant Staphylococcus aureus was found in 16% of patients (colonization; infection: 6%) and vancomycin-resistant enterococci in 27% (colonization; infection: 21%). The mean duration of tigecycline therapy was 9 +/- 4 days; 76% of patients received tigecycline in combination, with 64% being treated second line. APACHE score and renal replacement were identified as predictive factors for mortality. SICU mortality was 30%. CONCLUSIONS Tigecycline treatment of critically ill SICU patients with severe sepsis or septic shock appeared to result in remarkably low mortality. Tigecycline may be an important treatment option for septic patients with infections resistant to other available agents.

Antimicrobial properties and elution kinetics of linezolid-loaded hip spacers in vitro

Bacterial adhesion to and -persistence on antibiotic-loaded bone cement is an increasing problem. New antibiotics with good antimicrobial and pharmacokinetic properties (e.g. linezolid) may be the solution to this problem; however, few data concerning linezolid-loaded acrylic cement are currently available. Ten gentamicin-linezolid-loaded hip spacers (1 g gentamicin/2.4 g linezolid/80 g PMMA; five spacers including a metallic endoskeleton, five with no metallic components) were tested in vitro against a strain of methicillin-resistant Staphylococcus aureus with regard to antibiotic release and bacteria growth inhibition. Daily, the antibiotic elution was determined by high liquid performance chromatography (linezolid) and fluorescence polarization immunoassay (gentamicin), the bacteria growth inhibition photometrically at 546 nm. All spacers demonstrated growth inhibition for 8 days. Peak average concentrations were reached for both agents on day 1 (gentamicin-35.10 mug/mL [24.10-52.52], linezolid-36.28 mug/mL [22.87-71.76]). After 8 days, 0.97% [0.93-1.05%] of the initial amount of linezolid and 3.13% [2.85-3.31%] of gentamicin were meanly released from spacers containing a metallic endoskeleton. In those containing of simple cement these values were 1.22% [0.91-1.59%] and 2.67% [2.12-2.73%], respectively. Linezolid demonstrated acceptable elution kinetics from bone cement; however, further experimental research and animal studies should clarify any possible side effect of linezolid-loaded cement media before definitive use in the clinical practice.

Implementation of Practice Guidelines for Antifungal Therapy in a Surgical Intensive Care Unit and Its Impact on Use and Costs

Background: Considering the complexity of diagnosis, high costs of therapy and high morbidity and mortality of systemic fungal infections, antifungal therapy of intensive care patients should follow clearly defined guidelines. We outline the impact of a standardised practice of antifungal treatment in an interdisciplinary surgical intensive care unit of a university hospital. Methods: Therapy was intended to be optimised by implementation of standardised practice guidelines supported by the clinical pharmacist. Costs for antifungal agents during a period of 18 months before and after implementation of the practice guidelines were compared, respectively. Results: The intervention was associated with a significant decrease in use of antifungal agents. Analysis of data revealed a reduction in costs by 50%. This could substantially be attributed to the implementation of the practice guidelines. Conclusion: The implementation of standardised practice guidelines for antifungal therapy in intensive care units decreased the use of selected antifungal agents and resulted in substantial reduction in expenditure on antifungal agents.

Development and validation of a high-performance liquid chromatography assay for posaconazole utilizing solid-phase extraction

Abstract Background: Posaconazole is a new broad-spectrum triazole antifungal drug that is used in prophylaxis and therapy of opportunistic fungal infections in immunocompromised patients. Up to now, it is available as an oral suspension only. Due to variable systemic availability known from other azoles, such as itraconazole, it is important to measure blood levels, especially in patients undergoing abdominal surgery which may influence the intestinal resorption. Methods: A sensitive and selective high-performance liquid chromatography method for the precise determination of posaconazole and the internal standard clotrimazole in human plasma was developed and validated. Samples were extracted using solid-phase extraction and separated on a reversed-phase C8 column (150×4.6 mm, 5 μm) using phosphate buffer (pH 6.7, 0.04 M):acetonitrile:methanol (43:49:8, v/v/v) as mobile phase. UV detection was performed at 260 nm. Results: This method showed that a lower limit of quantification was 50 ng/mL and the limit of detection 3 ng/mL. Linearity was tested in the range from 50 to 5000 ng/mL (r2=0.9998). Mean recovery was 86%. Conclusions: The method proved to be a useful tool for therapeutic drug monitoring. It is specific, precise and showed excellent reproducibility as well as a favourable accuracy. Clin Chem Lab Med 2008;46:1747–51.

A simple isocratic HPLC assay to determine linezolid concentrations in different biomatrices for in vivo and in vitro studies.

Abstract Background: Linezolid is an important therapeutic option for the treatment of infections caused by multiresistant Gram-positive bacteria such as vancomycin-resistant Enterococci (VRE) and methicillin-resistant Staphylococcus aureus (MRSA). However, the clinical benefit of linezolid is threatened by the emergence of resistant strains of MRSA and VRE reported in North America and Europe. For effective antimicrobial treatment, it is extremely important to have exact knowledge of drug concentrations at the site of action. Methods: A simple HPLC method for the rapid and precise determination of linezolid in different biomatrices (e.g., plasma, soft tissue, bone, dialysis fluid and used microbiological broth) was developed and validated. Proteins were precipitated with acetonitrile and separation was performed on a reversed-phase C8 column with a mobile phase consisting of water/acetonitrile (80:20, v/v). UV detection was performed at 251 nm. Results: This method has a lower limit of quantification of 0.3 μg/mL and a linear calibration range of 0.5–40 μg/mL. The method showed excellent reproducibility, with an inter- and intra-day assay precision of <5% (% relative standard deviation), as well as excellent accuracy, with inter- and intra-day assay accuracy ranging from 100.6% to 103.2%. Stability up to 6 months in water and plasma was proven. Quantitative recovery was possible after up to three freeze thaw cycles. Conclusions: The method is useful in the acquisition of in vivo and in vitro data. It is simple, flexible, specific, precise and reproducible, as well as of adequate sensitivity for clinical use. Clin Chem Lab Med 2007;45:1019–22.

Tissue penetration of moxifloxacin into human gallbladder wall in patients with biliary tract infections

OBJECTIVES Moxifloxacin, the newest fourth-generation fluoroquinolone, has a broad spectrum of antibacterial activity covering both Gram-positive and Gram-negative aerobic and anaerobic bacteria and is therefore very well suited for the treatment of biliary tract infections. The present study aimed to determine the penetration of moxifloxacin into gallbladder tissue to evaluate its antibiotic potential in this indication. PATIENTS AND METHODS Hospitalized patients with acute cholecystitis received a single, 1 h infusion of 400 mg of moxifloxacin before cholecystectomy. Serum and gallbladder wall tissue samples were collected during surgery, and the moxifloxacin concentrations were measured by HPLC. RESULTS Sixteen patients (eight men and eight women) were included between January 2007 and April 2008. The time between start of infusion and gallbladder removal ranged from 50 min to 21 h 10 min. The serum concentration at the time of cholecystectomy was between 0.39 and 4.37 mg/L, and the tissue concentration between 1.73 and 17.08 mg/kg. The tissue-to-serum concentration ratio ranged from 1.72 to 6.33. CONCLUSIONS The results show that moxifloxacin penetrates well into gallbladder tissue and is therefore a therapeutic option for biliary tract infection. The highest concentrations in serum and gallbladder tissue were measured shortly after the end of a 1 h infusion. As perioperative prophylaxis, moxifloxacin should therefore be administered 30-60 min before the first surgical incision.

Posaconazole in intensive care patients I: invasive fungal infections in surgical intensive care and case presentation

Critically ill patients after extended surgical procedures are at high risk for postoperative infections. Fungal infections play a substantial role for immunocompromised patients, e.g. after solid organ transplantation or under chronic corticoid therapy. Posaconazole, a new broad‐spectrum triazole effective against Aspergillus and Candida species as well as many fungi that are resistant to other antifungals, is well tolerated and can be used as an alternative in salvage therapy. Posaconazole can be administered via gavage so that antifungal therapy can be switched from an expensive intravenously applied antifungal to oral posaconazole at an early stage. Two case reports are presented, which show that posaconazole was efficacious and well tolerated following antifungal therapy with another azole. It was administered without difficulty via gavage to a patient receiving artificial respiration and dialysis.

Update: invasive Pilzinfektionen

ZusammenfassungPilzinfektionen sind in der operativen Intensivmedizin nicht selten. Candida-Spezies bilden dabei den Großteil der pilzlichen Erreger. Insbesondere bei Patienten mit vorbestehenden Lungenerkrankungen ist auch auf die Entstehung einer pulmonalen Aspergillose zu achten. Der frühzeitige Beginn der adäquaten antimykotischen Therapie ist entscheidend für den Erfolg. Hierzu ist eine Risikoabschätzung notwendig, die anhand von individuellen Patientenmerkmalen den Zeitpunkt des Behandlungsbeginns festlegt. Im Fall einer Candida-Infektion des klinisch stabilen Intensivpatienten ohne Organdysfunktion, der im Vorfeld kein Azol erhielt, bleibt Fluconazol das Mittel der Wahl, sofern die lokalen epidemiologischen Bedingungen nicht dagegen sprechen. Für instabile Intensivpatienten mit Organdysfunktionen stellen die Echinocandine aufgrund ihres breiten Wirkspektrums und ihrer guten Verträglichkeit die erste Wahl dar. Empfindlichkeitstestungen werden aufgrund des relevanten Anteils azolresistenter Candida-Spezies empfohlen. Abhängig vom nachgewiesenen Erreger ist das Umsetzen der Therapie auf ein Azol nach klinischer Stabilisierung möglich. Eine Aspergillose wird primär mit Voriconazol behandelt.AbstractFungal infections are of great relevance in surgical intensive care and Candida species represent the predominant part of fungal pathogens. Invasive aspergillosis is also relevant especially in patients with chronic pulmonary diseases. It is crucial for therapy success to begin adequate antifungal treatment at an early stage of the disease. Risk stratification of individual patient symptoms is essential for therapy timing. In case of suspected or proven candida infection, fluconazole is the agent of choice when the patient is clinically stable and no azoles have been administrated in advance and the local epidemiology makes azol resistance unlikely. For clinically instable patients with organ dysfunction the echinocandins serve as primary therapy because of their broad spectrum and reasonable safety profile. Due to a relevant proportion of azole resistant Candida species, susceptibility testing should be done routinely. Depending on the species detected de-escalating to an azole is feasible if organ dysfunctions have resolved. An invasive aspergillosis is primarily treated with voriconazole.Fungal infections are of great relevance in surgical intensive care and Candida species represent the predominant part of fungal pathogens. Invasive aspergillosis is also relevant especially in patients with chronic pulmonary diseases. It is crucial for therapy success to begin adequate antifungal treatment at an early stage of the disease. Risk stratification of individual patient symptoms is essential for therapy timing. In case of suspected or proven candida infection, fluconazole is the agent of choice when the patient is clinically stable and no azoles have been administrated in advance and the local epidemiology makes azol resistance unlikely. For clinically instable patients with organ dysfunction the echinocandins serve as primary therapy because of their broad spectrum and reasonable safety profile. Due to a relevant proportion of azole resistant Candida species, susceptibility testing should be done routinely. Depending on the species detected de-escalating to an azole is feasible if organ dysfunctions have resolved. An invasive aspergillosis is primarily treated with voriconazole.

Implant stability in the treatment of MRSA bone implant infections with linezolid versus vancomycin in a rabbit model

The increasing prevalence of methicillin‐resistant Staphylococcus aureus (MRSA) infections represents a significant healthcare burden. Vancomycin and linezolid exhibit potent clinical and microbiological activity in MRSA infections. Our purpose was to investigate the efficacy of linezolid versus vancomycin in experimental implant infections and the influence on implant stability in a rabbit model. Thirty‐six female New Zealand White rabbits received surgical insertion of titanium implants into their distal femurs and were randomly assigned to six groups (A: infected, no treatment; B: infected, vancomycin; C: infected, linezolid; D: no infection, no treatment; E/F: no infection, vancomycin or linezolid, respectively). Antibiotics were administered, and plasma levels determined. Bone‐implant specimens were tested for mechanical stability of fixation. Quantitative histomorphometry of bone and soft tissue was performed using computerized image analysis. Plasma levels of linezolid and vancomycin were within the respective therapeutic ranges. Microbiological analysis of specimens from infected rabbits showed MRSA tissue colonization in all untreated animals, in two of six vancomycin‐treated animals, and in none of the linezolid‐treated animals. Antibiotic treatment improved mechanical stability significantly (p = 0.004) with both vancomycin and linezolid. Mechanical testing correlated with histomorphometry results. A significant negative correlation was found between displacement of the implant and the percentage of calcified tissue around the implant, and a significant positive correlation was found between displacement of the implant and the amount of noncalcified tissue. Our data indicate that both treatment regimens improved implant stability.

Revival of physostigmine – a novel HPLC assay for simultaneous determination of physostigmine and its metabolite eseroline designed for a pharmacokinetic study of septic patients

Abstract Background: Physostigmine, commonly used as an antidote in anticholinergic poisoning, is reported to have additional pharmacological effects, such as activation of the cholinergic anti-inflammatory pathway in sepsis models. Due to the narrow therapeutic range of physostigmine and its metabolite eseroline, however, the plasma concentrations of these substances need to be determined so as to understand their effect and ensure safety in the treatment of septic patients. Methods: To determine physostigmine and its metabolite eseroline, a rapid and sensitive high performance liquid chromatography (HPLC) method has been developed and validated. Spiked plasma samples were cleaned up and concentrated using a simple liquid-liquid extraction (LLE) procedure with N-methylphysostigmine as internal standard. Separation was achieved using reversed-phase HPLC on a Kinetex C18 column with gradient elution and fluorescence detection (254 nm excitation/355 nm emission). Results: LLE produced clean extracts and a mean recovery of 80.3% for eseroline and 84.9% for physostigmine. The HPLC assay revealed a limit of detection (LOD) of 0.025 ng/mL and a lower limit of quantification (LLOQ) of 0.05 ng/mL for both analytes. Linearity was observed at 0.05–10.0 ng/mL (r2>0.999). Intra- and inter-day precision ranged from 0.7% to 6.6%, and intra- and inter-day accuracy 97.5%–110.0%. Conclusions: The presented method is useful for human drug level monitoring of physostigmine and eseroline in accordance with current guidelines. Remarkably low plasma concentrations can be quantified after LLE with gradient elution and fluorescence detection, making this a suitable method for pharmacokinetic studies in a clinical setting.