Strategies to enhance rational use of antibiotics in hospital: a guideline by the German Society for Infectious Diseases.

INTRODUCTION: In the time of increasing resistance and paucity of new drug development there is a growing need for strategies to enhance rational use of antibiotics in German and Austrian hospitals. An evidence-based guideline on recommendations for implementation of antibiotic stewardship (ABS) programmes was developed by the German Society for Infectious Diseases in association with the following societies, associations and institutions: German Society of Hospital Pharmacists, German Society for Hygiene and Microbiology, Paul Ehrlich Society for Chemotherapy, The Austrian Association of Hospital Pharmacists, Austrian Society for Infectious Diseases and Tropical Medicine, Austrian Society for Antimicrobial Chemotherapy, Robert Koch Institute. MATERIALS AND METHODS: A structured literature research was performed in the databases EMBASE, BIOSIS, MEDLINE and The Cochrane Library from January 2006 to November 2010 with an update to April 2012 (MEDLINE and The Cochrane Library). The grading of recommendations in relation to their evidence is according to the AWMF Guidance Manual and Rules for Guideline Development. CONCLUSION: The guideline provides the grounds for rational use of antibiotics in hospital to counteract antimicrobial resistance and to improve the quality of care of patients with infections by maximising clinical outcomes while minimising toxicity. Requirements for a successful implementation of ABS programmes as well as core and supplemental ABS strategies are outlined. The German version of the guideline was published by the German Association of the Scientific Medical Societies (AWMF) in December 2013.

Molecular analysis of linezolid resistance in clinical Enterococcus faecium isolates by polymerase chain reaction and pyrosequencing.

Resistance to linezolid has been associated with a G2576T mutation in the 23 S rRNA gene. Clinical isolates of linezolid-sensitive and linezolid-resistant vancomycin-resistant Enterococcus faecium of a liver transplant patient have been analysed for the G2576T mutation by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP), conventional sequencing and pyrosequencing. A clear association between the number of mutated 23 S rRNA genes and the level of linezolid resistance has been demonstrated. Linezolid susceptibility re-emerged after cessation of linezolid therapy; however, the re-initiation of linezolid therapy resulted in the re-emergence of linezolid-resistant strains. Pyrosequencing rapidly detected the number of mutated alleles and is superior to conventional PCR-RFLP for the detection of heterozygous mutations.

Bone tissue and plasma concentrations of linezolid and vancomycin in rabbits with prosthesis-related infection due to MRSA.

BACKGROUND: Due to its safety profile and ease of oral administration, linezolid became an alternative to vancomycin in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. The aim of our study was to compare bone tissue and plasma concentrations of linezolid and vancomycin in prosthesis-related MRSA infection in a rabbit model. MATERIAL AND METHODS: During implantation of titanium cylinders into the femurs of nine rabbits, a bacterial suspension of MRSA was added to induce infection. Antibiotic treatment was started eight hours later. Antibiotic concentrations in plasma (day one, three and seven) and bone (day seven) were determined by HPLC analysis. RESULTS: At steady state the mean peak and trough plasma levels of linezolid were 29.0 microg/mL and 8.2 microg/ mL and for vancomycin 39.1 microg/mL and 28.2 microg/mL. On day seven the mean peak concentration of linezolid in plasma was 28.5 microg/mL and after six hours 26.3 microg/mL and for vancomycin 53.8 microg/mL and 29.1 microg/mL after six hours. Vancomycin showed a penetration into the infected bone (femur) of 53% of plasma concentration, into the uninfected 28%, linezolid 11% (for both six hours after administration). CONCLUSION: In conclusion, we observed a higher rate of tissue penetration for vancomycin than for linezolid into femur bone in this animal model. As linezolid offers the option for oral treatment of gram-positive organisms, results of further studies comparing vancomycin and linezolid are keenly awaited.

A risk profile for invasive aspergillosis in liver transplant recipients.

BACKGROUND: Given the high incidence (1.5%-10%) of invasive aspergillosis (IA) after liver transplantation and the associated mortality, prophylaxis according to the patients' circumstances is a reasonable approach. The purpose of this investigation was to determine the effect and significance of risk factors for IA in a specialized transplantation center. METHODS: We collected data from patients who underwent liver transplantation at the Transplantation Center of the University Hospital Heidelberg (Germany) between December 2001 and December 2004 in a specifically designed database for retrospective analysis. Invasive aspergillosis was defined according to the European Organization for Research and Treatment of Cancer classifications. Univariate analysis and logistic regression were performed to assess the influence of each assumed risk factor. RESULTS: A total of 195 liver transplantations were performed in 170 patients, with two patients (1.2%) developing a proven IA, seven (4.1%) developing a probable IA, and five developing a possible IA (2.9%). All patients received oral itraconazole prophylaxis. Of these 14 patients with proven, probable or possible IA, 13 died within 4 weeks after the initial diagnosis; this represents 33.3% of all patients with a fatal outcome. Univariate significant factors were retransplantation (p = 0.004), cytomegalovirus (CMV) infection (p = 0.024), dialysis (p < 0.001), renal insufficiency (p = 0.05), thrombocytopenia (p = 0.001), and leukocytopenia (p = 0.002). Multivariate analysis showed an independent influence of CMV infection (OR 6.032, 95% CI 1.446-25.163) and dialysis (OR 14.985, 95%CI 2.936-76.486). CONCLUSION: The rate of IA found in this investigation is within the range reported in published studies. Based on our data, extended antifungal prophylaxis should be given to liver transplant patients with specific risk factors, such as renal insufficiency, requirement for dialysis, CMV infection, or thrombocytopenia. Additional focus should be on the prevention of CMV infections.

Susceptibility of common aerobic pathogens to tigecycline: results of a surveillance study in Germany.

Tigecycline is a novel antimicrobial agent for parenteral use encompassing a broad spectrum of bacterial pathogens, including multi-resistant organisms. Here, we report the results of the first nationwide surveillance trial that was conducted in order to evaluate the susceptibility of bacterial isolates to tigecycline in a European country prior to its clinical use. A total of 2,610 Gram-positive and Gram-negative organisms recovered from hospitalized patients were tested. Minimum inhibitory concentrations (MICs) were determined using the microdilution method. All enterococci, staphylococci (including methicillin-resistant Staphylococcus aureus; MRSA), and streptococci tested were tigecycline-susceptible, except one isolate of Staphylococcus haemolyticus. Among the Gram-negative bacteria, 100% of the Escherichia coli isolates (including extended spectrum beta-lactamase [ESBL]-producers) were tigecycline-susceptible, while about 10% of the Enterobacter cloacae and Klebsiella pneumoniae isolates were resistant. Based on the results of this surveillance study, tigecycline may represent a suitable option most notably for the empiric treatment of bacterial mixed infections, including in clinical situations in which multi-resistant organisms are suspected.

Factors influencing caspofungin plasma concentrations in patients of a surgical intensive care unit.

BACKGROUND: Co-morbidity, medical and surgical interventions often cause alterations to drug plasma concentrations and pharmacokinetic parameters in critically ill patients. In the present study, we investigated parameters influencing plasma caspofungin concentrations in patients of a surgical intensive care unit (SICU). METHODS: In a monocentre open study, caspofungin trough concentrations (C(24)) were determined for a group of SICU patients. A linear-mixed model was then used to assess factors influencing caspofungin plasma concentrations. RESULTS: A total of 40 SICU patients were enrolled. Age and body weight ranged from 22 to 76 years and 47 to 108 kg, respectively. All participants received a caspofungin loading dose of 70 mg and a maintenance dose of 50 mg/day. The median duration of therapy was 10 days. Caspofungin C(24) in SICU patients varied more than those determined for healthy subjects reported in previous studies (0.52-4.08 microg/mL versus 1.12-1.78 microg/mL). According to our model, caspofungin C(24) were predicted to be significantly higher in patients with body weight <75 kg (P=0.019) and patients with albumin concentration >23.6 g/L (P=0.030). CONCLUSIONS: Our results show that body weight and albumin concentration influence caspofungin C(24) in SICU patients and should therefore be considered prognostic factors.

[Septic shock due to vancomycin-resistant enterococci infection. Tigecycline monotherapy]. / Septischer Schock durch Vancomycin-resistente Enterokokken. Tigecyclin-Monotherapie.

Adequate antimicrobial therapy is of crucial importance for the survival of critically ill patients with severe nosocomial infections. Tigecycline is an important therapeutic option for the treatment of infections caused by multi-resistant Gram-positive and Gram-negative bacteria including vancomycin-resistant enterococci (VRE). A large randomised study (patients with APACHE-II-score >30 excluded/mean APACHE-II-score 6) demonstrated that tigecycline is not inferior to imipenem/cilastatin for treatment of complicated intra-abdominal infections. However, no case has been reported with microbiological eradication and clinical cure in a patient with septic shock due to peritonitis caused by VRE and treatment with tigecycline monotherapy. Clinical details of a patient suffering from postoperative peritonitis are presented. The patient developed severe septic shock after pancreatic surgery (multiple organ failure, APACHE-II-score 34). As the site of anastomotic leakage was very small and could not be exactly identified, irrigation-suction drains were placed followed by closed postoperative continuous lavage. The pathogen responsible was identified as a vancomycin-resistant Enterococcus faecium, therefore monotherapy with tigecycline was started which resulted in microbiological response and clinical cure. Tigecycline is a new therapeutic option for the treatment of intra-abdominal infections and from an economic point of view financially rewarding when used as monotherapy.

Effect of a pneumoperitoneum on systemic cytokine levels, bacterial translocation, and organ complications in a rat model of severe acute pancreatitis with infected necrosis.

BACKGROUND: Infection of pancreatic necrosis (IPN) is strongly associated with sepsis and multiple organ dysfunction and is an absolute indication for surgery. Patients with IPN are critically ill at the time of surgery and may benefit from a minimally invasive approach with reduced surgical trauma. Recently, several minimally invasive necrosectomy techniques have been reported. However, the effects and potential dangers of a pneumoperitoneum in IPN cases are unknown. This study aimed to determine the effects of a pneumoperitoneum on systemic cytokine levels, bacterial translocation, and systemic organ complications in a rat model of IPN. METHODS: For this study, IPN was induced in Wistar rats using retrograde intraductal infusion of 3% taurocholate. After 8 h, the animals were subjected to either laparoscopy (pneumoperitoneum at 8 mmHg) or laparotomy for 1 h and killed after 1 or 3 h. Severe acute pancreatitis with IPN was proved by serum amylase and lipase, histology, tissue activity of myeloperoxidase (MPO), and bacteriology. Systemic levels for interleukin-10 (IL-10), IL-6, tumor necrosis factor-alpha (TNF-alpha), and lipopolysaccarides were determined by enzyme-linked immunoassay (ELISA). Systemic organ damage and dysfunction were evaluated using MPO activity (lung), serum creatinine (kidney), and serum aminotransferases (liver). RESULTS: Necrotizing pancreatitis developed in all the animals. Most of the animals (85%) had proven infected necrosis. Elevated cytokine levels and deteriorated organ parameters demonstrated systemic inflammation and organ failure. Although there was a tendency toward a higher level of proinflammatory cytokines after laparotomy, there were no significant differences between laparotomy and laparoscopy. Furthermore, these alterations were not accompanied by any differences in bacterial translocation (lipopolysaccharides), systemic organ damage, or mortality between laparoscopy and laparotomy. CONCLUSION: In the current model of infected pancreatic necrosis, a pneumoperitoneum did not result in increased cytokine release or bacterial translocation. However, the putative advantage of less surgical trauma with the laparoscopic approach did not play a significant role in the setting of severe acute pancreatitis with IPN.

[Detecting infectious agents in central nervous system inflammation by cerebrospinal fluid analysis]. / Liquoranalytik in der Diagnostik erregerbedingter Erkrankungen des Zentralnervensystems.

Cerebrospinal fluid analysis is the method of choice in CNS infection and provides the basis for appropriate treatment. Due to the proximity of CSF and CNS, the infectious agent may be detected directly by microscopy or antigen or nucleic acid detection--the latter by polymerase chain reaction--in native CSF or after culture. Furthermore, intrathecal antibody synthesis against the infectious agent may identify the cause of infection. This indirect antigen detection method requires correction for a systemic antibody response and a blood-CSF barrier disturbance. The following text gives an overview of appropriate detection methods and their relevance to the most important CNS infections.

Piperacillin/tazobactam vs ceftazidime in the treatment of neutropenic fever in patients with acute leukemia or following autologous peripheral blood stem cell transplantation: a prospective randomized trial.

Piperacillin/tazobactam was compared with ceftazidime for the empirical treatment of febrile neutropenia in patients with acute leukemia or following autologous peripheral blood stem cell transplantation. Owing to inclusion criteria, it was possible for the same patient to be randomized several times. A total of 219 individual patients were admitted to a prospective randomized clinical study: 24 patients were included twice. Patients (23.5%) remained afebrile. Patients who developed febrile neutropenia were randomized to receive intravenous ceftazidime (n = 74 patients, group I) or piperacillin/tazobactam (n = 87 patients, group II). Response to first-line antibiotic treatment was seen in 55% (group I) and 53% (group II). After the addition of vancomycin, a further 19% (group I) and 24% (group II) of the patients became afebrile. Causes of fever were: microbiologically documented infection in 36 and 34 patients of group I and II; Clostridium difficile in eight and 12 patients of group I and II, and fever of unknown origin in 30 and 41 patients of group I and II. One patient died in each group. Single-agent therapy with piperacillin/tazobactam is as effective as ceftazidime in the treatment of neutropenic fever and is well tolerated. Direct and indirect costs of both treatment regimes are equivalent.

Landouzy septicemia (sepsis tuberculosa acutissima) due to Mycobacterium microti in an immunocompetent man.

Even in developed countries, tuberculosis still contributes significantly to morbidity and mortality. The most frequent causative agent is Mycobacterium tuberculosis, while infections due to other mycobacterial species are usually associated with immunocompromised patients. In the following, we describe the case of a previously healthy man who underwent laparotomy for suspected adrenal carcinoma. Peritoneal "cancerous nodules" turned out to be tuberculous granulomas. After surgery the patient developed a protracted septic shock and died 6 days after surgery. Isolation and identification of the causative agent yielded Mycobacterium microti, an uncommon species of the M. tuberculosis complex. No other pathogen could be isolated during the clinical course, which finally led to the diagnosis of Landouzy septicemia (sepsis tuberculosa acutissima).

A novel colorimetric broth microdilution method to determine the minimum inhibitory concentration (MIC) of antibiotics and essential oils against Helicobacter pylori.

Helicobacter pylori infections have been associated with the pathogenesis of a number of stomach and gastroduodenal diseases. In order to find alternative drugs for their treatment the search is increasingly focused on new antimicrobial products. However, no standardized methods are available to test the anti-Helicobacter pylori activity in particular of natural substances. Therefore we developed a broth microdilution assay to investigate the susceptibility of this fastidious slow growing bacterium against 15 essential oils widely used to treat disorders of the gastrointestinal tract. The MIC values were determined colorimetrically using p-iodonitrophenyltetrazolium violet (INT) as an indicator for bacterial cell viability. The test sytem was evaluated with three common antibiotics: amoxicillin, ampicillin and levofloxacin. The antibiotic MICs were controlled by Etest. The Helicobacter reference strain was remarkably susceptible to both the antibiotics (amoxicillin MIC: 0.02 microg/ml, ampicillin MIC: 0.064 microg/ml, levofloxacin MIC: 0.39 microg/ml) and the essential oils. Most of their MICs ranged from 0.015 to 0.064% (v/v) and about 140.0 to 280.0 microg/ml, respectively. Interestingly, chamomile oil, orange flower oil and ginger oil inhibited the bacterial growth in extraordinarily low concentrations of 0.0075% (v/v) and about 65 microg/ml, respectively. The bactericidal concentrations were generally one to two dilution steps higher. In conclusion, we could develop an innovative assay for the MIC determination of essential oils and antibiotics against Helicobacter pylori, which is simple to handle, accurate, reproducible and not as time- and material-consuming as traditional agar dilution techniques.

Staphylococcus aureus positive for Panton-Valentine leukocidin genes but susceptible to methicillin in patients with furuncles.

A total of 75 Staphylococcus aureus isolates obtained from patients with either recurrent skin abscesses or furuncles (n=48) or chronic infections from other body sites (n=27) were screened for the presence of the lukS-PV and lukF-PV genes encoding Panton-Valentine leukocidin. Significantly more isolates (70.8% vs. 7.4%, p<0.001) from patients suffering skin abscesses or furuncles were positive for lukS-PV and lukF-PV. These isolates belonged to the accessory gene regulator (agr) group Ia (9/48), group III (13/48), or group IV (19/48). In contrast with results of other investigations, none of the isolates positive for the Panton-Valentine leukocidin genes in this study exhibited methicillin resistance.

[Improving microbiological diagnostics in septic orthopaedic surgery. Comparative study of patients receiving systemic antibiotic therapy]. / Mikrobiologische Diagnostik in der septisch-orthopädischen Chirurgie. Vergleichsstudie bei Patienten unter Antibiotikatherapie.

MATERIAL AND METHODS: This prospective study included 63 patients with confirmed infections of soft tissue, joints, bones or implants. During 110 surgical interventions, 124 swab and deep tissue sample pairs were taken and analysed microbiologically using standard procedures. RESULTS: In 40 patients who had not received prior antibiotic treatment, 57 sample pairs (swabs/tissue) were taken. In 70%, growth of microorganisms could be observed in both swabs and tissue samples. Growth in tissue sample only was observed in 14% and in 14% no growth could be detected. In 67 sample pairs taken from 23 patients who had received systemic antimicrobial treatment prior to surgery, microbial growth in both specimens was detected in 40%. Growth in tissue sample only was observed in 22% and 34% of the samples remained without detectable growth. The overall sensitivity of the tissue samples (70%) was significantly higher than in swab samples (44%) for the pretreated group. CONCLUSION: The use of intraoperative tissue samples for microbiological diagnostics in septic orthopaedic surgery must be considered a "gold standard". The higher sensitivity of intraoperative tissue samples is particularly important in patients receiving systemic antibiotic therapy prior to surgical interventions.

Tissue and serum levofloxacin concentrations in diabetic foot infection patients.

OBJECTIVES: Levofloxacin has a high bioavailability and a broad antibacterial spectrum which covers the common pathogens found in acute and chronic diabetic foot infections. The purpose of our study was to determine the serum and tissue concentrations of levofloxacin when administered orally in patients with infected diabetic foot ulcers and to compare these values with microbiological findings. PATIENTS AND METHODS: Ten outpatients with diabetes and ulcerations of the lower extremity were included. All patients received oral levofloxacin therapy at a dose of 500 mg once daily. Wound tissue and serum samples were collected and levofloxacin concentrations determined by HPLC with fluorescence detection. Additionally, microbiological cultures were performed from swabs and debrided wound tissue, both before and after treatment. MICs of levofloxacin for all bacterial isolates were determined using the Etest. RESULTS: Following oral treatment with levofloxacin for an average of 10 +/- 3.8 days, all patients received debridement at the affected limbs. The levofloxacin concentrations in necrotic wound tissue were between 2.33-23.23 mg/kg and between 0.12-6.41 mg/L in serum. Tissue-to-serum ratios of levofloxacin concentrations for each patient were >1.0. The MIC values for all 17 initially isolated bacteria were < or = 2 mg/L. In half of our patients, fluoroquinolones were one of the few oral monotherapy options where the spectrum covered all initially isolated pathogens. CONCLUSION: Our data showed good tissue penetration of levofloxacin in diabetic foot ulcers. In combination with adequate surgical debridement, levofloxacin seems well suited to the treatment of skin structure infections of diabetics caused by susceptible organisms.

Tissue and serum concentrations of levofloxacin 500 mg administered intravenously or orally for antibiotic prophylaxis in biliary surgery.

OBJECTIVES: Levofloxacin is a third-generation fluoroquinolone with a broad spectrum of antibacterial activity, comprising enterobacteria, non-fermenters, Gram-positive cocci and some anaerobic species. Members of these species are common pathogens in acute and chronic cholecystitis. This suggests that levofloxacin may be used as peri-operative prophylaxis in gall-bladder surgery. The purpose of our study was to determine serum and tissue levels of levofloxacin in cholecystectomy patients following pre-operative dosing. PATIENTS AND METHODS: Patients with gall-bladder surgery were given levofloxacin 500 mg as a single dose either intravenously (iv) or orally pre-operatively, at the treating physician's decision. Gall-bladder tissue and serum samples were collected, and drug concentrations were determined by HPLC with fluorescence detection. Additionally, all tissue samples underwent routine microbiological diagnostics. MICs for aerobic isolates were determined using the Etest. RESULTS: A total of 61 patients (48 female, 13 male) were included. The medians of the levofloxacin concentrations in serum were 11.37 mg/L (iv) and 9.65 mg/L (oral), and in gall-bladder tissue they were 15.61 mg/kg (iv) and 17.93 mg/kg (oral). Eleven pathogens were isolated from gall-bladder samples. Post-operative wound infection was observed in two of the 61 patients. CONCLUSION: Our data suggest that levofloxacin may be considered for peri-operative prophylaxis in biliary tract surgery.

Antifungal effect of Australian tea tree oil on Malassezia pachydermatis isolated from canines suffering from cutaneous skin disease.

The lipophilic yeast Malassezia pachydermatis is part of the normal skin flora of most warm-blooded organisms. In a number of surveys it could be demonstrated that this yeast species might be involved in different skin diseases like seborrhoeic dermatitis, especially in dogs and cats. In order to look for an alternative therapeutic agent to the commonly used antimycotic and antiseptic synthetic substances the in vitro activity of Australian tea tree oil, the essential oil of Melaleuca alternifolia, against several strains of Malassezia pachydermatis was examined. All tested strains showed remarkably high susceptibility to tea tree oil. With these results the excellent antibacterial activity of tea tree oil is extended to a new group of fungal pathogens colonizing mainly mammals' skin. During the last ten years there was an increasing popularity of tea tree oil containing human health care products. The presented data open up new horizons for this essential oil as a promising alternative agent for topical use in veterinary medicine as well.

[Microbiological and clinical effects of selective bowel decontamination in transthoracic resection of carcinoma of the esophagus and cardia]. / Mikrobiologische und klinische Wirksamkeit der selektiven Darmdekontamination bei der transthorakalen Resektion von Oesophagus- und Kardiacarcinomen.

INTRODUCTION: Surgical therapy of carcinoma of the esophagus or cardia by transthoracic esophageal resection is associated with a high morbidity in which nosocomial infections have a great importance. This study investigates the influence of prophylactic selective bowel decontamination on the course and results of transthoracic resection of the esophagus. METHODS: Seventy patients with carcinoma of the esophagus and cardia were included in this prospective and partially randomized study at the University of Heidelberg. Twenty-five patients received prophylactically selective bowel decontamination with tobramycin, polymyxin B and amphotericin B. The treatment course was documented uniformly. In addition, microbiological screening was performed by swab examinations of nose, throat and anus, by urine and blood cultures, and the documentation of results of additional microbiological diagnostic studies. RESULTS: Bacteriological screening confirmed a reduction in infectious agents and a change of their spectrum in the respiratory and digestive tract without an increase in multiresistant bacteria. Patients who received selective bowel decontamination had a lower infection rate, a shorter artificial respiration period and a shorter intensive care stay without statistically significant differences. The mortality rate was 4% vs 9% in the control group (95% confidence interval -0.172-0.116). CONCLUSION: This study confirms the feasibility and microbiological effectiveness of selective bowel decontamination in the context of surgical therapy which is associated with a high nosocomial infection rate. The result of the clinical treatment seems slightly more favorable in the treatment group. Decisive are complications caused by surgery which fundamentally determine the clinical course and frequently cause infectious complications. The prophylactic use of selective bowel decontamination may be useful in patients with an increased risk of prolonged ventilation support or colon interposition but it is not to be generally recommended.