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This is the 10th chapter of the guideline "Calculated initial parenteral treatment of bacterial infections in adults - update 2018" in the 2nd updated version. The German guideline by the Paul-Ehrlich-Gesellschaft für Chemotherapie e.V. (PEG) has been translated to address an international audience. This chapter deals with bacterial Infections of bones, joints and prosthetic joints. One of the most pressing points is that after an initial empirical therapy a targeted antimicrobial which penetrates well to the point of infection and is tolerated well over the usually long duration of the therapy is chosen.

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Enterobacterales belonging to the genus Enterobacter are well-known human pathogens and blaIMI carrying strains have been described in several countries. From Austria, we report on the first human Enterobacter mori isolate, typically a plant pathogen, which showed an undescribed multilocus sequence type and carried a blaIMI-2 carbapenemase.

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The Carba NP test is a simple confirmation method for carbapenemase-producing Enterobacteriaceae (CPE) but reagents have to be freshly prepared as imipenem sodium salt is unstable. We evaluated the Carba NP test performance based on a commercially available 10-fold cheaper drug formulation containing cilastatin against 217 CPE and 78 non-CPE isolates with reduced meropenem susceptibility. Specificity and sensitivity were 100 % and 98.6 %, respectively and 3 false negative results of blaVIM-1-producing Proteus mirabilis were reproducible with the RAPIDEC® Carba NP test. Cilastatin does not disturb test performance provided that the imipenem drug quantity is doubled.

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BACKGROUND: Katayama fever is an acute clinical condition characterised by high fever, dry cough and general malaise occurring during early Schistosoma spp. infection. It is predominantly reported in travellers from non-endemic regions. Whereas the immunological response to Schistosoma infection is well characterised, alterations in inflammatory markers and coagulation in response to acute infection are poorly understood. METHODS: Here we report the clinical, laboratory and radiological characteristics of three returning travellers with Katayama fever. Inflammatory markers and coagulation status were assessed repeatedly during follow-up to characterise the host response to infection. Radiographic findings were correlated with clinical and laboratory markers. RESULTS: Clinical symptoms were suggestive of a significant inflammatory response in all patients including high fever (>39°C), cough, and general malaise. Classical inflammatory markers including blood sedimentation rate, C-reactive protein, and serum amyloid A were only moderately elevated. Marked eosinophilia (33-42% of white blood cells) was observed and persisted despite anti-inflammatory and anthelminthic treatment for up to 32 weeks. Analysis of blood coagulation markers indicated increased coagulability reflected by elevated D-dimer values (0.57-1.17 µg/ml) and high thrombin generating potentials (peak thrombin activity: 311-384 nM). One patient showed particularly high levels of microparticle-associated tissue factor activity at initial presentation (1.64 pg/ml). Multiple pulmonary and hepatic opacities demonstrated by computed tomography (CT) scanning were associated with raised inflammatory markers in one patient. CONCLUSIONS: The characterisation of the inflammatory response, blood coagulation parameters and radiological findings in three patients adds to our current understanding of Katayama fever and serves as a starting point for further systematic investigations of the pathophysiology of this acute helminthic infection.

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Triggering receptor expressed on myeloid cells-1 (TREM-1) is an amplifier of TLR-mediated inflammation during bacterial infections. Thus far, TREM-1 is primarily associated with unwanted signs of overwhelming inflammation, rendering it an attractive target for conditions such as sepsis. Respiratory tract infections are the leading cause of sepsis, but the biological role of TREM-1 therein is poorly understood. To determine the function of TREM-1 in pneumococcal pneumonia, we first established TREM-1 up-regulation in infected lungs and human plasma together with augmented alveolar macrophage responsiveness toward Streptococcus pneumoniae. Mice treated with an agonistic TREM-1 Ab and infected with S. pneumoniae exhibited an enhanced early induction of the inflammatory response that was indirectly associated with lower levels of negative regulators of TLR signaling in lung tissue in vivo. Later in infection, TREM-1 engagement altered S. pneumoniae-induced IRAK-M (IL-1R-associated kinase-M) kinetics so as to promote the resolution of pneumonia and remarkably led to an accelerated elimination of bacteria and consequently improved survival. These data show that TREM-1 exerts a protective role in the innate immune response to a common bacterial infection and suggest that caution should be exerted in modulating TREM-1 activity during certain clinically relevant bacterial infections.

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OBJECTIVES: To assess the influence of acetyl-salicylic acid (ASA) on clinical outcomes in Staphylococcus aureus infective endocarditis (SA-IE). METHODS: The International Collaboration on Endocarditis - Prospective Cohort Study database was used in this observational study. Multivariable analysis of the SA-IE cohort compared outcomes in patients with and without ASA use, adjusting for other predictive variables, including: age, diabetes, hemodialysis, cancer, pacemaker, intracardiac defibrillator and methicillin resistance. RESULTS: Data were analysed from 670 patients, 132 of whom were taking ASA at the time of SA-IE diagnosis. On multivariable analysis, ASA usage was associated with a significantly decreased overall rate of acute valve replacement surgery (OR 0.58 [95% CI 0.35-0.97]; p<0.04), particularly where valvular regurgitation, congestive heart failure or periannular abscess was the indication for such surgery (OR 0.46 [0.25-0.86]; p<0.02). There was no reduction in the overall rates of clinically apparent embolism with prior ASA usage, and no increase in hemorrhagic strokes in ASA-treated patients. CONCLUSIONS: In this multinational prospective observational cohort, recent ASA usage was associated with a reduced occurrence of acute valve replacement surgery in SA-IE patients. Future investigations should focus on ASA's prophylactic and therapeutic use in high-risk and newly diagnosed patients with SA bacteremia and SA-IE, respectively.

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In this study we addressed the question of whether an underlying hematological malignancy may affect the immune response to vaccination against bacterial polysaccharide antigens (e.g. Haemophilus influenzae type b, Streptococcus pneumoniae) in splenectomized patients. Between 1993 and 2003, 44 splenectomized adults from the outpatient clinic for infectious diseases were prospectively included in the study: 23 patients suffered from hematological malignancies (HM) and had undergone splenectomy; 21 were splenectomized following trauma (T) and served as the control group. Each patient received an intradeltoid injection with 0.5 ml of a single lot of a 23-valent pneumococcal polysaccharide vaccine, and 0.5 ml of a polyribosyl ribitol phosphate capsular polysaccharide vaccine of H. influenzae type b (Hib) into the opposite arm. Blood samples for determination of pneumococcal and Hib antibodies were taken prior to vaccination and again 6-8 weeks later. In assessing responses to the 23-valent pneumococcal polysaccharide vaccine, we found significant differences in antibody titer increase between the HM and T groups (median IgG increase 1.27 [0.7; 2.39] vs. 3.9 [2.1; 15.3], P < 0.001; and median IgM increase 1.33 [1.0;2.67] vs. 5.25 [2.3; 7.78], P < 0.001). In the HM group, only 8/23 and 6/23 showed a titer increase of twice or more the base value for IgG and IgM respectively, whereas in the trauma group an adequate response was shown by 16/21 and 16/20 respectively. Patients with splenectomy and hematological malignancies responded poorly to the 23-valent polysaccharide vaccine. Response to the conjugated Hib vaccine was slightly better, but still significantly lower than in individuals with posttraumatic splenectomy. Data suggest that vaccination response to the polysaccharide vaccines should be evaluated at least in the high-risk group.

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OBJECTIVES: Dosage recommendations for fosfomycin are available for haemodialysed patients but there are no data for patients undergoing continuous renal replacement therapy. Therefore, the present study was designed to determine the concentration-versus-time profile of fosfomycin in continuous venovenous haemofiltration (CVVH). PATIENTS AND METHODS: A total of 12 anuric intensive care patients (10 males and 2 females) with suspected or proven infection requiring parenteral antibiotic therapy were included in the study. All patients underwent CVVH. Blood samples were drawn from the arterial (input) and venous (output) line of the extracorporeal circuit after application of a single dose of 8 g of fosfomycin. Ultrafiltration samples were collected from the outlet of the ultrafiltrate compartment of the haemofilter. Fosfomycin in the samples was quantified by gas chromatography. RESULTS: The peak serum concentration was 442.7+/-124 mg/L at the arterial port. The trough serum level was 103.1+/-36.6 mg/L at the arterial port after 720 min. The mean value of the area under the concentration-versus-time curve from 0 to 12 h (AUC0-12) was 2159.4+/-609.8 mg.h/L. Mean total removal of the drug was 76.7+/-6.2%. The mean calculated clearance was 1.1+/-0.2 L/h for CLHF. Mean CLtot was 6.4+/-7.7 L/h. CONCLUSIONS: A regimen of 8.0 g of fosfomycin every 12 h, which is usually used in patients with intact renal function, should be an appropriate antimicrobial treatment for patients undergoing CVVH.

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The present study was performed to evaluate the ability of fosfomycin, a broad-spectrum antibiotic, to penetrate into abscess fluid. Twelve patients scheduled for surgical or computer tomography-guided abscess drainage received a single intravenous dose of 8 g of fosfomycin. The fosfomycin concentrations in plasma over time and in pus upon drainage were determined. A pharmacokinetic model was developed to estimate the concentration-time profile of fosfomycin in pus. Individual fosfomycin concentrations in abscess fluid at drainage varied substantially, ranging from below the limit of detection up to 168 mg/liter. The fosfomycin concentrations in pus of the study population correlated neither with plasma levels nor with the individual ratios of abscess surface area to volume. This finding was attributed to highly variable abscess permeability. The average concentration in pus was calculated to be 182 +/- 64 mg/liter at steady state, exceeding the MIC(50/90)s of several bacterial species which are commonly involved in abscess formation, such as streptococci, staphylococci, and Escherichia coli. Hereby, the exceptionally long mean half-life of fosfomycin of 32 +/- 39 h in abscess fluid may favor its antimicrobial effect because fosfomycin exerts time-dependent killing. After an initial loading dose of 10 to 12 g, fosfomycin should be administered at doses of 8 g three times per day to reach sufficient concentrations in abscess fluid and plasma. Applying this dosing regimen, fosfomycin levels in abscess fluid are expected to be effective after multiple doses in most patients.

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A high-performance liquid chromatography method for the quantitative determination of telithromycin in biological fluids is described. The method is suitable for plasma and microdialysates from the interstitial space fluid of skeletal muscle and subcutaneous adipose tissue. Plasma samples were deproteinised with trichloroacetic acid and neutralised with sodium hydroxide. Microdialysates were analysed without further preparation step. Telithromycin was separated isocratically on a reverse-phase column using acetonitrile-0.03 M ammonium acetate, pH 5.2 (43:57, v/v) at a flow rate of 0.8 mlmin(-1), and fluorescence detection (excitation 263 nm, emission 460 nm). The calibration curve was linear from 0.01 to 5 microgml(-1). Within- and between-day imprecision and inaccuracy was < or =10%. The limits of quantification were 0.02 and 0.015 microgml(-1) for plasma and microdialysates, respectively. Since telithromycin is decomposed in aqueous solution at ambient temperature, it is strongly recommended to store samples frozen at -80 degrees C, to maintain the temperature at 4 degrees C during all preparation steps, and to analyse samples within 120 min after thawing.

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By use of microdialysis we assessed the concentrations of telithromycin in muscle and adipose tissue to test its ability to penetrate soft tissues. The ratios of the area under the concentration-versus-time curve from 0 to 24 h to the MIC indicated that free concentrations of telithromycin in tissue and plasma might be effective against Streptococcus pyogenes but not against staphylococci and human and animal bite pathogens.

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The increase detected in macrolide resistance in streptococci in various parts of the world has brought into question the usefulness of macrolides as first line therapy for respiratory tract infections. In a nationwide study, a total of 3012 Streptococcus pneumoniae and 499 Streptococcus pyogenes isolates were collected from 1996 to 2002 and tested for their susceptibility to penicillin, azithromycin, clarithromycin and telithromycin (2002 only). Penicillin-intermediate and -resistant isolates of S. pneumoniae comprised 4.9% (2.9 and 2.0%, respectively) of all isolates in 1996; macrolide resistance was also comparatively low at 3.2%. In the following years the rate of penicillin-resistant pneumococci increased steadily, reaching the 10% mark in 2002. A similar trend was recorded for the macrolides. No penicillin-resistant strain of S. pyogenes was found during the observation period. The prevalence of macrolide-resistance in S. pyogenes climbed from 4.7% in 1996 to the present rate of 7.2% (clarithromycin) and 9.4% (azithromycin). Telithromycin showed excellent activity against both S. pneumoniae and S. pyogenes with 99.8 and 100% strains sensitive, respectively.

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A total of 341 clinical isolates of Streptococcus pyogenes from Vienna, Austria and three Hungarian cities were tested for susceptibility to four macrolides and 12 other antibiotics. All isolates were fully susceptible to penicillin and the other beta-lactams tested. A high level of tetracycline resistance was found in Austria (26.7%) and in Hungary (30.5%). The rate of resistance to erythromycin, clarithromycin and azithromycin was 4.7% in Vienna and 3.7% in the Hungarian communities. In both countries, the MIC(90) values of erythromycin and clarithromycin were 0.12 mg/L and the MIC(90) of josamycin was 0.5mg/L. The M phenotype of resistance conferred by the mefA genes was predominant (n = 9) among the macrolide-resistant isolates (n = 14).

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The purpose of the present study was to determine the antimicrobial resistance among Streptococcus pyogenes in Bavaria, Germany. Five hundred and forty isolates of S. pyogenes were collected from patients with tonsillopharyngitis. Of these, 425 isolates were obtained from children and 115 from adult patients. All isolates were tested for susceptibility to macrolides, clindamycin, penicillin and 10 other commonly prescribed antimicrobial agents, using broth microdilution tests. All isolates were fully susceptible to penicillin, amoxicillin and cephalosporins; 16.1% of the isolates were resistant to tetracycline. MIC(90) values of erythromycin, clarithromycin, azithromycin and josamycin were 16, 4, 16 and 0.5 mg/L. The overall resistance rate of S. pyogenes to erythromycin, clarithromycin and azithromycin was 13.3%. All isolates resistant to erythromycin were also resistant to clarithromycin and azithromycin, and vice versa. Erythromycin resistance rates were higher in adult patients (19.1%) than in children (11.8%). The resistance rate to josamycin was only 1.5%, a value similar to that of clindamycin (1.1%). Among the 72 erythromycin-resistant isolates the M phenotype of macrolide resistance predominated (78%), while percentages of cMLS(B) (8%) and iMLS(B) (14%) phenotypes were low. Of the iMLS(B) strains (n = 10), the majority were of the subtype C (n = 8). The M phenotype was associated with a low, and the iMLS(B)-C phenotype with a high, rate of resistance to tetracycline. Conclusively, present data point to rising macrolide resistance among S. pyogenes in Bavaria.

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BACKGROUND AND OBJECTIVE: Until recently, the main field of Er:YAG laser application was the removal of dental hard substances within the scope of cavity preparation. Nowadays, several new delivery-systems are available, permitting the application of the Er:YAG laser in endodontics. The aim of the present study was to assess the effects of Er:YAG laser irradiation on root canals in vitro. STUDY DESIGN/MATERIALS AND METHODS: For this purpose, 220 extracted human teeth were endodontically processed and subsequently irradiated at different settings using an Er:YAG laser imitating in vivo irradiation procedures. The teeth were then subdivided into three groups and subjected to bacteriological evaluations, scanning electron microscopy, and temperature measurements. RESULTS: The bacteriological evaluation revealed a decisive bactericidal effect of the Er:YAG laser in the root canal. The bactericidal effect was dependent on the applied output power and specific for the different species of bacteria investigated. Scanning electron microscopy showed discrete removal of dentine from the root canal walls. The temperature rise during irradiation was moderate when standardized power settings were used. CONCLUSION: The investigations indicate that the Er:YAG laser is a suitable tool for the elimination of bacteria in root canals under in vitro conditions.

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The MIDITECH colorimetric susceptibility test with automated reading is a modification of the standard broth microdilution method that uses a 3-(4,5-dimetylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) dye for detecting viable bacteria. The method can be applied to non-fastidious aerobic Gram-negative bacteria, staphylococci and Enterococcus faecalis. To assess the reliability of this method, we compared susceptibility data obtained by this test with standard NCCLS microdilution assay results. For this purpose, 15 antibiotics and a well characterized set of 527 Gram-negative and Gram-positive bacterial isolates collected and stored at the Division of Infectious Diseases and Chemotherapy (Vienna General Hospital, Austria), yielding 5751 organism-antibiotic combinations, were analysed in duplicate. The overall essential agreement (+/-1 log(2) dilution) between the MIDITECH and NCCLS methods was 96.18 +/- 0.67%. The colorimetric assay compared with the reference method produced MICs < or = 2 log(2) dilutions and > or = 2 log(2) dilutions in 2.34% and 1.48% comparisons, respectively. For 326 Gram-negative bacteria, the absolute interpretative agreement of both methods ranged from 87.12% for ampicillin-sulbactam to 99.85% for meropenem (mean 94.86%); 417 (4.92%) minor, three (0.05%) major and 15 (0.63%) very major errors were found. For 127 staphylococci and 74 E. faecalis isolates, the absolute interpretative agreement ranged from 90.80% for ciprofloxacin to 100% for vancomycin and linezolid (mean 96.96%); 81 (2.77%) minor, three (0.15%) major and eight (0.83%) very major errors were found. For most of the clinically important aerobically growing pathogens, the MIDITECH colorimetric test provided reliable quantitative susceptibility data. The main advantage of this method is simple performance, automated reading and data processing without expensive investments.

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