[S2k guidelines of the PEG on calculated parenteral initial treatment of bacterial diseases in adults : Focussed summary and supplementary information on antibiotic treatment of critically ill patients]. / S2k-Leitlinie der PEG zur kalkulierten parenteralen Initialtherapie bakterieller Erkrankungen bei Erwachsenen : Fokussierte Zusammenfassung und ergänzende Informationen zur Antibiotikatherapie kritisch kranker Patienten.

In January 2018 the recent revision of the S2k guidelines on calculated parenteral initial treatment of bacterial diseases in adults-update 2018 (Editor: Paul Ehrlich Society for Chemotherapy, PEG) was realized. It is a helpful tool for the complex infectious disease setting in an intensive care unit. The present summary of the guidelines focuses on the topics of anti-infective agents, including new substances, pharmacokinetics and pharmacodynamics as well as on microbiology, resistance development and recommendations for calculated drug therapy in septic patients. As in past revisions the recent resistance situation and results of new clinical studies are considered and anti-infective agents are summarized in a table.

Antimicrobial susceptibility of bacterial isolates from patients presenting with ear, nose and throat (ENT) infections in the German community healthcare setting.

Empiric initial antibiotic therapy of bacterial infections is based primarily upon the susceptibility of the most common causative pathogens. The purpose of this study was to provide susceptibility data on six bacterial species known to cause ear, nose and throat (ENT) infections. A total of 1066 isolates collected during a nationwide laboratory-based surveillance study were analysed. All Streptococcus pyogenes isolates were penicillin (PEN)-susceptible, indicating that natural penicillins can still be recommended as the first-line treatment for group A streptococcal tonsillopharyngitis. Of the S. pneumoniae isolates, 92.9% were PEN-susceptible and of the Haemophilus influenzae isolates, 89.7% were amoxicillin-susceptible, retaining aminopenicillins as the first-line treatment for acute otitis media (AOM) and acute rhinosinusitis (ARS), in case antibiotic therapy is considered. In contrast, cefuroxime axetil seems less likely to be suitable for the treatment of AOM or ARS, as all Moraxella catarrhalis and >99% of the H. influenzae isolates were categorised as intermediate or resistant. The susceptibility rates of Pseudomonas aeruginosa were 97-100% for the drugs tested, except for the fluoroquinolones (87.6%). Overall, bacterial isolates from outpatients presenting with ENT infections showed low frequencies of resistance in Germany. However, given the emergence of multidrug resistance to standard antibiotics in Escherichia coli and other pathogens, inappropriate use of broad-spectrum antibiotics for the treatment of ENT infections has to be avoided.

[Multiresistant pathogens--a challenge for clinicians]. / Multiresistente Erreger--eine infektiologische Herausforderung.

Gram-negative pathogens are currently isolated frequently in invasive nosocomial infections and give rise to major therapeutic problems due to their resistance pattern. Metaanalyses of randomised controlled studies have demonstrated that an antibiotic combination treatment is not indicated in many cases. However, in critically ill patients (septic shock) and also in immunocompromised patients with previous intensive care as well as broad spectrum antibiotic treatment, a combination of antibiotics is recommended. This therapy should be based on the source of the infection, on local resistance data, on antibiotic pretreatment, on basic diseases of the patient and on current liver and renal functions. The start of therapy should be as fast as possible after collection of optimal materials for microbiological analysis. Dosage of selected antibiotics should be based on rational pharmacokinetic and pharmacodynamic parameters. A de-escalation of antibiotics is strongly recommended in all international guidelines based on the microbiological results and the clinical response of the patient. New antibiotics or therapeutic strategies against multiresistant Gram-negative pathogens will not be available in the next 5 to 10 years; therefore, it is absolute mandatory to use the currently still effective antibiotics, like carbapenems and polymyxins, very rationally and restrictively.

[Surveillance of antibiotic consumption : clarification of the "definition of data on the nature and extent of antibiotic consumption in hospitals according to § 23 paragraph 4 sentence 2 of the IfSG"]. / Antibiotika-Verbrauchs-Surveillance : Ausführungen und Erläuterungen zur Bekanntmachung "Festlegung der Daten zu Art und Umfang des Antibiotika-Verbrauchs in Krankenhäusern nach § 23 Abs. 4 Satz 2 IfSG"

According to § 23 paragraph 4 of the German Infection Prevention Act (IfSG; July 2011), hospitals and clinics for ambulatory surgery are obliged to establish a continuous monitoring system of antibiotic consumption. This is aimed at contributing to an optimization of antibiotic prescription practices in order to confine the development and spread of resistant pathogens. The general requirements (restricted to hospitals) on the method and extent of data collection are provided by the national public health institution after discussion with representatives of various professional societies (Robert Koch-Institut, Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 59, 2013). The article aims to clarify these specifications and to provide background details. In agreement with national and European surveillance systems, the Anatomical Therapeutic Chemical (ATC)/Defined Daily Dose (DDD) classification system recommended by the WHO should be used as reference standard. Antibiotic consumption should be expressed as the number of DDDs per 100 patient days and per 100 admissions. The categories of antimicrobials and hospital organizational units to be monitored and the time intervals in which analyses should be conducted are determined. Furthermore, various approaches of data assessment are described.

Comparative activity of pradofloxacin and marbofloxacin against coagulase-positive staphylococci in a pharmacokinetic-pharmacodynamic model based on canine pharmacokinetics.

Pradofloxacin (PRA), a novel veterinary 8-cyano-fluoroquinolone (FQ), is active against Staphylococcus pseudintermedius, the primary cause of canine pyoderma. An in vitro pharmacokinetic-pharmacodynamic model was used to compare the activities of PRA and marbofloxacin (MAR) against three clinical isolates of S. pseudintermedius and reference strain Staphylococcus aureus ATCC 6538. Experiments were performed involving populations of 10(10) CFU corresponding to an inoculum density of approximately 5 × 10(7) CFU/mL. The time course of free drug concentrations in canine serum was modelled, resulting from once daily standard oral dosing of 3 mg of PRA/kg and 2 mg of MAR/kg. In addition, experimentally high doses of 6 mg of PRA/kg and 16 mg of MAR/kg were tested against the least susceptible strain. Viable counts were monitored over 24 h. At concentrations associated with standard doses, PRA caused a faster and more sustained killing than MAR of all strains. The ratios of free drug under the concentration-time curve for 24 h over MIC and the maximum concentration of free drug over MIC were at least 90 and 26, and 8.5 and 2.1 for PRA and MAR, respectively. At experimentally high doses, PRA was superior to MAR in terms of immediate killing. Subpopulations with reduced susceptibility to either FQ did not emerge. We conclude that PRA is likely to be an efficacious therapy of canine staphylococcal infections.

Resistance trends and in vitro activity of tigecycline and 17 other antimicrobial agents against Gram-positive and Gram-negative organisms, including multidrug-resistant pathogens, in Germany.

To document the development of resistance to tigecycline in comparison with 17 other antimicrobials, the susceptibilities of 2,741 isolates comprising 16 bacterial species recovered from hospitalised patients in 15 German centres in 2009 were assessed. The results were compared with those of previous trials (German Tigecycline Evaluation Surveillance Trial, G-TEST I and II, performed in 2005 and 2007, respectively) conducted prior to and shortly after the introduction of tigecycline in Germany. Moreover, the in vitro activities of tigecycline against the subset of multidrug-resistant (MDR) pathogens recovered within all three sampling periods (n = 4,988) were evaluated in comparison to the corresponding non-MDR isolates. All susceptibility tests were performed by broth microdilution. Between 2005 and 2009, tigecycline retained its high activity against Gram-positive and Gram-negative organisms, including MDR pathogens. By contrast, an in part marked increase in resistance to broad-spectrum beta-lactams and fluoroquinolones was observed for many Enterobacteriaceae and for non-fermenting Gram-negative bacteria. Against a background of a steadily increasing number of multiresistant pathogens, the activity of tigecycline remained unaltered. With the exception of Acinetobacter isolates with decreased susceptibility to carbapenems, tigecycline's activity profile was not notably affected by organisms resistant to other drug classes and, thus, holds promise as an important therapeutic agent, particularly for situations in which MDR organisms are suspected.

Susceptibility of clinical isolates of frequently encountered bacterial species to tigecycline one year after the introduction of this new class of antibiotics: results of the second multicentre surveillance trial in Germany (G-TEST II, 2007).

Tigecycline, a broad-spectrum antibiotic for parenteral use, was introduced in Germany in May 2006. In the G-TEST-II trial, the susceptibility of isolates, recovered in 2007 from hospitalised patients in 15 centres, was assessed against tigecycline and comparators. Susceptibility tests were performed by the microdilution procedure. This study reports on the susceptibility of the isolates of 16 bacterial species and compares the results with those of a trial (G-TEST I) conducted prior to the introduction of tigecycline. Between 2005 and 2007, tigecycline retained activity against Gram-positive and Gram-negative organisms. By contrast, the rate of vancomycin-resistant strains among Enterococcus faecium isolates almost doubled. Moreover, an increase in resistance to broad-spectrum beta-lactams and fluoroquinolones was observed for members of the family Enterobacteriaceae. Against a background of a steadily rising number of pathogens that are resistant to various antibiotic classes, tigecycline represents an important treatment option.

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.

Bactericidal activity of daptomycin, vancomycin, teicoplanin and linezolid against Staphylococcus aureus, Enterococcus faecalis and Enterococcus faecium using human peak free serum drug concentrations.

The bactericidal activities of daptomycin, vancomycin, teicoplanin and linezolid at human peak free serum concentrations (C(max,free)) were determined against Staphylococcus aureus (one methicillin-susceptible and two methicillin-resistant strains), Enterococcus faecalis and Enterococcus faecium (one vancomycin-susceptible and one vancomycin-resistant strain of each). Daptomycin was rapidly bactericidal against 7/7 strains at C(max,free) of 22.0 mg/L (corresponding to 63% protein binding) and against 3/7 strains at 4.8 mg/L (corresponding to 92% protein binding). Vancomycin (18.0 mg/L) was bactericidal against only two strains. Both teicoplanin (4.5 mg/L) and linezolid (10.4 mg/L) were consistently bacteriostatic. Daptomycin is a useful option for the treatment of Gram-positive infections owing to its strong bactericidal activity.

Comparative in vitro activity of oral antimicrobial agents against Enterobacteriaceae from patients with community-acquired urinary tract infections in three European countries.

Enterobacteriaceae causing community-acquired urinary tract infections were examined in selected outpatient clinics and hospitals in Belgium, Germany and Spain using EUCAST breakpoints for susceptibility. A total of 1190 isolates were collected. Escherichia coli isolates were resistant to amoxicillin-clavulanic acid (28.1%), ciprofloxacin (23.4%) and trimethoprim-sulfamethoxazole (21.4%) compared with fosfomycin and nitrofurantoin (each, <1.5%). Ceftibuten (MIC50/90 0.25/0.5 mg/L) and ceftriaxone activity (MIC50/90 ≤0.25 mg/L) was comparable. Ceftibuten (MIC90 ≤0.25 mg/L) was also active against Proteus mirabilis and Klebsiella spp. Extended-spectrum ß-lactamase phenotypes were 7.1% for E. coli, 5.6% for Klebsiella pneumoniae and 0.4% for P. mirabilis. Resistance was common among men and elderly women.

Activities of various beta-lactams and beta-lactam/beta-lactamase inhibitor combinations against Acinetobacter baumannii and Acinetobacter DNA group 3 strains.

Acinetobacter baumannii and Acinetobacter DNA group 3 are members of the so-called A. calcoaceticus-A. baumannii complex and are important nosocomial pathogens. Multiresistance in these organisms is increasingly frequent, and alternative treatment options are needed. The beta-lactamase inhibitors clavulanate, sulbactam and tazobactam have intrinsic activity against Acinetobacter strains. In the present study, broth microdilution was used to assess the in-vitro activities of currently available beta-lactam/beta-lactamase inhibitor combinations and sulbactam alone against 469 Acinetobacter isolates (A. baumannii, n=395; Acinetobacter DNA group 3, n=74) collected from various laboratories in Germany. Fixed concentrations and fixed ratios of beta-lactamase inhibitors were used. Sulbactam-containing combinations (susceptibility rates of 90.4-92.7% for A. baumannii and 97.3-100% for Acinetobacter DNA group 3) and sulbactam alone were superior to clavulanate- and tazobactam-containing combinations. The activity of sulbactam-containing combinations against members of the A. calcoaceticus-A. baumannii complex was conferred exclusively by the intrinsic activity of the beta-lactamase inhibitor and did not result from enhanced beta-lactam activity. Testing with the inhibitor added at a fixed ratio of inhibitor to beta-lactam appeared to give more reliable results than testing at a fixed concentration of the inhibitor. Resistance to carbapenems (0.3%) remains low in Germany.

Surveillance of linezolid resistance in Germany, 2001-2002.

A surveillance study was performed throughout Germany from November 2001 to June 2002 to assess the prevalence of linezolid-resistant isolates among Gram-positive bacteria from routine susceptibility data and to compare the in-vitro activity of linezolid to that of other antibacterial agents. Each of 86 laboratories provided routine susceptibility data for 100 consecutive isolates. Most laboratories (c. 60%) used the disk diffusion test. Laboratories were also requested to send a representative sample of their isolates, as well as all isolates reported as intermediate or resistant to linezolid, to a reference laboratory for MIC determination. Susceptibility data for 8594 isolates were evaluated. Sites of infection were skin and soft tissue (29.9%), upper and lower respiratory tract (19.1%), foreign body or catheter (10.5%), or urinary tract (9.8%). Routine linezolid susceptibility data were reported for 6433 isolates. The prevalence of linezolid resistance, as reported to the clinician, was 0.4% in Staphylococcus aureus, 0.3% in Staphylococcus epidermidis, 2.9% in Enterococcus faecalis, 2.3% in Enterococcus faecium, 1.4% in Streptococcus pyogenes and 2.9% in Streptococcus agalactiae. Linezolid resistance was not detected in Streptococcus pneumoniae or in viridans group streptococci. Sixty-nine of 115 isolates reported as intermediate or resistant to linezolid were retested, but none was resistant to linezolid. Linezolid exhibited excellent in-vitro activity against representative isolates of the six most frequently encountered species (MIC90, 1-2 mg/L). The prevalence of resistance to linezolid was very low in Germany. Organisms reported as linezolid-resistant should be retested, either in the same laboratory with an alternative method or in a reference laboratory.

Changing pattern of antibiotic resistance in methicillin-resistant Staphylococcus aureus from German hospitals.

OBJECTIVE: To investigate the background of changes of resistance phenotypes in methicillin-resistant Staphylococcus aureus (MRSA) from nosocomial infections in German hospitals by molecular typing and identification of particular resistance genes. METHODS: Isolates from the network for monitoring the spread of MRSA in Germany were subjected to quantitative susceptibility testing, to molecular typing, and to polymerase chain reaction identification of resistance genes. PARTICIPANTS: The network consists of 175 German clinical microbiological laboratories collaborating with the German Reference Center for Staphylococci, which performs typing of staphylococcal isolates from nosocomial infections and data analysis. RESULTS: During the past 5 years, MRSA susceptible to other antibiotics such as oxytetracycline, erythromycin, and gentamicin became more frequent. The proportion of epidemic MRSA clones that had been disseminated in the past and that exhibited broad resistance phenotypes decreased, whereas the proportion of recently emerging MRSA carrying only a few other resistance determinants has increased (1994, 11.5%; 1998, 39%). CONCLUSIONS: The changing pattern of resistance phenotypes of MRSA from nosocomial infections in Germany is mainly due to the spread of recently emerging epidemic strains that are less frequently resistant to antibacterials other than oxacillin. The observed changes cannot simply be attributed to overall antibiotic consumption.

Pefloxacin single-dose in the treatment of acute uncomplicated lower urinary tract infections in women: a meta-analysis of seven clinical trials.

The objective of the meta-analysis was to assess the efficacy and safety of a single oral dose of 800 mg pefloxacin in the treatment of acute uncomplicated lower urinary tract infections in women. A total of 1578 women were enrolled in five controlled (four double-blind and one open) and two non-comparative multicentre clinical trials. The comparative treatment regimen in the five controlled trials was trimethoprim-sulfamethoxazole in four studies, and norfloxacin in one study. Trimethoprim-sulfamethoxazole was administered orally 160/800 mg twice daily for 3-7 days, norfloxacin 400 mg b.i.d. for 5 days. Analyses of these studies were performed for the intent-to-treat population and safety population. The 1298 patients (815 patients with pefloxacin, 404 with trimethoprim-sulfamethoxazole, and 79 with norfloxacin) included in the intent-to-treat-analysis were those with clinical signs and symptoms of acute cystitis and significant bacteriuria (>/=10(5) cfu/ml midstream urine) who received a single oral dose of pefloxacin or were treated with the control drug. Success rates of pefloxacin achieved 4 to 6 weeks after the start of treatment ranged from 65.8% to 97.7% for cure or improvement of clinical signs and symptoms and from 53.8% to 90.5% for bacteriological eradication (trimethoprim-sulfamethoxazole 69.1% to 92.5% abd 52.1% to 85.1%, and norfloxacin 74.7% and 58.2%, respectively). The pooled percentage of patients in whom pefloxacin therapy cured or improved clinical symptoms was 82.5% (95% CI: 79.7% to 85.0%). The pooled rate of bacteriological eradication was 76.3% (95% CI: 73.2% to 79.2%). The pooled success rates of trimethoprim-sulfamethoxazole were 82.7% (95% CI: 78.6% to 86.2%) for clinical cure or improvement, and 74.3% (95% CI: 69.7% to 78.5%) for bacteriological eradication. Testing for equivalence between pefloxacin and trimethoprim-sulfamethoxazole in an exploratory sense, the minimal equivalence region with significant results was 4.1% points for clinical cure or improvement (P < 0.05) and 6.5% points for bacteriological eradication (P < 0.05). Adverse events were reported in 235 out of 987 patients treated with pefloxacin. The pooled incidence was 23.8% (incidence in individual studies 13.5% to 47.3%). The pooled incidence of adverse events associated with the use of the comparative drugs was 20.5% (incidence in individual studies 5.9 to 47.7%).

Molecular epidemiology of Acinetobacter baumannii and Acinetobacter nosocomialis in Germany over a 5-year period (2005-2009).

To investigate the species distribution within the Acinetobacter calcoaceticus-Acinetobacter baumannii complex and the molecular epidemiology of A. baumannii and Acinetobacter nosocomialis, 376 Acinetobacter isolates were collected prospectively from hospitalized patients at 15 medical centres in Germany during three surveillance studies conducted over a 5-year period. Species identification was performed by molecular methods. Imipenem minimum inhibitory concentrations (MIC) were determined by broth microdilution. The prevalence of the most common carbapenemase-encoding genes was investigated by oxacillinase (OXA) -multiplex polymerase chain reaction (PCR). The molecular epidemiology was investigated by repetitive sequence-based PCR (rep-PCR; DiversiLab™). Acinetobacter pittii was the most prevalent Acinetobacter species (n = 193), followed by A. baumannii (n = 140), A. calcoaceticus (n = 10) and A. nosocomialis (n = 8). The majority of A. baumannii was represented by sporadic isolates (n = 70, 50%) that showed unique rep-PCR patterns, 25 isolates (18%) clustered with one or two other isolates, and only 45 isolates (32%) belonged to one of the previously described international clonal lineages. The most prevalent clonal lineage was international clone (IC) 2 (n = 34) and IC 1 (n = 6). According to CLSI, 25 A. baumannii isolates were non-susceptible to imipenem (MIC ≥ 8 mg/L), all of which produced an OXA-58-like or OXA-23-like carbapenemase. The rate of imipenem susceptibility among A. baumannii isolates decreased from 96% in 2005 to 76% in 2009. All other Acinetobacter isolates were susceptible to imipenem. The population structure of carbapenem-susceptible A. baumannii in Germany is highly diverse. Imipenem non-susceptibility was strongly associated with the clonal lineages IC 2 and IC 1. These data underscore the high clonality of carbapenem-resistant A. baumannii isolates.

Development of resistance to nalidixic acid and the fluoroquinolones after the introduction of norfloxacin and ofloxacin.

Since 1975, the group Resistenz of the Paul-Ehrlich-Gesellschaft für Chemotherapie has monitored the development of resistance in isolates of members of the family Enterobacteriaceae, Pseudomonas aeruginosa, Staphylococcus aureus, and Enterococcus faecalis in the Federal Republic of Germany, West Berlin, Austria, and Switzerland. Despite a marked increase in the use of 4-quinolones, there was no increase in the percentages of nalidixic acid-resistant strains of Enterobacteriaceae between 1975 and 1986. However, different bacterial species showed considerable variation, and there were also considerable differences in the percentages of nalidixic acid-resistant strains of Enterobacteriaceae from different centers. The frequency of resistance to fluoroquinolones was unchanged from 1983 to 1986 and was less than 4% in all species except P. aeruginosa. In this species, there was an increase from about 3 to 10% from 1983 to 1986 for strains for which the MIC was fourfold above the mode MIC of ciprofloxacin, enoxacin, and ofloxacin.

The incidence and development of resistance in Staphylococcus aureus from three European countries.

In a multicentre study conducted by the Paul Ehrlich Society we tested 3482 Staphylococcus aureus strains, isolated in different hospitals in West Germany, Austria and Switzerland, against 12 antibiotics with standardized techniques between 1976 and 1982. In order to avoid mistakes in the classification of the strains into sensitive, intermediate and resistant, we adapted breakpoints to the population distribution. There were no marked changes in the incidence of sensitive strains during the period. Striking differences from one hospital to another were observed. The percentage of strains sensitive to penicillin remains low (27%). The other antibiotics studied show activity against 80-100% of strains.