[New antibiotics for severe infections due to multidrug-resistant pathogens : Definitive treatment and escalation]. / Neue Antibiotika bei schweren Infektionen durch multiresistente Erreger : Definitive Therapie und Eskalation.

Multidrug-resistant pathogens often lead to treatment failure of antimicrobial regimens. After a period of imbalance between the occurrence/spread of resistance mechanisms and the development of new substances, some new substances have meanwhile been approved and many more are currently undergoing clinical testing. They are particularly effective against specific resistance mechanisms/pathogens and should be preserved for definitive treatment of an isolated pathogen. In the absence of alternatives reserve antibiotics, such as aztreonam and colistin have experienced a renaissance. They are again used in special infection scenarios and clinically tested in combination with new substances. Despite the introduction and development of new substances the building of resistance will at some time also render these (at least partially) ineffective. Therefore, their implementation must be carried out according to the antibiotic or infectious diseases stewardship.

[Infections due to multidrug-resistant pathogens : Pathogens, resistance mechanisms and established treatment options]. / Infektionen durch multiresistente Erreger : Erreger, Resistenzmechanismen und etablierte Therapieoptionen.

The increase in resistant pathogens has long been a global problem. Complicated life-threatening infections due to multidrug-resistant pathogens (MRD) meanwhile occur regularly in intensive care medicine. An important and also potentially modifiable factor of the rapid spread of resistance is the irrational use of broad spectrum antibiotics in human medicine. In addition to many other resistance mechanisms, beta-lactamases play an important role in Gram-negative pathogens. They are not uncommonly the leading reason of difficult to treat infections and the failure of known routinely used broad spectrum antibiotics, such as cephalosporins, (acylamino)penicillins and carbapenems. Strategies for containment of MRDs primaríly target the rational use of antibiotics. In this respect interdisciplinary treatment teams, e.g. antibiotic stewardship (ABS) and infectious diseases stewardship (IDS) play a major role.

Bacterial sepsis : Diagnostics and calculated antibiotic therapy.

The mortality of patients with sepsis and septic shock is still unacceptably high. An effective calculated antibiotic treatment within 1 h of recognition of sepsis is an important target of sepsis treatment. Delays lead to an increase in mortality; therefore, structured treatment concepts form a rational foundation, taking relevant diagnostic and treatment steps into consideration. In addition to the assumed infection and individual risks of each patient, local resistance patterns and specific problem pathogens must be taken into account during the selection of anti-infective treatment. Many pathophysiologic alterations influence the pharmacokinetics (PK) of antibiotics during sepsis. The principle of standard dosing should be abandoned and replaced by an individual treatment approach with stronger weighting of the pharmacokinetics/pharmacodynamics (PK/PD) index of the substance groups. Although this is not yet the clinical standard, prolonged (or continuous) infusion of ß­lactam antibiotics and therapeutic drug monitoring (TDM) can help to achieve defined PK targets. Prolonged infusion is sufficient without TDM, but for continuous infusion, TDM is generally necessary. A further argument for individual PK/PD-oriented antibiotic approaches is the increasing number of infections due to multidrug-resistant (MDR) pathogens in the intensive care unit. For effective treatment, antibiotic stewardship teams (ABS teams) are becoming more established. Interdisciplinary cooperation of the ABS team with infectious disease (ID) specialists, microbiologists, and clinical pharmacists leads not only to rational administration of antibiotics, but also has a positive influence on treatment outcome. The gold standards for pathogen identification are still culture-based detection and microbiologic resistance testing for the various antibiotic groups. Despite the rapid investigation time, novel polymerase chain reaction(PCR)-based procedures for pathogen identification and resistance determination are currently only an adjunct to routine sepsis diagnostics, due to the limited number of studies, high costs, and limited availability. In complicated septic courses with multiple anti-infective therapies or recurrent sepsis, PCR-based procedures can be used in addition to treatment monitoring and diagnostics. Novel antibiotics represent potent alternatives in the treatment of MDR infections. Due to the often defined spectrum of pathogens and the practically (still) absent resistance, they are suitable for targeted treatment of severe MDR infections (therapy escalation). (Contribution available free of charge by "Free Access" [ https://link.springer.com/article/10.1007/s00101-017-0396-z ].).

[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.

[Epidemiology, Diagnosis and Treatment of Adult Patients with Nosocomial Pneumonia - Update 2017 - S3 Guideline of the German Society for Anaesthesiology and Intensive Care Medicine, the German Society for Infectious Diseases, the German Society for Hygiene and Microbiology, the German Respiratory Society and the Paul-Ehrlich-Society for Chemotherapy, the German Radiological Society and the Society for Virology]. / Epidemiologie, Diagnostik und Therapie erwachsener Patienten mit nosokomialer Pneumonie ­ Update 2017.

Nosocomial pneumonia (HAP) is a frequent complication of hospital care. Most data are available on ventilator-associated pneumonia. However, infections on general wards are increasing. A central issue are infections with multidrug resistant (MDR) pathogens which are difficult to treat in the empirical setting potentially leading to inappropriate use of antimicrobial therapy.This guideline update was compiled by an interdisciplinary group on the basis of a systematic literature review. Recommendations are made according to GRADE giving guidance for the diagnosis and treatment of HAP on the basis of quality of evidence and benefit/risk ratio.This guideline has two parts. First an update on epidemiology, spectrum of pathogens and antimicrobials is provided. In the second part recommendations for the management of diagnosis and treatment are given. New recommendations with respect to imaging, diagnosis of nosocomial viral pneumonia and prolonged infusion of antibacterial drugs have been added. The statements to risk factors for infections with MDR pathogens and recommendations for monotherapy vs combination therapy have been actualised. The importance of structured deescalation concepts and limitation of treatment duration is emphasized.

[Bacterial sepsis : Diagnostics and calculated antibiotic therapy]. / Bakterielle Sepsis : Diagnostik und kalkulierte Antibiotikatherapie.

The mortality of patients with sepsis and septic shock is still unacceptably high. An effective antibiotic treatment within 1 h of recognition of sepsis is an important target of sepsis treatment. Delays lead to an increase in mortality; therefore, structured treatment concepts form a rational foundation, taking relevant diagnostic and treatment steps into consideration. In addition to the assumed focus and individual risks of each patient, local resistance patterns and specific problem pathogens must be taken into account for selection of anti-infection treatment. Many pathophysiological alterations influence the pharmacokinetics of antibiotics during sepsis. The principle of standard dosing should be abandoned and replaced by an individual treatment approach with stronger weighting of the pharmacokinetics/pharmacodynamics (PK/PD) index of the substance groups. Although this is not yet the clinical standard, prolonged (or continuous) infusion of beta-lactam antibiotics and therapeutic drug monitoring (TDM) can help to achieve defined PK targets. Prolonged infusion is sufficient without TDM but for continuous infusion TDM is basically necessary. A further argument for individual PK/PD-oriented antibiotic approaches is the increasing number of infections due to multidrug resistant pathogens (MDR) in the intensive care unit. For effective treatment antibiotic stewardship teams (ABS team) are becoming more established. Interdisciplinary cooperation of the ABS team with infectiologists, microbiologists and clinical pharmacists leads not only to a rational administration of antibiotics but also has a positive influence on the outcome. The gold standards for pathogen detection are still culture-based detection and microbiological resistance testing for the various antibiotic groups. Despite the rapid investigation time, novel polymerase chain reaction (PCR)-based procedures for pathogen identification and resistance determination, are currently only an adjunct to routine sepsis diagnostics due to the limited number of studies, high costs and limited availability. In complicated septic courses with multiple anti-infective treatment or recurrent sepsis, PCR-based procedures can be used in addition to therapy monitoring and diagnostics. Novel antibiotics represent potent alternatives in the treatment of MDR infections. Due to the often defined spectrum of pathogens and the practically absent resistance, they are suitable for targeted treatment of severe MDR infections (therapy escalation).

[Strategies for antifungal treatment failure in intensive care units]. / Strategien bei Versagen einer antimykotischen Therapie auf Intensivstation.

Recent epidemiologic studies reveal both an increasing incidence and an escalation in resistance of invasive fungal infections in intensive care units. Primary therapy fails in 70 % of cases, depending on the underlying pathogens and diseases. The purpose of this review is to raise awareness for the topic of antifungal therapy failure, describe the clinical conditions in which it occurs, and suggest a possible algorithm for handling the situation of suspected primary therapy failure.

[Epidemiology, diagnosis and treatment of adult patients with nosocomial pneumonia. S-3 Guideline of the German Society for Anaesthesiology and Intensive Care Medicine, the German Society for Infectious Diseases, the German Society for Hygiene and Microbiology, the German Respiratory Society and the Paul-Ehrlich-Society for Chemotherapy]. / Epidemiologie, Diagnostik und Therapie erwachsener Patienten mit nosokomialer Pneumonie. S-3 Leitlinie der Deutschen Gesellschaft für Anästhesiologie und Intensivmedizin e.V., der Deutschen Gesellschaft für Infektiologie e.V., der Deutschen Gesellschaft für Hygiene und Mikrobiologie e.V., der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin e.V. und der Paul-Ehrlich-Gesellschaft für Chemotherapie e.V.

Nosocomial pneumonia (HAP) is a frequent complication of hospital care. Most data are available on ventilator-associated pneumonia. However infections on general wards are also increasing. A central issue are infections with multi drug resistant (MDR) pathogens which are difficult to treat particularly in the empirical setting potentially leading to inappropriate use of antimicrobial therapy. This guideline was compiled by an interdisciplinary group on the basis of a systematic literature review. Recommendations are made according to GRADE giving guidance for the diagnosis and therapy of HAP on the basis of quality of evidence and benefit/risk ratio. The guideline has two parts. First an update on epidemiology, spectrum of pathogens and antiinfectives is provided. In the second part recommendations for the management of diagnosis and treatment are given. Proper microbiologic work up is emphasized for knowledge of the local patterns of microbiology and drug susceptibility. Moreover this is the optimal basis for deescalation in the individual patient. The intensity of antimicrobial therapy is guided by the risk of infections with MDR. Structured deescalation concepts and strict limitation of treatment duration should lead to reduced selection pressure.

[Necrotizing fasciitis. 2011 update]. / Nekrotisierende Fasziitis. Update 2011.

Necrotizing fasciitis belongs to a group of complicated soft tissue infections that can be even life threatening. Despite growing knowledge about its etiology, predictors, and the clinical progression, the mortality remains at a high level with 20%. A relevant reduction can be achieved only by an early diagnosis followed by consistent therapy. The clinical findings in about 75% of the cases are pain out of proportion, edema and tenderness, blisters, and erythema. It is elementary to differentiate a necrotizing or a non-necrotizing soft tissue infection early. In uncertain cases it can be necessary to perform a surgical exploration to confirm the diagnosis. The histopathologic characteristics are the fascial necrosis, vasculitis, thrombosis of perforating veins, the presence of the disease-causing bacteria as well as inflammatory cells like macrophages and polymorphonuclear granulocytes. Secondly, both the cutis and the muscle can be affected. In many cases there is a disproportion of the degree of local and systemic symptoms. Depending on the infectious agents there are two main types: type I is a polymicrobial infection and type II is a more invasive, serious, and fulminant monomicrobial infection mostly caused by group A Streptococcus pyogenes.Invasive, severe forms of streptococcal infections seem to occur more often in recent years. Multimodal and interdisciplinary therapy should be based on radical surgical débridement, systemic antibiotic therapy as well as enhanced intensive care therapy, which is sometimes combined with immunoglobulins (in streptococcal or staphylococcal infections) or hyperbaric oxygen therapy (HBOT, in clostridial infections). For wound care of extensive soft tissue defects vacuum-assisted closure has shown its benefit.

Microbiological analysis of epidermal growth factor receptor inhibitor therapy-associated paronychia.

BACKGROUND: Paronychia is a well-known, but difficult to treat cutaneous toxicity associated with epidermal growth factor receptor (EGFR) inhibitor therapy. Although bacterial and fungal infections as well as mechanical trauma may play a role as co-pathogens, there is no good basis for an empirical antimicrobial chemotherapy in these patients. MATERIALS AND METHODS: We retrospectively analysed the microbiological results and resistance analysis of 42 cases of EGFR inhibitor-associated paronychia induced by cetuximab. RESULTS: We identified 20 different species, among these 72% Gram-positive bacteria, 23% Gram-negative bacteria and 5%Candida species. About half of the microbes identified may be considered as residential bacterial flora of the skin, but isolation of microbes from paronychia may indicate a pathogenic relevance for this type of reaction. Eight of our patients were treated with oral antibiotics, whereas two patients received oral antimycotic therapy. All other cases of paronychia were controlled using topical antiseptic, antibiotic and antimycotic agents. CONCLUSION: Empirical oral antibiotic treatment may be performed with oral cephalosporines, ciprofloxacin, levofloxacin or moxifloxacin, as these antimicrobials have high in vitro activity against the majority of the isolated microorganisms and reach high concentrations in the relevant tissue.

[Disseminated nocardiosis : Diagnostic challenge]. / Disseminierte Nocardiose : Diagnostische Herausforderung.

Nocardiosis is a rarely found bacterial infection in Europe which can particularly affect immunocompromized patients. Localized infections of the dermis and lungs, as well as disseminated infections can be observed. Suspicion of nocardiosis should be reported to the microbiological laboratory so that goal-directed molecular genetic techniques and extended cultivation can be implemented for identification of the causative agent. A multitude of antibiotics can be used for successful therapy but the duration of therapy must be extended over 6-12 months. The mortality of disseminated infections ranges between 15-85% depending on the underlying immune status of the patient. The polymorphic appearance of nocardiosis is described based on the case of an intensive care patient.

The ONTAI study - a survey on antimicrobial dosing and the practice of therapeutic drug monitoring in German intensive care units.

PURPOSE: Optimization of antibiotic therapy is still urgently needed in critically ill patients. The aim of the ONTAI survey (online survey on the use of Therapeutic Drug Monitoring of antibiotics in intensive care units) was to evaluate which strategies intensive care physicians in Germany use to improve the quality of antibiotic therapy and what role a Therapeutic Drug Monitoring (TDM) plays. METHODS: Among the members of the German Society for Anaesthesiology and the German Society for Medical Intensive Care Medicine and Emergency Medicine, a national cross-sectional survey was conducted using an online questionnaire. RESULTS: The questionnaire was completely answered by 398 respondents. Without TDM, prolonged infusion was judged to be the most appropriate dosing regimen for beta lactams. A TDM for piperacillin, meropenem and vancomycin was performed in 17, 22 and 75% of respondents, respectively. For all beta lactams, a TDM was requested more often than it was available. There was great uncertainty as to the optimal pharmacokinetic/pharmacodynamic index for beta-lactams. 86% of the respondents who received minimal inhibitory concentrations adapted the therapy accordingly. CONCLUSION: German intensive care physicians are convinced of TDM for dose optimization. However, practical implementation, the determination of MICs and defined target values are still lacking.

[Relevance of ESBL-producing pathogens for clinical surgery: diagnostics, therapy, and prevention]. / Bedeutung ESBL-produzierender Keime für die klinische Chirurgie : Diagnostik, Prävention und Therapie.

BACKGROUND: Multiresistant, extended spectrum beta lactamase (ESBL)-producing pathogens are an increasing problem in daily clinical life. This paper summarizes the development of resistance as well as epidemiology, diagnostics, and treatment of ESBL-producing micro-organisms. We analyzed microbiological data collected at the Grosshadern Clinic in Germany between 1996 and 2007, in order to assess the importance of these micro-organisms to medical practice and surgical care units. PATIENTS AND METHODS: Pathogens were isolated from 28,894 patients with Escherichia coli and 10,903 with Klebsiella pneumoniae pathogens between 1996 and 2006 and tested for ESBL production. For the year 2007 we have analyzed the complete spectrum of ESBL-producing pathogens and their distribution to different departments of the clinic. The agar diffusion test with five cephalosporins and an automated detection system (BD Phoenix) were used for screening purposes. Positive results were verified with the E- and double-disc agar diffusion tests. RESULTS: The most important pathogens isolated from patients were E. coli and K. pneumoniae. Analysis of ESBL-producing E. coli pathogens from 1996 to 2006 showed the prevalence increasing from 0% to 4.1%. For ESBL-producing K. pneumoniae, we also found a prevalence rising from 0.3% in 1996 to 6.6% in 2006. For the year 2007 a further increase in ESBL-producing pathogens was detected, reaching 182 cases, with 118 of ESBL-producing E. coli (5.7 %) and 39 of ESBL-producing K. pneumoniae (7.4%). Of these, 24 cases with E. coli and nine with K. pneumoniae were surgery patients (20% and 23%, respectively). CONCLUSION: The results show an increasing prevalence of ESBL-producing pathogens in hospitalized patients and in surgical departments. The resulting rise in treatment costs and patient risk require thorough knowledge of risk factors, therapy, and preventive measures.

Eradication of Acinetobacter baumannii/Enterobacter cloacae complex in an open proximal tibial fracture and closed drop foot correction with a multidisciplinary approach using the Taylor Spatial Frame®: a case report.

BACKGROUND: Multi-drug-resistant bacteria (e.g. Carbapenem-resistant Acinetobacter baumannii, extended-spectrum betalactamase or carbapenemase-producing enterobacteriaceae) are emerging in early-onset infections. So far, there is no report describing the eradication of these bacteria in a osseous infection of an open proximal tibial fracture in combination with the hexapod technology to address both osseous consolidation and closed drop foot correction. CASE PRESENTATION: After sustaining a proximal tibial fracture (Gustilo 3B), a 41-year-old man was primarily treated with open reduction and internal fixation by a locking plate and split-thickness skin graft in the home country. At the time of admission to our hospital there was a significant anterolateral soft tissue defect covered with an already-necrotic split-thickness graft and suspicious secretion. CAT and MRI scans revealed no signs of osseous healing, intramedullary distinctive osteomyelitis, as well as a large abscess zone in the dorsal compartment. Multiple wound smears showed multi-drug-resistant bacteria: Acinetobacter baumannii (Carbapenem resistant) as well as Enterobacter cloacae complex (AmpC overexpression). After implant removal, excessive osseous and intramedullary debridements using the Reamer Irrigator Aspirator (RIA®) as well as initial negative pressure wound therapy were performed. Colistin hand-modelled chains and sticks were applied topically as well as an adjusted systemic antibiotic scheme was applied. After repetitive surgical interventions, the smears showed bacterial eradication and the patient underwent soft tissue reconstruction with a free vascularized latissimus dorsi muscle flap. External fixation was converted to a hexapod fixator (TSF®) to correct primary varus displacement, axial assignment and secure osseous healing. A second ring was mounted to address the fixed drop foot in a closed fashion without further intervention. At final follow-up, 12 months after trauma, the patient showed good functional recovery with osseous healing, intact soft tissue with satisfactory cosmetics and no signs of reinfection. CONCLUSIONS: A multidisciplinary approach with orthopaedic surgeons for debridement, planning and establishing osseous and joint correction and consolidation, plastic surgeons for microvascular muscle flaps for soft tissue defect coverage as well as clinical microbiologists for the optimized anti-infective treatment is essential in these challenging rare cases. LEVEL OF EVIDENCE: Level IV.

[Multidrug resistant gram-negative bacteria : Clinical management pathway for patients undergoing elective interventions in visceral surgery]. / Multiresistente gramnegative Bakterien : Klinischer Managementpfad für Patienten mit elektiven Eingriffen in der Viszeralchirurgie.

BACKGROUND: Only a few antibiotics are available for treatment of infections with multidrug resistant gram-negative bacteria (MRGN). The management of patients with MRGN colonization or infection is therefore of great importance with respect to postoperative morbidity and mortality. OBJECTIVE: This article presents a description of the management pathway for patients with MRGN colonization. RESULTS: The prevalence of MRGN colonization is increasing, particularly for persons with contact to the healthcare system in endemic regions. The Robert Koch Institute demands an obligatory MRGN screening and isolation of patients with geographic or contact-related exposure risk for colonization with 4MRGN (carbapenemase producers). For patients with elective visceral interventions a prompt sensitive screening before inpatient admission is wise. Strict basic hygiene measures are essential to prevent transmission. Isolation is indicated for patients with 4MRGN and also for patients with 3MRGN in risk areas. Risk patients with unknown status are preemptively isolated. Perioperative antibiotic prophylaxis should be administered as a single dose and in cases of MRGN colonization substances effective against MRGN should be given if necessary. For treatment of secondary/tertiary peritonitis with a risk of MRGN involvement and in hemodynamically instable patients, effective extended spectrum beta-lactamase (ESBL) substances should primarily be used (e.g. tigecycline, carbapenems, ceftolozane/tazobactam and ceftazidim/avibactam). Ceftazidim/avibactam is also a novel therapy option for infections with carbapenamase-producing enterobacteria. CONCLUSION: The structured implementation of MRGN screening in patients at risk, stringent basic hygiene, targeted isolation and adequate calculated antibiotic therapy are essential measures in the management of the problem of MRGN in visceral surgery.

Intravenous fosfomycin-back to the future. Systematic review and meta-analysis of the clinical literature.

OBJECTIVES: We conducted a systematic review and meta-analysis to summarize the clinical evidence and usage patterns of intravenous fosfomycin from its development to the present time. METHODS: PubMed, the Cochrane Library and local journals were searched for relevant studies reporting aggregated data of intravenous fosfomycin use in adults and children, with no restrictions regarding study design. Single case reports were excluded. Data were systematically abstracted for all included studies. Clinical and microbiological efficacy from randomized controlled and comparative observational studies were synthesized using meta-analysis to calculate pooled effect sizes. RESULTS: In all, 128 studies on intravenous fosfomycin in 5527 patients were evaluated. Fosfomycin was predominantly used for sepsis/bacteraemia, urinary tract, respiratory tract, bone and joint, and central nervous system infections. No difference in clinical (OR 1.44, 95% CI 0.96-2.15) or microbiological (OR 1.28, 95% CI 0.82-2.01) efficacy between fosfomycin and other antibiotics was observed in comparative trials. The pooled estimate for resistance development during fosfomycin monotherapy was 3.4% (95% CI 1.8%-5.1%). Fosfomycin showed a favourable safety profile, with generally mild adverse events not requiring discontinuation of treatment. Included studies explored intravenous fosfomycin as an anti-staphylococcal agent in monotherapy and combination therapy, whereas studies from 1990 focused on combination therapy (fosfoymcin + ß-lactams or aminoglycosides) for challenging infections frequently caused by multidrug-resistant organisms. CONCLUSION: Intravenous fosfomycin can play a vital role in the antibiotic armamentarium, given its long history of effective and safe use. However, well-designed randomized controlled trials are still desired.