Impaired Semen Quality in Patients with Chronic Prostatitis.

Background/Objectives: Chronic prostatitis/chronic pelvic pain syndrome CP/CPPS is a rather common condition and in recent years many studies have shown contradictory results regarding its impact on semen quality. This prospective cohort study set out to investigate how CP/CPPS affected the parameters of semen in a prospective cohort of patients compared with the WHO 2021 reference group. Methods: From 2013 to 2022, a total of 1071 patients with suspicion of CP/CPPS received a comprehensive andrological examination. Complete semen analysis was carried out in compliance with WHO 2010 guidelines, comparing every study population semen variable to the WHO 2021 reference group (n~3500). Results: All evaluated semen parameters had median values that fell within a normal range. Nonetheless, approximately 25% of patients had values for each semen variable that were lower than the WHO reference group's fifth percentile. In particular, bacteriospermia was associated with a negative impact on semen volume. Conclusions: This is the largest study that compares all standard semen parameters in patients suffering from CP/CPPS to WHO 2021 reference values. It provides evidence of an impairment of conventional semen parameters.

Epidemiological trends and susceptibility patterns of bloodstream infections caused by Enterococcus spp. in six German university hospitals: a prospectively evaluated multicentre cohort study from 2016 to 2020 of the R-Net study group.

PURPOSE: To analyse recent epidemiological trends of bloodstream infections (BSI) caused by Enterococcus spp. In adult patients admitted to tertiary care centres in Germany. METHODS: Epidemiological data from the multicentre R-NET study was analysed. Patients presenting with E. faecium or E. faecalis in blood cultures in six German tertiary care university hospitals between October 2016 and June 2020 were prospectively evaluated. In vancomycin-resistant enterococci (VRE), the presence of vanA/vanB was confirmed via molecular methods. RESULTS: In the 4-year study period, 3001 patients with BSI due to Enterococcus spp. were identified. E. faecium was detected in 1830 patients (61%) and E. faecalis in 1229 patients (41%). Most BSI occurred in (sub-) specialties of internal medicine. The pooled incidence density of enterococcal BSI increased significantly (4.0-4.5 cases per 10,000 patient days), which was primarily driven by VRE BSI (0.5 to 1.0 cases per 10,000 patient days). In 2020, the proportion of VRE BSI was > 12% in all study sites (range, 12.8-32.2%). Molecular detection of resistance in 363 VRE isolates showed a predominance of the vanB gene (77.1%). CONCLUSION: This large multicentre study highlights an increase of BSI due to E. faecium, which was primarily driven by VRE. The high rates of hospital- and ICU-acquired VRE BSI point towards an important role of prior antibiotic exposure and invasive procedures as risk factors. Due to limited treatment options and high mortality rates of VRE BSI, the increasing incidence of VRE BSI is of major concern.

New Perianal Sepsis Risk Score Predicts Outcome of Elderly Patients with Perianal Abscesses.

Antibiotic therapy following surgical perianal abscess drainage is debated, but may be necessary for high-risk patients. Frailty has been shown to increase the risk of unfavorable outcomes in elderly surgical patients. This study aims to identify high-risk patients by retrospectively analyzing a single-center cohort and using a pretherapeutic score to predict the need for postoperative antibiotics and extended nursing care following perianal abscess drainage surgery. The perianal sepsis risk score was developed through univariable and multivariable analysis. Internal validation was assessed using the area under receiver-operating characteristic curve. Elderly, especially frail patients exhibited more severe perianal disease, higher frequency of antibiotic therapy, longer hospitalization, poorer clinical outcomes. Multivariable analysis revealed that scores in the 5-item modified frailty index, severity of local infection, and preoperative laboratory markers of infection independently predicted the need for prolonged hospitalization and anti-infective therapy after abscess drainage surgery. These factors were combined into the perianal sepsis risk score, which demonstrated better predictive accuracy for prolonged hospitalization and antibiotic therapy compared with chronological age or frailty status alone. Geriatric assessments are becoming increasingly important in clinical practice. The perianal sepsis risk score identifies high-risk patients before surgery, enabling early initiation of antibiotic therapy and allocation of additional nursing resources.

The microbiome landscape in pediatric Crohn's disease and therapeutic implications.

Dysbiosis of the gut microbiome and a pathological immune response in intestinal tissues form the basis of Crohn's disease (CD), which is a debilitating disease with relevant morbidity and mortality. It is increasing in childhood and adolescents, due to western life-style and nutrition and a large set of predisposing genetic factors. Crohn's disease-associated genetic mutations play an essential role in killing pathogens, altering mucosal barrier function, and protecting the host microbiome, suggesting an important pathogenic link. The intestinal microbiome is highly variable and can be influenced by environmental factors. Changes in microbial composition and a reduction in species diversity have been shown to be central features of disease progression and are therefore the target of therapeutic approaches. In this review, we summarize the current literature on the role of the gut microbiome in childhood, adolescent, and adult CD, current therapeutic options, and their impact on the microbiome.

Acute orchitis deciphered: Coxsackievirus B strains are the main etiology and their presence in semen is associated with acute inflammation and risk of persistent oligozoospermia.

Although various viruses are considered to be the clinical cause for acute orchitis, it is completely unclear to what extent and which viruses are etiologically involved in acute orchitis and what the clinic and course of these patients are like. Therefore, a prospective study was set up to decipher acute isolated orchitis. Between July 2007 and February 2023, a total of 26 patients with isolated orchitis were recruited and compared with 530 patients with acute epididymitis. We were able to show for isolated orchitis, that (1) orchitis is usually of viral origin (20/26, 77%) and enteroviruses with coxsackievirus B strains (16/26, 62%) are predominant, (2) virus isolates could be received from semen indicating the presence of replication-competent virus particles, (3) a polymerase chain reaction (PCR) for enteroviruses should be conducted using semen provided at the onset of disease, because the virus is not detectable in serum/urine, (4) there is a circannual occurrence with the maximum in summer, (5) orchitis is associated with a characteristic inflammatory cytokine panel in the semen and systemic inflammation, (6) orchitis is usually rapidly self-limiting, and (7) about 30% of patients (6/20) suffer ongoing oligozoospermia. These seven emerging aspects are likely to fundamentally change thinking and clinical practice regarding acute isolated orchitis.

Comprehensive evaluation of hematospermia in patients with acute epididymitis compared to patients with isolated hematospermia.

BACKGROUND: Among the most commonly known causes of hematospermia are infections in the genitourinary tract, but no study exists that has comprehensively investigated hematospermia in patients with acute epididymitis. OBJECTIVES: To assess the impact of hematospermia in patients with acute epididymitis and its association with clinical, microbiological, and semen parameters. MATERIALS AND METHODS: Since May 2007, a total of 324 sexually active patients with acute epididymitis were recruited in a prospective cohort study. Patients received a comprehensive medical and sexual history, and clinical, sonographic, laboratory, and microbiological diagnostics. Antibiotic therapy was given according to European Association of Urology guidelines. Semen analysis was offered 14 days after the first presentation and initiation of therapy. Since 2013, a separate control group of 56 patients presenting with isolated hematospermia (= no other urogenital symptoms) was prospectively recruited, and differences between the groups were statistically evaluated. RESULTS: Of 324 patients with acute epididymitis, 50 patients (15%) had self-reported hematospermia. This occurred with a median of 24 h before the onset of scrotal symptoms and was associated with significantly elevated prostate-specific antigen levels compared to 274 patients without hematospermia (3.1 vs. 1.8 ng/ml, p < 0.01). The two most common etiological pathogens were Escherichia coli and Chlamydia trachomatis, and the bacterial spectrum was comparable in both epididymitis subgroups (p = 0.859). Semen analysis at 14 days still showed hematospermia in 24% of patients associated with massive leukocytospermia. Compared to the hematospermia control group, the two epididymitis subgroups showed significantly increased inflammation markers (pH, leukocytes, and elastase), reduced sperm concentration, and reduced levels of alpha-glucosidase and zinc (always p < 0.01). DISCUSSION AND CONCLUSION: In sexually active patients who develop acute epididymitis, self-reported hematospermia is evident in 15% of patients as early as one day before the onset of scrotal symptoms. Conversely, none of the 56 patients presenting with isolated hematospermia developed epididymitis within the next 4 weeks.

Increasing numbers and complexity of Staphylococcus aureus bloodstream infection-14 years of prospective evaluation at a German tertiary care centre with multi-centre validation of findings.

OBJECTIVES: Staphylococcus aureus bloodstream infection (SAB) is a common and severe infection. This study aims to describe temporal trends in numbers, epidemiological characteristics, clinical manifestations, and outcomes of SAB. METHODS: We performed a post-hoc analysis of three prospective SAB cohorts at the University Medical Centre Freiburg between 2006 and 2019. We validated our findings in a large German multi-centre cohort of five tertiary care centres (R-Net consortium, 2017-2019). Time-dependent trends were estimated using Poisson or beta regression models. RESULTS: We included 1797 patients in the mono-centric and 2336 patients in the multi-centric analysis. Overall, we observed an increasing number of SAB cases over 14 years (6.4%/year and 1000 patient days, 95% CI: 5.1% to 7.7%), paralleled by an increase in the proportion of community-acquired SAB (4.9%/year [95% CI: 2.1% to 7.8%]) and a decrease in the rate of methicillin-resistant-SAB (-8.5%/year [95% CI: -11.2% to -5.6%]). All of these findings were confirmed in the multi-centre validation cohort (6.2% cases per 1000 patient cases/year [95% CI: -0.6% to 12.6%], community-acquired-SAB 8.7% [95% CI: -1.2% to 19.6%], methicillin-resistant S. aureus-SAB -18.6% [95% CI: -30.6 to -5.8%]). Moreover, we found an increasing proportion of patients with multiple risk factors for complicated/difficult-to-treat SAB (8.5%/year, 95% CI: 3.6% to 13.5%, p < 0.001), alongside an overall higher level of comorbidities (Charlson comorbidity score 0.23 points/year, 95% CI: 0.09 to 0.37, p 0.005). At the same time, the rate of deep-seated foci such as osteomyelitis or deep-seated abscesses significantly increased (6.7%, 95% CI: 3.9% to 9.6%, p < 0.001). A reduction of in-hospital mortality by 0.6% per year (95% CI: 0.08% to 1%) was observed in the subgroup of patients with infectious diseases consultations. DISCUSSION: We found an increasing number of SAB combined with a significant increase in comorbidities and complicating factors in tertiary care centres. The resulting challenges in securing adequate SAB management in the face of high patient turnover will become an important task for physicians.

Drug resistant bacteria in perianal abscesses are frequent and relevant.

Perianal abscesses are frequent diseases in general surgery. Principles of standard patient care are surgical drainage with exploration and concomitant treatment of fistula. Antiinfective therapy is frequently applied in cases of severe local disease and perianal sepsis. However, the role of microbiologic testing of purulence from perianal abscesses is disputed and the knowledge concerning bacteriology and bacterial resistances is very limited. A retrospective cohort study was performed of consecutive patients (≥ 12 years of age) from a tertiary care hospital, who underwent surgical treatment for perianal abscess from 01/2008 to 12/2019. Subdividing the cohort into three groups regarding microbiological testing results: no microbiological testing of purulence (No_Swab, n = 456), no detection of drug resistant bacteria [DR(-), n = 141] or detection of bacteria with acquired drug resistances from purulence [DR(+), n = 220]. Group comparisons were performed using Kruskall-Wallis test and, if applicable, followed by Dunn´s multiple comparisons test for continuous variables or Fishers exact or Pearson's X2 test for categorical data. Fistula persistence was estimated by Kaplan Meier and compared between the groups using Log rank test. Corralation analysis between perioperative outcome parameters and bacteriology was performed using Spearman´s rho rank correlation. Higher pretherapeutic C-reactive protein (p < 0.0001) and white blood cell count (p < 0.0001), higher rates of supralevatoric or pararectal abscesses (p = 0.0062) and of complicated fistula-in-ano requiring drainage procedure during index surgery (p < 0.0001) reflect more severe diseases in DR(+) patients. The necessity of antibiotic therapy (p < 0.0001), change of antibiotic regimen upon microbiologic testing results (p = 0.0001) and the rate of re-debridements during short-term follow-up (p = 0.0001) were the highest, the duration until definitive fistula repair was the longest in DR(+) patients (p = 0.0061). Escherichia coli, Bacteroides, Streptococcus and Staphylococcus species with acquired drug resistances were detected frequently. High rates of resistances against everyday antibiotics, including perioperative antibiotic prophylaxis were alarming. In conclusion, the knowledge about individual bacteriology is relevant in cases of complex and severe local disease, including locally advanced infection with extended soft tissue affection and perianal sepsis, signs of systemic inflammatory response as well as the need of re-do surgery for local debridements during short-term and fistula repair during long-term follow-up. Higher rates of acquired antibiotic resistances are to be expected in patients with more severe diseases.

Hodgkin Lymphoma after Disseminated Mycobacterium genavense Infection, Germany.

Mycobacterium genavense infection, a rare nontuberculous mycobacteria infection, occurs in heavily immunocompromised patients (i.e., those with advanced HIV disease, genetic disorders, or acquired immunologic disorders and those undergoing immunosuppressive therapy). We report a case of disseminated M. genavense infection preceding Hodgkin lymphoma in a patient without obvious risk factors for this infection.

Comparison of Urine Flow Cytometry on the UF-1000i System and Urine Culture of Urine Samples from Urological Patients.

INTRODUCTION: The aims of this study were to evaluate urine flow cytometry (UFC) as a tool to screen urine samples of urological patients for bacteriuria and to compare UFC and dipstick analysis with urine culture in a patient cohort at a urological department of a university hospital. METHODS AND MATERIAL: We screened 662 urine samples from urological patients (75.2% male; 80.7% inpatients; mean age 58 years). UFC results were compared to microbiological urine culture. RESULTS: The accuracy in using the UFC-based parameters for detecting cultural bacteriuria was 91.99% and 88.97% for ≥105 colony-forming units (CFU)/mL and ≥104 CFU/mL, respectively. UFC and leukocyte dipstick analysis measured leukocyturia similarly (Pearson correlation coefficient 0.87, p value <0.01%), but dipstick analysis scored less accurately on bacteriuria (accuracy 59.37% and 62.69%). UFC remained effective in subgroup analysis of patients of both sexes and with different urological conditions with its overall use only slightly impaired when assessing gross hematuria (NPV 84.62% for ≥104 CFU/mL). UFC also reliably removed those urine samples below cutoffs with negative predictive values of 99.28% for ≥105 CFU/mL and 95.86% for ≥104 CFU/mL. CONCLUSION: Counting bacteria with UFC is an accurate and rapid method to determine significant bacteriuria in urological patients and is superior to dipstick analysis or indirect surrogate parameters such as leukocyturia. When UFC is available, we recommend it to be used for the diagnosis of bacteriuria over findings obtained by dipstick analysis.

Changing epidemiology of vancomycin-resistant Enterococcus faecium: Results of a genome-based study at a regional neurological acute hospital with intensive care and early rehabilitation treatment.

BACKGROUND: Vancomycin-resistant Enterococcus faecium (VREfm) are an emerging threat worldwide. In Germany, a VRE-belt with higher VREfm prevalences transversing its central east-west axis and including the state of Hesse was previously described. Recently, we detected a predominant VREfm clone in hospitals throughout the Rhine-Main metropolitan area of Hesse. AIM: Here we expanded our study on VREfm to a regional neurological acute hospital outside of the metropolitan area with patient referrals from throughout Hesse and the neighboring federal state of Rhineland-Palatinate. MATERIAL/METHODS: VREfm isolates obtained between 2016-2018 from a regional neurological acute hospital with intensive care and early rehabilitation units were investigated (n=55). Patient data was collected and analyzed together with whole-genome sequencing data to investigate antibiotic resistance and virulence determinants of the VREfm. The population structure of VREfm was investigated using the Core genome-based multilocus sequence typing (cgMLST). FINDINGS: The average age of the patients was 67.1 years. For 96% of the patients, a previous hospital stay was reported. 64% of the patients were treated with antibiotics. All VREfm harbored the vanB vancomycin resistance gene. The multilocus sequence types (STs) detected changed abruptly from four different STs in 2016 to a predominant ST in 2017 and 2018 (ST117). Most of the ST117 isolates were members of the cgMLST type CT71. CONCLUSION: The results indicate a sudden shift of the VREfm population structure from a semi-heterogeneous population to a pre-dominant clone within an interval of two years. Further investigations are warranted to understand the epidemiology and emergence of this clone.

Needs for an Integration of Specific Data Sources and Items - First Insights of a National Survey Within the German Center for Infection Research.

State-subsidized programs develop medical data integration centers in Germany. To get infection disease (ID) researchers involved in the process of data sharing, common interests and minimum data requirements were prioritized. In 06/2019 we have initiated the German Infectious Disease Data Exchange (iDEx) project. We have developed and performed an online survey to determine prioritization of requests for data integration and exchange in ID research. The survey was designed with three sub-surveys, including a ranking of 15 data categories and 184 specific data items and a query of available 51 data collecting systems. A total of 84 researchers from 17 fields of ID research participated in the survey (predominant research fields: gastrointestinal infections n=11, healthcare-associated and antibiotic-resistant infections n=10, hepatitis n=10). 48% (40/84) of participants had experience as medical doctor. The three top ranked data categories were microbiology and parasitology, experimental data, and medication (53%, 52%, and 47% of maximal points, respectively). The most relevant data items for these categories were bloodstream infections, availability of biomaterial, and medication (88%, 87%, and 94% of maximal points, respectively). The ranking of requests of data integration and exchange is diverse and depends on the chosen measure. However, there is need to promote discipline-related digitalization and data exchange.

Amidochelocardin Overcomes Resistance Mechanisms Exerted on Tetracyclines and Natural Chelocardin.

The reassessment of known but neglected natural compounds is a vital strategy for providing novel lead structures urgently needed to overcome antimicrobial resistance. Scaffolds with resistance-breaking properties represent the most promising candidates for a successful translation into future therapeutics. Our study focuses on chelocardin, a member of the atypical tetracyclines, and its bioengineered derivative amidochelocardin, both showing broad-spectrum antibacterial activity within the ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) panel. Further lead development of chelocardins requires extensive biological and chemical profiling to achieve favorable pharmaceutical properties and efficacy. This study shows that both molecules possess resistance-breaking properties enabling the escape from most common tetracycline resistance mechanisms. Further, we show that these compounds are potent candidates for treatment of urinary tract infections due to their in vitro activity against a large panel of multidrug-resistant uropathogenic clinical isolates. In addition, the mechanism of resistance to natural chelocardin was identified as relying on efflux processes, both in the chelocardin producer Amycolatopsis sulphurea and in the pathogen Klebsiella pneumoniae. Resistance development in Klebsiella led primarily to mutations in ramR, causing increased expression of the acrAB-tolC efflux pump. Most importantly, amidochelocardin overcomes this resistance mechanism, revealing not only the improved activity profile but also superior resistance-breaking properties of this novel antibacterial compound.

Vancomycin-resistant Enterococcus faecium colonizing patients on hospital admission in Germany: prevalence and molecular epidemiology.

OBJECTIVES: To analyse the rectal carriage rate and the molecular epidemiology of vancomycin-resistant Enterococcus faecium (VREfm) recovered from patients upon hospital admission. METHODS: Adult patients were screened at six German university hospitals from five different federal states upon hospital admission for rectal colonization with VREfm between 2014 and 2018. Molecular characterization of VREfm was performed by WGS followed by MLST and core-genome MLST analysis. RESULTS: Of 16350 patients recruited, 263 were colonized with VREfm, with increasing prevalence rates during the 5 year study period (from 0.8% to 2.6%). In total, 78.5% of the VREfm were vanB positive and 20.2% vanA positive, while 1.2% harboured both vanA and vanB. The predominant ST was ST117 (56.7%) followed by ST80 (15%), ST203 (10.9%), ST78 (5.7%) and ST17 (3.2%). ST117/vanB VREfm isolates formed a large cluster of 96 closely related isolates extending across all six study centres and four smaller clusters comprising 13, 5, 4 and 3 isolates each. In contrast, among the other STs inter-regional clonal relatedness was rarely observed. CONCLUSIONS: To our knowledge, this is the largest admission prevalence and molecular epidemiology study of VREfm. These data provide insight into the epidemiology of VREfm at six German university hospitals and demonstrate the remarkable inter-regional clonal expansion of the ST117/vanB VREfm clone.

Correction: The Mitochondrial Genomes of the Zoonotic Canine Filarial Parasites Dirofilaria (Nochtiella) repens and Candidatus Dirofilaria (Nochtiella) Honkongensis Provide Evidence for Presence of Cryptic Species.

[This corrects the article DOI: 10.1371/journal.pntd.0005028.].

ASA3P: An automatic and scalable pipeline for the assembly, annotation and higher-level analysis of closely related bacterial isolates.

Whole genome sequencing of bacteria has become daily routine in many fields. Advances in DNA sequencing technologies and continuously dropping costs have resulted in a tremendous increase in the amounts of available sequence data. However, comprehensive in-depth analysis of the resulting data remains an arduous and time-consuming task. In order to keep pace with these promising but challenging developments and to transform raw data into valuable information, standardized analyses and scalable software tools are needed. Here, we introduce ASA3P, a fully automatic, locally executable and scalable assembly, annotation and analysis pipeline for bacterial genomes. The pipeline automatically executes necessary data processing steps, i.e. quality clipping and assembly of raw sequencing reads, scaffolding of contigs and annotation of the resulting genome sequences. Furthermore, ASA3P conducts comprehensive genome characterizations and analyses, e.g. taxonomic classification, detection of antibiotic resistance genes and identification of virulence factors. All results are presented via an HTML5 user interface providing aggregated information, interactive visualizations and access to intermediate results in standard bioinformatics file formats. We distribute ASA3P in two versions: a locally executable Docker container for small-to-medium-scale projects and an OpenStack based cloud computing version able to automatically create and manage self-scaling compute clusters. Thus, automatic and standardized analysis of hundreds of bacterial genomes becomes feasible within hours. The software and further information is available at: asap.computational.bio.

Complete Genome Sequence of the Plant Growth-Promoting Bacterium Hartmannibacter diazotrophicus Strain E19T.

Strain E19T described as Hartmannibacter diazotrophicus gen. nov. sp. nov. was isolated from the rhizosphere of Plantago winteri from a natural salt meadow in a nature protection area. Strain E19T is a plant growth-promoting rhizobacterium able to colonize the rhizosphere of barley and to promote its growth only under salt stress conditions. To gain insights into the genetic bases of plant growth promotion and its lifestyle at the rhizosphere under salty conditions, we determined the complete genome sequence using two complementary sequencing platforms (Ilumina MiSeq and PacBio RSII). The E19T genome comprises one circular chromosome and one plasmid containing several genes involved in salt adaptation and genes related to plant growth-promoting traits under salt stress. Based on previous experiments, ACC deaminase activity was identified as a main mechanism of E19T to promote plant growth under salt stress. Interestingly, no genes classically reported to encode for ACC deaminase activity are present. In general, the E19T genome provides information to confirm, discover, and better understand many of its previously evaluated traits involved in plant growth promotion under salt stress. Furthermore, the complete E19T genome sequence helps to define its previously reported unclear 16S rRNA gene-based phylogenetic affiliation. Hartmannibacter forms a distinct subcluster with genera Methylobrevis, Pleomorphomonas, Oharaeibacter, and Mongoliimonas subclustered with genera belonging to Rhizobiales.

Near-ubiquitous presence of a vancomycin-resistant Enterococcus faecium ST117/CT71/vanB -clone in the Rhine-Main metropolitan area of Germany.

Whole-genome sequencing analysis of Vancomycin-resistant Enterococcus faecium isolates from the Frankfurt metropolitan region revealed that 78/94 isolates were MLST type ST117, cgMLST complex type CT71 with a common vanB chromosomal insertion site. This indicates circulation of a single VRE clone in a catchment area of 5,000-km2 with 3 million inhabitants.

Genome Sequence of Listeria monocytogenes 2542, a Serotype 4b Strain from a Cheese-Related Outbreak in Portugal.

We report here the draft genome sequence of Listeria monocytogenes 2542, a serotype 4b clinical strain recovered from a placental sample during a cheese-related listeriosis outbreak in Portugal.

Treatment Options for Carbapenem- Resistant Gram-Negative Infections.

BACKGROUND: Rates of colonization and infection with carbapenem-resistant Gram-negative pathogens are on the rise, particularly in southeastern European countries, and this is increasingly true in Germany as well. The organisms in question include enterobacteriaceae such as Klebsiella pneumoniae and Escherichia coli and non-fermenting bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii. As the carbapenems have been the gold standard to date for the systemic treatment of serious infections with Gram-negative bacteria, carbapenem resistance presents new and difficult challenges in therapeutic decision-making, particularly because of the high frequency of coresistance. METHODS: This review is based on pertinent publications retrieved by a selective search in PubMed and on other applicable literature. RESULTS: Multiresistant Gram-negative (MRGN) pathogens are classified in Germany according to their resistance to four different classes of antibiotics; fluoroquinolones, piperacillin, third-generation cephalosporins, and carbapenems. Quadruple MRGN pathogens are resistant to all four groups, triple MRGN pathogens to three of them. There are a number of therapeutic alternatives to carbapenems that can be applied with the aid of sensitive microbiological and/or molecular genetic testing. The following antibiotics are often the only ones that can be used to treat quadruple MRGN pathogens: colistin, aminoglycosides, tigecycline, fosfomycin, ceftazidime/avibactam, and ceftolozan/tazobactam. Carbapenems, too, may still be an option in certain situations. There is also evidence that combinations of antibiotics against which the pathogen is resistant individually can some- times be a valid treatment option; these include combinations of colistin with one or two carbapenems. CONCLUSION: The treatment of severe infection with carbapenem-resistant pathogens should be individualized and carried out in an interdisciplinary framework, in consideration of antibiotic pharmacokinetics and pharmacodynamics in each case. The treat- ment options are based on evidence from in vitro studies, retrospective studies, and case series, which must be interpreted with caution. Randomized clinical trials are needed to test each of the various combined approaches.