Multidrug-resistant Gram-negative Research Articles

The volatile organic compounds detection in MDR Gram-negatives antimicrobial susceptibility testing: Results from a four-month laboratory experience

Systemic bacterial infections represent a significant clinical challenge due to the increasing resistance rate towards antimicrobials. An essential key to controlling antimicrobial resistance spread is to administer targeted therapy after a precise minimum inhibitory concentration reporting. Among the available fast technologies for antimicrobial susceptibility testing (AST), the VITEKⓇ REVEAL™ (Biomerieux, Florence, Italy) proposes volatile organic compounds (VOC) colourimetric arrays to discriminate between susceptible and resistant Gram-negative isolates directly from positive blood cultures. We evaluated this methodology during a four-month laboratory experience on 40 positive blood culture samples, reporting a comparison to standard culture-based methods. The protocol revealed an essential agreement of 100 % between the conventional and the experimental procedures, while the categorical agreement resulted in 97.5 % due to one very major error (VME) for meropenem/vaborbactam in K. pneumoniae. Although further studies will be necessary to investigate its performance on rare microorganisms, the VITEKⓇ REVEAL™ demonstrated an optimal sensitivity in defining MIC values for multi-drug resistant (MDR) microorganisms. These results encourage the application of the method in all high-risk epidemiological areas, confirming the effectiveness of VOC detection in monitoring bacterial susceptibility profiles.

Retrospective ANalysis of multi-drug resistant Gram-nEgative bacteRia on veno-venous extracorporeal membrane oxygenation. The multicenter RANGER STUDY

BackgroundVeno-venous extracorporeal membrane oxygenation (V-V ECMO) is a rapidly expanding life-support technique worldwide. The most common indications are severe hypoxemia and/or hypercapnia, unresponsive to conventional treatments, primarily in cases of acute respiratory distress syndrome. Concerning potential contraindications, there is no mention of microbiological history, especially related to multi-drug resistant (MDR) bacteria isolated before V-V ECMO placement. Our study aims to investigate: (i) the prevalence and incidence of MDR Gram-negative (GN) bacteria in a cohort of V-V ECMOs; (ii) the risk of 1-year mortality, especially in the case of predetected MDR GN bacteria; and (iii) the impact of annual hospital V-V ECMO volume on the probability of acquiring MDR GN bacteria.MethodsAll consecutive adults admitted to the Intensive Care Units of 5 Italian university-affiliated hospitals and requiring V-V ECMO were screened. Exclusion criteria were age < 18 years, pregnancy, veno-arterial or mixed ECMO-configuration, incomplete records, survival < 24 h after V-V ECMO. A standard protocol of microbiological surveillance was applied and MDR profiles were identified using in vitro susceptibility tests. Cox-proportional hazards models were applied for investigating mortality.ResultsTwo hundred and seventy-nine V-V ECMO patients (72% male) were enrolled. The overall MDR GN bacteria percentage was 50%: 21% (n.59) detected before and 29% (n.80) after V-V ECMO placement. The overall 1-year mortality was 42%, with a higher risk observed in predetected patients (aHR 2.14 [1.33–3.47], p value 0.002), while not in ‘V-V ECMO-acquired MDR GN bacteria’ group (aHR 1.51 [0.94–2.42], p value 0.090), as compared to ‘non-MDR GN bacteria’ group (reference). Same findings were found considering only infections. A larger annual hospital V-V ECMO volume was associated with a lower probability of acquiring MDR GN bacteria during V-V ECMO course (aOR 0.91 [0.86–0.97], p value 0.002).Conclusions21% of MDR GN bacteria were detected before; while 29% after V-V ECMO connection. A history of MDR GN bacteria, isolated before V-V ECMO, was an independent risk factor for mortality. The annual hospital V-V ECMO volume affected the probability of acquiring MDR GN bacteria.Trial Registration ClinicalTrial.gov Registration Number NCTNCT06199141, date 12.26.2023.

Nontoxic and proteolytic-resistant self-assembled peptide dendrimer aggregates to combat multidrug-resistant gram-negative bacterial infections

Peptide-based antimicrobial biomaterials hold considerable promise to treat the prevalent infections caused by multidrug-resistant (MDR) pathogens. However, their clinical translation is hampered by high toxicity, proteolytic degradation, and poorly understood in vivo efficacy. Here, we present a novel multi-functional blocks intelligent combination approach to create low-toxicity and proteolytic-resistant self-assembled peptide dendrimer aggregates (SPDAs) that exhibit low-micromolar activity (≤4 μM) against gram-negative bacteria and MDR Escherichia coli. We investigated the in vivo biosafety of SPDAs and found that they were substantially less systemically toxic than polymyxin B at the same dose. In a peritonitis-sepsis mouse model, the SPDAs demonstrated significant in vivo therapeutic potential for the treatment of MDR E. coli infections. Importantly, the antimicrobial activity of the SPDAs was exerted via multimodal mechanism that included rapid plasma membrane rupture, interference with cellular growth and metabolism, and triggering reactive oxygen species accumulation. Collectively, SPDAs show tremendous promise in addressing the prevalent infections caused by MDR gram-negative pathogens, and these findings may offer unique insights that will inspire the development of novel peptide-based therapeutics.

Risk Factors for Multi-Drug Resistant Gram-negative Infections across a Pediatric Hospital System

Background: Infections due to antibiotic resistant bacteria are increasing worldwide and while, the epidemiology of these pathogens is well described in adults, pediatric specific data are lacking. We sought to gain an understanding of the risk factors for multi-drug resistant Gram-negative (MDRGN) infections in our pediatric population. Methods: We performed a retrospective review of pediatric patients seen at a pediatric hospital system in 2022 who had a culture-positive MDRGN, which was defined as a gram-negative bacteria resistant or intermediate to at least 1 antibiotic in ≥ 3 antibiotic groups. Repeat positive cultures for the same MDRGN were considered a single infection episode if occurring within a 14-day period. Demographic, clinical, and microbiologic data was obtained from the electronic medical record. Fisher’s exact was used for analysis. Results: One hundred and seventy-nine children had 237 infection episodes during the study period. Eighty-one patients (45%) were male and the median age was 5.3 years. The most prevalent MDRGNs included: Escherichia coli (154, 65%), Klebsiella spp (52, 22%), and Enterobacter spp (16, 7%). Escherichia coli was significantly more likely than other pathogens to be isolated from the urine (P = 0.008). Compared to multi-drug resistant E. coli, patients with a non-E. coli MDRGN were significantly more likely to have an underlying medical condition, recent hospitalization and antibiotic use (P≤0.001 for each, Table 1). A carbapenem was administered in 32% (75/237) of infection episodes. There were only 6 carbapenem resistant organisms. Conclusions: In our study, E. coli was the most frequent MDRGN. Most patients with a non-E. coli MDRGN infection episode had an underlying medical condition, recent hospitalization and antibiotic use. Carbapenem resistance was infrequent, though surveillance studies are needed to identify changing antibiotic resistance patterns and to direct prevention measures.

Impact of Discontinuing Contact Precautions for Multidrug-resistant Gram-negative Enterobacteriaceae in a Large Health System

Background: Contact precautions (CP) to prevent transmission of multidrug-resistant gram-negative (MDRGN) Enterobacteriaceae are recommended, although studies of discontinuation of CP (DcCP) have found no change in healthcare associated infections (HAI) due to extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae. Limited data exists on DcCP for MDRGN in a large health system. Methods: We performed a retrospective observational study analyzing the relationship between use of CP and HAI due to two definitions of MDRGN Enterobacteriaceae: ESBL, and non-susceptibility to ≥3 drug classes (3DC-GNR), with carbapenem resistant Enterobacteriaceae (CRE) serving as control. The study included all inpatient admissions from 2/2017 through 9/2022 at 21 acute care hospitals. Hospitals had latitude to determine CP practices based on local risk assessment, but in 2/2018, system-wide transmission-based precautions guidance was updated to recommend DcCP for MDRGN Enterobacteriaceae and in 12/2019 was updated to clarify DcCP specifically for ESBL and 3DC-GNR while continuing CP for carbapenem-resistant organism carriage. We interviewed infection preventionists to define when CP were used for CRE, ESBL, and 3DC-GNR Enterobacteriaceae. HAI were defined using National Healthcare Safety Network criteria including all HAI categories. We compared the incidence rate of HAI attributable to the two MDRGN types in hospital months with and without use of CP, with HAI due to CRE as a comparison group since all hospitals used CP for CRE throughout the study period. Results: The periods of CP use, by hospital, are shown in Figure 1. Throughout the study period, there were 987 HAI attributed to ESBL Enterobacteriaceae, 579 due to 3DC-GNR Enterobacteriaceae, and 329 due to CRE. Figure 2 shows the unadjusted aggregate rate of HAI for each of the three MRGN types, including among hospitals with and without CP in each month, for ESBL and 3DC-GNR. In months with and without CP, the rate of HAI was 1.482/10,000 and 1.093/10,000 patient days (incidence rate ratio [IRR], 1.356 [95% confidence interval, 1.195-1.540]) for ESBL Enterobacteriaceae. In months with and without CP, the rate of HAI was 1.071/10,000 and 0.493/10,000 patient days (IRR,2.173[95% confidence interval, 1.838-2.569]) for 3DC-GNR Enterobacteriaceae. Conclusion: DcCP was not associated with an increase in HAI due to ESBL and 3DC-GNR Enterobacteriaceae in aggregated facilities that self-selected for DcCP. Facilities that used CP were associated with significantly higher rates of ESBL and 3DC-GNR Enterobacteriaceae, a relationship that did not change as hospitals DcCP for these MDRGN. Further analyses are necessary to assess for a causal relationship.

Antimicrobial efficacy of Punica granatum Lythraceae peel extract against pathogens belonging to the ESKAPE group.

The improper use and abuse of antibiotics have led to an increase in multidrug-resistant (MDR) bacteria resulting in a failure of standard antibiotic therapies. To date, this phenomenon represents a leading public health threat of the 21st century which requires alternative strategies to fight infections such as the identification of new molecules active against MDR strains. In the last 20 years, natural extracts with biological activities attracted scientific interest. Following the One Health Approach, natural by-products represent a sustainable and promising alternative solution. Consistently, the aim of the present study was to evaluate the antimicrobial activity of hydro-alcoholic pomegranate peel extract (PPE) against MDR microorganisms belonging to Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp. "ESKAPE" group pathogens. Through semiquantitative and quantitative methods, the PPE showed effective antimicrobial activity against Gram-positive and Gram-negative MDR bacteria. The kinetics of bactericidal action of PPE highlighted that microbial death was achieved in a time- and dose-dependent manner. High concentrations of PPE exhibited antioxidant activity, providing a protective effect on cellular systems and red blood cell membranes. Finally, we report, for the first time, a significant intracellular antibacterial property of PPE as highlighted by its bactericidal action against the staphylococcal reference strain and its bacteriostatic effect against clinical resistant strain in the HeLa cell line. In conclusion, due to its characterized content of polyphenolic compounds and antioxidant activity strength, the PPE could be considered as a therapeutic agent alone or in conjunction with standard antibiotics against challenging infections caused by ESKAPE pathogens.

Gram-negative bacterial colonizations before bilateral lung transplant. The impact of ‘targeted’ versus ‘standard’ surgical prophylaxis

BackgroundInfections are one of the most common causes of death after lung transplant (LT). However, the benefit of ‘targeted’ prophylaxis in LT recipients pre-colonized by Gram-negative (GN) bacteria is still unclear.MethodsAll consecutive bilateral LT recipients admitted to the Intensive Care Unit of the University Hospital of Padua (February 2016–2023) were retrospectively screened. Only patients with pre-existing GN bacterial isolations were enrolled and analyzed according to the antimicrobial surgical prophylaxis (‘standard’ vs. ‘targeted’ on the preoperative bacterial isolation).ResultsOne hundred eighty-one LT recipients were screened, 46 enrolled. Twenty-two (48%) recipients were exposed to ‘targeted’ prophylaxis, while 24 (52%) to ‘standard’ prophylaxis. Overall prevalence of postoperative multi-drug resistant (MDR) GN bacteria isolation was 65%, with no differences between the two surgical prophylaxis (p = 0.364). Eleven (79%) patients treated with ‘standard’ prophylaxis and twelve (75%) with ‘targeted’ therapy reconfirmed the preoperative GN pathogen (p = 0.999). The prevalence of postoperative infections due to MDR GN bacteria was 50%. Of these recipients, 4 belonged to the ‘standard’ and 11 to the ‘targeted’ prophylaxis (p = 0.027).ConclusionsThe administration of a ‘targeted’ prophylaxis in LT pre-colonized recipients seemed not to prevent the occurrence of postoperative MDR GN infections.

In vitro activity of human defensins HNP-1 and hBD-3 against multidrug-resistant ESKAPE Gram-negatives of clinical origin and selected peptidoglycan recycling-defective mutants.

In the current scenario of critical need for new antimicrobials against multidrug-resistant bacteria, all options must be considered, including classic ideas such as the use of purified immune compounds. However, information regarding the activity of certain human defensins against ESKAPE Gram-negatives was incomplete. This is the first study comparatively assessing the in vitro activity of two membrane-permeabilizing/peptidoglycan construction-blocking defensins (HNP-1 and hBD-3) against relevant clinical collections of ESKAPE Gram-negatives, alone or in combination with permeabilizers, additional peptidoglycan-targeting attacks, or the blockade of its recycling. Our data suggest that hBD-3 has a notable bactericidal activity against multidrug-resistant Acinetobacter baumannii and Enterobacter cloacae strains that should be considered as potential adjuvant option. Our results suggest for the first time an increased resistance of Pseudomonas aeruginosa strains from chronic infection compared to acute origin ones, and provide new clues about the predominant mode of action of hBD-3 against Gram-negatives (permeabilization rather than peptidoglycan-targeting).

Polymyxins with Potent Antibacterial Activity against Colistin-Resistant Pathogens: Fine-Tuning Hydrophobicity with Unnatural Amino Acids.

In view of the increased prevalence of antimicrobial resistance among human pathogens, antibiotics against multidrug-resistant (MDR) bacteria are in urgent demand. In particular, the rapidly emerging resistance to last-resort antibiotic colistin, used for severe Gram-negative MDR infections, is critical. Here, a series of polymyxins containing unnatural amino acids were explored, and some analogues exhibited excellent antibacterial activity against Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa. Hydrophobicity of the compounds within this series (as measured by retention in reversed-phase analytical HPLC) exhibited a discernible correlation with their antimicrobial activity. This trend was particularly pronounced for colistin-resistant pathogens. The most active compounds demonstrated competitive activity against a panel of Gram-negative pathogens, while exhibiting low in vitro cytotoxicity. Importantly, most of these hits also retained (or even had increased) potency against colistin-susceptible strains. These findings infer that fine-tuning hydrophobicity may enable the design of polymyxin analogues with favorable activity profiles.

The impact of environmental cleaning protocol featuring PX-UV in reducing the incidence of multidrug-resistant gram-negative healthcare-associated infection and colonization in intensive care units in Thailand.

In this quasi-experimental study, implementing PX-UV to the standard environmental cleaning protocol was associated with a reduction in the overall incidence of multidrug-resistant (MDR) gram-negative organisms (P = .01) and MDR Acinetobacter baumannii (P = .001) in intervention intensive care units. However, the intervention did not reduce patient length of stay and 30-day mortality.

Approach to multidrug resistant infections in pediatric transplant recipients.

There is increasing recognition of infections due to multidrug-resistant Gram negative (MDRGN) bacterial infections among children undergoing solid organ and hematopoietic cell transplantation, which may be associated with morbidity and mortality. We present two vignettes that highlight the clinical challenges of evaluation, management, and prevention of MDRGN bacterial infections in children prior to and after transplantation. The goal of this discussion is to provide a framework to help develop an approach to evaluation and management of these infections. Source control remains the utmost priority in management of MDR infections and is paired with antibiotic selection guided by in vitro susceptibilities, adverse effect profiles, and clinical response. Identification and confirmation of resistance can be challenging and often requires additional testing for recognition of complex mechanisms. Current antimicrobial approaches to MDRGN infections include use of novel agents, prolonged infusion, and/or combination therapy. We also discuss preventative efforts including infection control, antimicrobial stewardship, targeted pre-emptive or prophylactic treatment, and decolonization. The impact of MDRGN infections on patient and graft survival highlights the need to optimize treatment and prevention strategies.

Eravacycline, the first four years: health outcomes and tolerability data for 19 hospitals in 5 U.S. regions from 2018 to 2022.

The rise of multidrug-resistant (MDR) pathogens, especially MDR Gram-negatives, poses a significant challenge to clinicians and public health. These resilient bacteria have rendered many traditional antibiotics ineffective, underscoring the urgency for innovative therapeutic solutions. Eravacycline, a broad-spectrum fluorocycline tetracycline antibiotic approved by the FDA in 2018, emerges as a promising candidate, exhibiting potential against a diverse array of MDR bacteria, including Gram-negative, Gram-positive, anaerobic strains, and Mycobacterium. However, comprehensive data on its real-world application remain scarce. This retrospective cohort study, one of the largest of its kind, delves into the utilization of eravacycline across various infectious conditions in the USA during its initial 4 years post-FDA approval. Through assessing clinical, microbiological, and tolerability outcomes, the research offers pivotal insights into eravacycline's efficacy in addressing the pressing global challenge of MDR bacterial infections.

Green Synthesis of Silver Nanoparticles Using Jacobaea maritima and the Evaluation of Their Antibacterial and Anticancer Activities.

Much attention has been gained on green silver nanoparticles (green-AgNPs) in the medical field due to their remarkable effects against multi-drug resistant (MDR) microorganisms and targeted cancer treatment. In the current study, we demonstrated a simple and environment-friendly (i.e., green) AgNP synthesis utilizing Jacobaea maritima aqueous leaf extract. This leaf is well-known for its medicinal properties and acts as a reducing and stabilizing agent. Nanoparticle preparation with the desired size and shape was controlled by distinct parameters; for instance, temperature, extract concentration of salt, and pH. The characterization of biosynthesized AgNPs was performed by the UV-spectroscopy technique, dynamic light scattering, scanning electron microscopy, X-ray diffraction, and Fourier-transform infrared. The successful formation of AgNPs was confirmed by a surface plasmon resonance at 422 nm using UV-visible spectroscopy and color change observation with a particle size of 37± 10 nm and a zeta potential of -10.9 ± 2.3 mV. SEM further confirmed the spherical size and shape of AgNPs with a size varying from 28 to 52 nm. Antibacterial activity of the AgNPs was confirmed against all Gram-negative and Gram-positive bacterial reference and MDR strains that were used in different inhibitory rates, and the highest effect was on the E-coli reference strain (MIC = 25 μg/mL). The anticancer study of AgNPs exhibited an IC50 of 1.37 μg/mL and 1.98 μg/mL against MCF-7 (breast cancer cells) and A549 (lung cancer cells), respectively. Therefore, this green synthesis of AgNPs could have a potential clinical application, and further in vivo study is required to assess their safety and efficacy.

Antibacterial Efficiency of Tanacetum vulgare Essential Oil against ESKAPE Pathogens and Synergisms with Antibiotics.

Medicinal plants with multiple targets of action have become one of the most promising solutions in the fight against multidrug-resistant (MDR) bacterial infections. Tanacetum vulgare (Tansy) is one of the medicinal plants with antibacterial qualities that deserve to be studied. Thus, this research takes a closer look at tansy extract's composition and antibacterial properties, aiming to highlight its potential against clinically relevant bacterial strains. In this respect, the antibacterial test was performed against several drug-resistant pathogenic strains, and we correlated them with the main isolated compounds, demonstrating the therapeutic properties of the extract. The essential oil was extracted via hydrodistillation, and its composition was characterized via gas chromatography. The main isolated compounds known for their antibacterial effects were α-Thujone, β-Thujone, Eucalyptol, Sabinene, Chrysanthenon, Camphor, Linalool oxide acetate, cis-Carveol, trans-Carveyl acetate, and Germacrene. The evaluation of the antibacterial activity was carried out using the Kirby-Bauer and binary microdilution methods on Gram-positive and Gram-negative MDR strains belonging to the ESKAPE group (i.e., Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.). Tansy essential oil showed MIC values ranging from 62.5 to 500 μg/mL against the tested strains. Synergistic activity with different classes of antibiotics (penicillins, cephalosporins, carbapenems, monobactams, aminoglycosides, and quinolones) has also been noted. The obtained results demonstrate that tansy essential oil represents a promising lead for developing new antimicrobials active against MDR alone or in combination with antibiotics.

Clinical Value Of Intravenous Fosfomycin Combinations

Aims:Due to the increasing number of Multi-Drug Resistance (MDR) and Extensively Drug Resistant (XDR) pathogens and the difficulties in developing new antibiotics, some combinations are being tried. Fosfomycin is a phosphonic acid derivative UDP-N-acetyl glucosamine (MurA) inhibitor. Fosfomycin inhibits bacteria cell wall synthesis in its first step. It acts against both gram-positive and gram-negative Multi-Drug Resistance (MDR) and Extensive Drug-Resistant (XDR) bacteria. It prevents bacterial invasion into the urinary system and respiratory tract epithelİum. It was aimed to evaluate the clinical and microbiological response rates of intravenous fosfomycin treatment in gram-negative MDR and XDR bacterial infections in this study.&#x0D; Methods: Total 77 patients from four different centers where used intravenous fosfomycin treatment were involved to the study. It was evaluated clinical and microbiological response in 72 hours after the beginning of treatment and at the end of treatment. Clinical and microbiological response have been evaluated in the study population. &#x0D; Results: While 41 of the patients were female (53.2%), 36 were male (46.8%), it is found that their mean age was 60.5. Clinical response rates 72 hours after the initiation of treatment and at the end of treatment were 46 (59.7%) and 45 (58.4%), respectively. Microbiological eradication rate was achieved in 40 (51.9%) patients in the first 72 hours and in 39 (50.6%) patients at the end of the treatment. Clinical response and microbiological eradication rates after seventy two hours and at the end of treatment were found to be similar with together. &#x0D; Conclusions: As a result, fosfomycin may be an alternative in combination therapy due to its low side effect profile and lack of drug interaction in the treatment of MDR and XDR pathogens.

Early-life surface colonization with multi-drug resistant organisms in the neonatal intensive care unit

ObjectivesIn this study, we aim to describe the patterns of early-life surface colonization with multi-drug resistant (MDR) organisms (MDROs) among newborns admitted to the neonatal intensive care unit (NICU). MethodsWe conducted a retrospective descriptive study of infants with culture-positive external ear surface swabs performed immediately after admission to our NICU from January 1, 2017 – December 31, 2021. Clinical characteristics, culture and antibiotic susceptibility data were extracted from the department data collection and hospital electronic databases. ResultsA total of 314 infants were included - median 34 weeks gestation (interquartile range [IQR] 30, 38) and median birthweight 2147 g (IQR 1470, 2875). Of the 379 bacterial isolates obtained, 259 (68.3%) were gram-negative with Escherichia coli (149/379, 39.3%) and Klebsiella spp (57/379, 15.0%) the most common gram-negatives isolated. MDROs accounted for 17.4% (45/259) of gram-negative isolates. There was no methicillin-resistant Staphylococcus aureus (0/22 isolates) or vancomycin-resistant Enterococcus (0/68) detected among isolates tested. A total of 27 (8.6%) infants developed bacteremia, of which 21/27 (77.8%) had concordant bacteria isolated from surface cultures, with identical resistance patterns, and 4/21 (19.0%) isolates were MDROs. ConclusionIn our setting where gram-negative bacteria accounted for a high proportion of initial colonization, MDR gram-negatives accounted for up to 17% of colonizing gram-negative bacteria detected.

Use of Newer and Repurposed Antibiotics against Gram-Negative Bacteria in Neonates.

Antimicrobial resistance has become a significant public health problem globally with multidrug resistant Gram negative (MDR-GN) bacteria being the main representatives. The emergence of these pathogens in neonatal settings threatens the well-being of the vulnerable neonatal population given the dearth of safe and effective therapeutic options. Evidence from studies mainly in adults is now available for several novel antimicrobial compounds, such as new β-lactam/β-lactamase inhibitors (e.g., ceftazidime-avibactam, meropenem-vaborbactam, imipenem/cilastatin-relebactam), although old antibiotics such as colistin, tigecycline, and fosfomycin are also encompassed in the fight against MDR-GN infections that remain challenging. Data in the neonatal population are scarce, with few clinical trials enrolling neonates for the evaluation of the efficacy, safety, and dosing of new antibiotics, while the majority of old antibiotics are used off-label. In this article we review data about some novel and old antibiotics that are active against MDR-GN bacteria causing sepsis and are of interest to be used in the neonatal population.

Treatment options for multidrug-resistant Gram-negatives in urinary tract infections.

Infections due to multidrug-resistant (MDR) Gram-negative bacteria are challenging to treat because of limited treatment options and potential side effects of less frequently used anti-infectives. In the past few years, several new antimicrobial agents effective against MDR Gram-negatives have become available. This review focuses on the treatment options for complicated urinary tract infections (cUTIs) caused by MDR Gram-negatives. The novel combinations, betalactam or carbapenem and betalactamase inhibitor, ceftazidime/avibactam and meropenem/vaborbactam, are effective for infections caused by KPC-carbapenemase-producing pathogens. Imipenem/relebactam, another carbapenem/betalactamase inhibitor combination, has been approved for the treatment of cUTI. However, data on the efficacy of imipenem/relebactam against carbapenem-resistant pathogens is still limited. Ceftolozane/tazobactam is mainly used for the treatment of MDR Pseudomonas aeruginosa infections. For the treatment of cUTI caused by extended-spectrum betalactamases producing Enterobacterales aminoglycosides or intravenous fosfomycin should be considered. To ensure prudent use and to avoid the development of resistance to novel anti-infective substances, an interdisciplinary approach, including urologists, microbiologists, and infectious disease physicians, is strongly advised.

Antimicrobial Activity of Ceftazidime-Avibactam, Ceftolozane-Tazobactam, Cefiderocol, and Novel Darobactin Analogs against Multidrug-Resistant Pseudomonas aeruginosa Isolates from Pediatric and Adolescent Cystic Fibrosis Patients.

The emergence and spread of antimicrobial resistance (AMR) in Gram-negative pathogens, such as carbapenem-resistant Pseudomonas aeruginosa, pose an increasing threat to health care. Patients with immunodeficiencies or chronic pulmonary disease, like cystic fibrosis (CF), are particularly vulnerable to Pseudomonas infections and depend heavily on antibiotic therapy. To broaden limited treatment options, this study evaluated the potency of the recently licensed drugs ceftazidime-avibactam (CZA), ceftolozane-tazobactam (C/T), and cefiderocol (FDC) as well as two novel preclinical antibiotics, darobactins B (DAR B) and B9 (DAR B9), against clinical P. aeruginosa isolates derived from respiratory samples of CF patients. We observed high levels of resistance to all three newly licensed drugs, with cefiderocol exhibiting the best activity. From the 66 investigated P. aeruginosa isolates, a total of 53% were resistant to CZA, 49% to C/T, and 30% to FDC. Strikingly, 52 of the evaluated isolates were obtained from CF patients prior to market introduction of the drugs. Thus, our results suggest that resistance to CZA, C/T, and FDC may be due to preexisting resistance mechanisms. On the other hand, our two novel preclinical compounds performed better than (CZA and C/T) or close to (FDC) the licensed drugs-most likely due to the novel mode of action. Thus, our results highlight the necessity of global consistency in the area of antibiotic stewardship to prevent AMR from further impairing the potency of antibiotics in clinical practice. Ultimately, this study demonstrates the urgency to support the development of novel antimicrobials, preferably with a new mode of action such as darobactins B and B9, two very promising antimicrobial compounds for the treatment of critically ill patients suffering from multidrug-resistant Gram-negative (MRGN) infections. IMPORTANCE Antimicrobial resistance (AMR) represents an ever increasing threat to the health care system. Even recently licensed drugs are often not efficient for the treatment of infections caused by Gram-negative bacteria, like Pseudomonas aeruginosa, a causative agent of lung infections. To address this unmet medical need, innovative antibiotics, which possess a new mode of action, need to be developed. Here, the antibiogram of clinical isolates derived from cystic fibrosis patients was generated and new bicyclic heptapeptides, which inhibit the outer membrane protein BamA, exhibited strong activity, also against multidrug-resistant isolates.

Evaluating the Use of Neonatal Colonization Screening for Empiric Antibiotic Therapy of Sepsis and Pneumonia

(1) Background: Since 2013, weekly screening for multidrug-resistant Gram-negative (MDRGN) bacteria has been performed in German neonatal intensive care units (NICU). National guidelines recommend considering these colonization analyses for antibiotic treatment regimens. Our retrospective single center study provides insight into the clinical dichotomy of bacterial colonization and infection rates in neonates. (2) Methods: We analyzed microbiological data of neonates admitted to our tertiary level NICU over nine years. Colonization with MDRGN/Serratia marcescens (SERMA) was compared to microbiological findings in sepsis and pneumonia. (3) Results: We analyzed 917 blood and 1799 tracheal aspirate samples. After applying criteria from the Nosocomial Infection Surveillance for Neonates (NEO-KISS), we included 52 and 55 cases of sepsis and pneumonia, respectively; 19.2% of sepsis patients and 34.5% of pneumonia patients had a prior colonization with MDRGN bacteria or SERMA. In these patients, sepsis was not attributable to MDRGN bacteria yet one SERMA, while in pneumonias, ten MDRGN bacteria and one SERMA were identified. We identified late-onset pneumonia and cesarean section as risk factors for MDRGN/SERMA acquisition. (4) Conclusions: Colonization screening is a useful tool for hygiene surveillance. However, our data suggest that consideration of colonization with MDRGN/SERMA might promote extensive use of last resort antibiotics in neonates.