Navigating the Current Treatment Landscape of Metallo-ß-Lactamase-Producing Gram-Negative Infections: What are the Limitations?

The spread of carbapenemase-producing gram-negative pathogens, especially those producing metallo-ß-lactamases (MBLs), has become a major health concern. MBLs are molecularly the most diverse carbapenemases, produced by a wide spectrum of gram-negative organisms, including the Enterobacterales, Pseudomonas spp., Acinetobacter baumannii, and Stenotrophomonas maltophilia, and can hydrolyze most ß-lactams using metal ion cofactors in their active sites. Over the years, the prevalence of MBL-carrying isolates has increased globally, particularly in Asia. MBL infections are associated with adverse clinical outcomes including longer length of hospital stay, ICU admission, and increased mortality across the globe. The optimal treatment for MBL infections not only depends on the pathogen but also on the underlying resistance mechanisms. Currently, there are only few drugs or drug combinations that can efficiently offset MBL-mediated resistance, which makes the treatment of MBL infections challenging. The rising concern of MBLs along with the limited treatment options has led to the need and development of drugs that are specifically targeted towards MBLs. This review discusses the prevalence of MBLs, their clinical impact, and the current treatment options for MBL infections and their limitations. Furthermore, this review will discuss agents currently in the pipeline for treatment of MBL infections.

The Uncommon Suspect: Pseudomonas aeruginosa and Cavitary Lung Lesions in an Immunocompetent Patient.

Cavitary lung lesions pose a formidable diagnostic challenge due to their multifaceted etiologies. While tuberculosis and other prevalent pathogens typically dominate discussions, instances of community-acquired Pseudomonas aeruginosa (P. aeruginosa) pneumonia leading to cavitation in immunocompetent individuals remain exceptionally rare. Herein, we present a compelling case of such pneumonia in a 61-year-old man with a past medical history of hypertension and coronary artery disease who presented with cough, chest pain, and subjective fever. Chest imaging revealed cavitary lung lesions, which is atypical for community-acquired pneumonia (CAP). Initial workup excluded common CAP pathogens, following which bronchoscopy with bronchoalveolar lavage (BAL) definitively diagnosed P. aeruginosa, prompting targeted antibiotic therapy. Treatment led to clinical and radiographic improvement. P. aeruginosa rarely causes CAP, especially in immunocompetent patients, and cavitary lesions further complicate diagnosis. This case highlights the importance of considering P. aeruginosa in CAP with unusual features and emphasizes the utility of bronchoscopy with BAL for diagnosis and guiding management.

Continuously producible aztreonam-loaded inhalable lipid nanoparticles for cystic fibrosis-associated Pseudomonas aeruginosa infections - Development and in-vitro characterization.

Cystic fibrosis (CF) is a genetic disorder affecting nearly 105,000 patients worldwide and is characterized by poor respiratory function due to accumulation of thick mucus in the lungs, which not just acts as a physical barrier, but also provides a breeding ground for bacterial infections. These infections can be controlled with the help of antibiotics which can be delivered directly into the lungs for amplifying the local anti-bacterial effect. More than 50 % of CF patients are associated with Pseudomonas aeruginosa infection in their lungs which requires antibiotics such as Aztreonam (AZT). In this study, we prepared inhalable AZT-loaded lipid nanoparticles using Hot-melt extrusion (HME) coupled with probe sonication to target Pseudomonas aeruginosa infection in the lungs. The optimized nanoparticles were tested for physicochemical properties, stability profile, in-vitro aerosolization, and antimicrobial activity against Pseudomonas aeruginosa. The optimized nanoparticles with a PEI concentration of 0.1 % demonstrated a uniform particle size of <50 nm, a spherical shape observed under a transmission electron microscope, and >70 % drug entrapment. Incorporating cationic polymer, PEI, resulted in sustained drug release from the lipid nanoparticles. The in-vitro aerosolization studies exhibited a mass median aerodynamic diameter (MMAD) of <4.3 µm, suggesting deposition of the nanoparticles in the respirable airway. The antimicrobial activity against Pseudomonas aeruginosa showed the minimum inhibitory concentration of the formulation is 2-fold lower than plain AZT. Stability profile showed the formulations are stable after exposure to accelerated conditions. In conclusion, hot-melt extrusion in combination with probe sonication can be used as a potential method for the continuous production of AZT-loaded lipid nanoparticles with enhanced anti-bacterial activity.

Understanding the rationale and clinical impact of the revised CLSI 2024 minocycline susceptibility breakpoints against Stenotrophomonas maltophilia.

Stenotrophomonas maltophilia is challenging to treat due to the presence of multiple intrinsic and acquired resistance mechanisms. TMP-SMZ is the standard care of therapy for treating S. maltophilia infections; levofloxavin and minocycline are the preferred potential alternatives. Recently, in 2024, CLSI has lowered the susceptibility breakpoints for minocycline against S. maltophilia. Applying the revised minocycline's susceptibility breakpoint of ≤ 1 mg/L, susceptibility to minocycline dropped significantly from 77% (previous breakpoint, ≤ 4 mg/L) to 35% (revised breakpoint of ≤ 1 mg/L). In the wake of this change, minocycline's dependency has been questioned for treating S. maltophilia infections.

In vitro activities of the essential antimicrobial agents including aztreonam/avibactam, eravacycline, colistin, and other comparators against carbapenem-resistant bacteria with different carbapenemase genes: a multicenter study in China, 2021.

OBJECTIVE: Carbapenem-resistant bacteria (CRB), including carbapenem-resistant Acinetobacter baumannii (CRAB), carbapenem-resistant Pseudomonas aeruginosa (CRPA), and carbapenem-resistant Enterobacterales (CRE), pose a considerable threat to public health in China. Eravacycline, aztreonam/avibactam, and colistin are important antimicrobial agents for the treatment of serious infections caused by CRB. The study aims to evaluate the prevalence of CRB strains and the susceptibility of commonly used clinical antimicrobial agents against the strains with different carbapenemase genes . METHODS: We collected 7,194 gram-negative bacteria (GNB) strains from different regions of China and identified 924 carbapenem-resistant strains. All strains were from infections with confirmed diagnoses. Antimicrobial susceptibility testing, covering 21 antimicrobial agents including aztreonam/avibactam, eravacycline, colistin, and other comparators, was performed using the broth microdilution method. Carbapenemase genes (blaKPC, blaNDM, blaOXA, blaIMP, and blaVIM) were screened by PCR amplification and sequence analysis. All statistical analyses were performed using Statistical Package for the Social Sciences version 23.0 software. RESULTS: The isolation rates of CRE, CRAB, and CRPA were 6.31% (332/5265), 62.95% (440/699), and 15.20% (152/1000), respectively. The predominant carbapenemase in carbapenem-resistant Escherichia coli (CRECO) was NDM, while in CRKP it was KPC. All CRAB produced OXA-23 and 85.52 % of CRPA did not produce any of the following carbapenemases: NDM, KPC, VIM, IMP and OXA. Aztreonam/avibactam, colistin, and eravacycline exhibited high antimicrobial activity against different species producing various carbapenemases. Compared to ceftazidime/avibactam, aztreonam/avibactam demonstrated superior antimicrobial activity, particularly pronounced in CRECO and strains producing metallo-beta-lactamases (MBLs). In comparisons between tigecycline and eravacycline, the latter maintained higher antimicrobial activity across different species. Antimicrobial agents exhibited varying levels of activities when against strains with different resistance mechanisms. CONCLUSIONS: Our results support the fact that using aztreonam/avibactam, eravacycline, and colistin to treat infections caused by CRB offers significant advantages. These fingdings will guide clinical practice and optimize antimicrobial administration.

Recent updates in treating carbapenem-resistant infections in patients with hematological malignancies.

INTRODUCTION: Patients with hematological malignancies (PHMs) are at increased risk for infections caused by carbapenem-resistant organisms (CROs) due to frequent exposure to broad-spectrum antibiotics and prolonged hospital stays. These infections result in high mortality and morbidity rates along with delays in chemotherapy, longer hospitalizations, and increased health care costs. AREAS COVERED: Treatment alternatives for CRO infections in PHMs. EXPERT OPINION: The best available treatment option for KPC and OXA-48 producers is ceftazidime/avibactam. Imipenem/cilastatin/relebactam and meropenem/vaborbactam remain as the alternative options. They can also be used as salvage therapy in KPC-positive Enterobacterales infections resistant to ceftazidime/avibactam, if in vitro susceptibility is shown. Treatment of metallo-ß-lactamase producers is an unmet need. Ceftazidime/avibactam plus aztreonam or aztreonam/avibactam seems to be the most reliable option for metallo-ß-lactamase producers. As a first-line option for carbapenem-resistant Pseudomonas aeruginosa infections, ceftolozane/tazobactam is preferable and ceftazidime/avibactam and imipenem/cilastatin/relebactam constitute alternative regimens. Although sulbactam/durlobactam is the most reliable option against carbapenem-resistant Acinetobacter baumannii infections, its utility as monotherapy and in PHMs is not yet known. Cefiderocol can be selected as a 'last-resort' option for CRO infections. New risk score models supported by artificial intelligence algorithms can be used to predict the exact risk of infections in previously colonized patients.

Aztreonam-avibactam for the treatment of intra-abdominal infections.

INTRODUCTION: Intra-abdominal infections are becoming increasingly common, and can lead to significant morbidity and mortality. The incidence of these infections due to resistant gram-negative organisms is also increasing. Given this resistance, new antibiotic combinations are being developed, often utilizing older antibiotics and newer ß-lactamase inhibitors. Aztreonam/avibactam (ATM-AVI) is one of the combination antibiotics, which combines aztreonam, a monobactam, with avibactam, a broad-spectrum ß-lactamase inhibitor for the treatment of complicated intra-abdominal infections in combination with metronidazole. AREAS COVERED: In this drug evaluation manuscript, we provide an overview of intra-abdominal infections, an overview of currently available antimicrobial agents used to treat these infections. ATM-AVI is introduced, including the chemistry, pharmacodynamics and pharmacokinetics and clinical studies of this compound. EXPERT OPINION: There are limited treatment options for complicated intra-abdominal infections due to resistant gram-negative organisms, especially those with metallo-ß-lactamases. One treatment option for these infections is ATM-AVI, which was recently approved in Europe, in addition to metronidazole. These bacteria are difficult to treat, and this new compound is a safe and effective option for empiric treatment in places with a high incidence of infections due to these bacteria, and also treatment for infections when these resistant bacteria are isolated in culture.

Maximally precise combinations to overcome metallo-ß-lactamase-producing Klebsiella pneumoniae.

Gram-negatives harboring metallo-ß-lactamases (MBLs) and extended-spectrum ß-lactamases (ESBLs) pose a substantial risk to the public health landscape. In ongoing efforts to combat these "superbugs," we explored the clinical combination of aztreonam and ceftazidime/avibactam together with varying dosages of polymyxin B and imipenem against Klebsiella pneumoniae (Kp CDC Nevada) in a 9-day hollow fiber infection model (HFIM). As previously reported by our group, although the base of aztreonam and ceftazidime/avibactam alone leads to 3.34 log10 fold reductions within 72 hours, addition of polymyxin B or imipenem to the base regimen caused maximal killing of 7.55 log10 and 7.4 log10 fold reduction, respectively, by the 72-hour time point. Although low-dose polymyxin B and imipenem enhanced the bactericidal activity as an adjuvant to aztreonam +ceftazidime/avibactam, regrowth to ~9 log10CFU/mL by 216 hours rendered these combinations ineffective. When aztreonam +ceftazidime/avibactam was supplemented with high-dose polymyxin B and or low-dose polymyxin B + imipenem, it resulted in effective long-term clearance of the bacterial population. Time lapse microscopy profiled the emergence of long filamentous cells in response to PBP3 binding due to aztreonam and ceftazidime. The emergence of spheroplasts via imipenem and damage to the outer membrane via polymyxin B was visualized as a mechanism of persister killing. Despite intrinsic mgrB and blaNDM-1 resistance, polymyxin B and ß-lactam combinations represent a promising strategy. Future studies using an integrated molecularly precise pharmacodynamic approach are warranted to unravel the mechanistic details to propose optimal antibiotic combinations to combat untreatable, pan-drug-resistant Gram-negatives.

In vitro Synergistic and Bactericidal Effects of Aztreonam in Combination with Ceftazidime/ Avibactam, Meropenem/Vaborbactam and Imipenem/Relebactam Against Dual-Carbapenemase-Producing Enterobacterales.

Objective: Our aim was to elucidate the resistance mechanisms and assess the combined synergistic and bactericidal activities of aztreonam in combination with ceftazidime/avibactam (CZA), meropenem/vaborbactam (MEV), and imipenem/relebactam (IMR) against Enterobacterales strains producing dual carbapenemases. Methods: Species identification, antimicrobial susceptibility testing and determination of carbapenemase type were performed for these strains. Plasmid sizes, plasmid conjugation abilities and the localization of carbapenemase genes were investigated. Whole-genome sequencing was performed for all strains and their molecular characteristics were analyzed. In vitro synergistic and bactericidal activities of the combination of aztreonam with CZA, MEV and IMR against these strains were determined using checkerboard assay and time-kill curve assay. Results: A total of 12 Enterobacterales strains producing dual-carbapenemases were collected, including nine K. pneumoniae, two P. rettgeri, and one E. hormaechei. The most common dual-carbapenemase gene pattern observed was bla (KPC-2+NDM-5) (n=4), followed by bla KPC-2+IMP-26 (n=3), bla (KPC-2+NDM-1) (n=2), bla (KPC-2+IMP-4) (n=1), bla (NDM-1+IMP-4) (n=1) and bla (KPC-2+KPC-2) (n=1). In each strain, the carbapenemase genes were found to be located on two distinct plasmids which were capable of conjugating from the original strain to the receipt strain E. coli J53. The results of the checkerboard synergy analysis consistently revealed good synergistic effects of the combination of ATM with CZA, MEV and IMR. Except for one strain, all strains exhibited significant synergistic activity and bactericidal activity between 2 and 8 hours. Conclusion: Dual-carbapenemase-producing Enterobacterales posed a significant threat to clinical anti-infection treatment. However, the combination of ATM with innovative ß-lactam/ß-lactamase inhibitor compounds had proven to be an effective treatment option.

Assessment of broth disk elution method for aztreonam in combination with ceftazidime/avibactam against Enterobacterales isolates.

The combination of aztreonam with ceftazidime/avibactam is considered a potential therapeutic approach for the treatment of infections caused by metallo-ß-lactamase (MBL)-producing isolates. In this study, in vitro antibacterial activity of aztreonam with avibactam against 204 carbapenemase-producing Enterobacterales was determined by broth disk elution (BDE) method of two detection volumes (5- and 2-mL broth), with broth microdilution (BMD) method as a reference. For the BDE-5mL test, the categorical agreement (CA) of ATM+CZA-lo tube (aztreonam/ceftazidime/avibactam: 6/6/4 mg/L) was 99.5%, with 0.5% major error (ME) and 0% very major error (VME); the CA of 2ATM+CZA-lo tube (12/6/4 mg/L) was 100%, with no ME and VME. For the BDE-2mL test, the CA of ATM+2CZA-hi tube (15/10/4 mg/L) was 98.5%, with 0% ME and 37.5% VME; the CA of 2ATM+2CZA-hi tube (30/10/4 mg/L) was 97.1%, with 0% ME and 75% VME. The BDE-5 mL test is an economical and practical method for clinical microbiology laboratories to determine the antibacterial susceptibility of aztreonam with avibactam against Enterobacterales, especially the 2ATM+CZA-lo tube with a final concentration of 12/6/4 mg/L of aztreonam/ceftazidime/avibactam. IMPORTANCE: Infections caused by metallo-ß-lactamase (MBL)-producing Enterobacterales are increasingly reported worldwide, and it is a significant challenge for clinical infection treatment. MBLs are adept at hydrolyzing almost all traditional ß-lactam antibiotics except aztreonam, and the enzyme activity cannot be inhibited by traditional or novel ß-lactamase inhibitors. The good thing is that the combination of aztreonam with ceftazidime/avibactam has been proven to be one of the potential therapeutic approaches for treating infections related with MBL-producing isolates. Broth microdilution (BMD) method is recommended as a reference method for its accuracy, but it is too complex to perform in most routine laboratories. Finding a more convenient, practical, and accurate susceptibility testing method for aztreonam/avibactam in clinical microbiology laboratories is very necessary. Here, we evaluated the performance of broth disk elution (BDE) method for aztreonam in combination with ceftazidime/avibactam against Enterobacterales isolates, with BMD as a reference.

Novel agents in development for the treatment of resistant Gram-negative infections.

INTRODUCTION: Several novel agents are in advanced stages of clinical development, potentially expanding our treatment options against third- and fourth-generation cephalosporin-resistant and carbapenem-resistant Gram-negative bacteria (GNB), including those pathogens for which the current number of effective treatments is limited. AREAS COVERED: This review focuses on agents that have completed or ongoing phase-3 studies. A PubMed search was conducted up to 31 May 2024. EXPERT OPINION: Novel agents in late-stage clinical development belong to the ß-lactam or ß-lactam/ß-lactamase inhibitor combinations class and display variable antimicrobial activity depending on the specific ß-lactamases expressed by GNB, particularly carbapenemases. While many of these novel agents demonstrate in vitro activity against carbapenem-resistant GNB, their efficacy has mainly been evaluated in phase-3 randomized controlled trials (RCT) for infections caused by carbapenem-susceptible GNB. Although evidence from real-world observational studies is generally less robust than that from RCT, it could be crucial for updating clinical guidelines on treating carbapenem-resistant GNB with these new agents in the absence of dedicated RCT.

Evaluation of gradient strip diffusion for susceptibility testing of aztreonam-avibactam in metallo-ß-lactamase-producing Enterobacterales.

The emergence of metallo-ß-lactamase (MBL)-producing Enterobacterales presents unique clinical treatment challenges. Recently developed ß-lactam/ ß-lactamase inhibitor combination agents, while effective against other carbapenemase-producing organisms, are notably ineffective against MBL producers. While MBLs do not hydrolyze monobactams (aztreonam), many MBL-producing organisms are resistant to aztreonam through alternate mechanisms, leaving cefiderocol as the sole monotherapy treatment option recommended for MBL producers. Recent guidelines for the treatment of MBL-harboring organisms have added combination therapy with aztreonam and ceftazidime-avibactam, using ceftazidime-avibactam as a source of the ß-lactamase inhibitor avibactam. Current laboratory testing options for the combination of aztreonam-avibactam are limited to broth microdilution (BMD) and broth disk elution (BDE) methods, which are not practical in most clinical laboratories. In this study, we evaluated the performance of aztreonam/avibactam gradient strips on 103 MBL-producing Enterobacterales patient isolates as well as an additional 31 isolates from the CDC AR Bank. All MBL Enterobacterales patient isolates included in this study harbored a New Delhi metallo-ß-lactamase (blaNDM) gene. Essential agreement of gradient strip minimal inhibitory concentrations (MICs) for patient isolates compared to BMD was 93.2%. While there are no established breakpoints for aztreonam-avibactam, category agreement (CA) for patient isolates was 97.1% when using the CLSI aztreonam breakpoints. There were no major or very major errors observed. There were three minor errors. Precision for aztreonam-avibactam gradient strip diffusion was 100%. These data demonstrate that the use of gradient strip diffusion for aztreonam-avibactam MIC determination in MBL-producing Enterobacterales is a viable option for clinical laboratories.

The Immediate and Delayed Maximal Nonirritating Skin Testing Concentrations of ß-Lactam Antibiotics.

BACKGROUND: Maximal skin testing (ST) nonirritant concentrations (NICs) are consistent for penicillin and aminopenicillin among guidelines. However, there is variability among guidelines for maximal ST NICs of cephalosporins. OBJECTIVE: To determine maximal immediate and delayed ST NICs of 15 ß-lactams in ß-lactam-tolerant and ß-lactam-naïve participants. METHODS: We performed a single-center, nonrandomized prospective study between September 2019 and January 2022 in adult participants. Participants received skin prick testing (SPT) and intradermal test (IDT) injections at 6 increasing concentrations of 1 or more ß-lactams. A concentration was considered irritant when more than 5% of participants had a positive test. A positive test was defined as a wheal ≥3 mm compared with negative control accompanied by a ≥5 mm flare for SPT/IDT and induration ≥5 mm with associated erythema at 48 hours for delayed readings (dIDT). Sensitivity analyses using 3 alternative IDT positive criteria were conducted. RESULTS: A total of 747 participants with a median age of 64 (interquartile range: 54-72) years (52% male, 85% White, and 92% non-Hispanic) underwent 20,858 skin tests. All undiluted SPT concentrations were nonirritant. We found the following maximal IDT/dIDT NICs (mg/mL): ampicillin (41.6/125), ampicillin-sulbactam (93.8/187.5), aztreonam (6.3/25), cefazolin (55/165), cefepime (35/140), cefoxitin (45/90), ceftaroline (7.5/15), ceftriaxone (58.3/175), cefuroxime (55/110), ertapenem (16.6/50), imipenem-cilastin (6.3/25), meropenem (8.3/25), nafcillin (31.3/62.5), oxacillin (20.9/83.5), and piperacillin-tazobactam (112.5/225). dIDTs were almost all completely nonirritant close to or at undiluted concentrations. There were no differences when we applied 3 IDT positivity criteria to our raw data. CONCLUSIONS: Our results suggest that SPTs with undiluted stock ß-lactam antibiotic concentrations are nonirritant. Compared with previously published nonirritant concentrations, we propose a 2- to 50-fold increase to the maximal IDT and dIDT NICs of 15 ß-lactam antibiotics. When performing dIDTs, a higher concentration should be used rather than the same IDT concentration.

3D-QSAR, ADMET, and molecular docking studies of aztreonam analogs as E. colis inhibitors.

Background: The development of multidrug resistant strains of extended-spectrum ß-lactamase-producing Escherichia coli has become a global problem; therefore, the discovery of new antibacterial agents is the only available solution. Objective: To improve and propose new compounds with antibacterial activity, the three-dimensional quantitative structure-activity relationship and molecular docking studies were carried out on Aztreonam analogs as E. coli inhibitors in DNA gyrase B. Method: This study's 3D-Quantitative structure-activity relationship model was created using on the Comparative Molecular Field Analysis and the Comparative Molecular Similarity Indices Analysis. Using the Comparative Molecular Field Analysis (Q 2 = 0.73; R 2 = 0.82), excellent predictability was achieved, and the best Comparative Molecular Similarity Indices Analysis model (Q 2 = 0.88; R 2 = 0.9). The generated model's ability to predict outcomes was assessed through external validation using a test set compound and an applicability domain technique. In this study, the steric, electrostatic, and hydrogen bond acceptor fields played a key role in antibacterial activity. Results: The results of the molecular docking revealed that the newly generated compound A6 has the highest binding affinity with DNA gyrase B. It forms 10 hydrogen bonds with amino acid residues of Asn104, Asn274, Asn132, Ser70, Ser237, Thr105, Glu273, and 2 salt bridges with amino acid residues of Ser70 and Glu273 and one pi-pi interacting with Gys271 amino acid residue in the binding site of 5G1, and this result was validated by a new assessment method. We created some novel, highly effective DNA gyrase B inhibitors based on the earlier findings, and the most accurate model predicted their inhibitory actions. The ADMET characteristics and pharmacological similarity of these novel inhibitors were also examined. Conclusion: These findings would be very beneficial in guiding the optimization process for the identification of novel drugs that can address the issue of multiple drug resistance.

Synergistic efficacy of ceftazidime/avibactam and aztreonam against carbapenemase-producing Pseudomonas aeruginosa: insights from the hollow-fiber infection model.

BACKGROUND: Combination therapy is an attractive therapeutic option for extensively drug-resistant (XDR) Pseudomonas aeruginosa infections. Existing data support the combination of aztreonam and ceftazidime/avibactam (CZA) against class serine-ß-lactamase (SBL)- and metallo-ß-lactamase (MBL) - producing Enterobacterales. However, data about that combination against SBL- and MBL-producing P. aeruginosa are scarce. The objective of the study was to assess the in vitro activity of CZA and aztreonam alone and in combination against SBL- and MBL-producing XDR P. aeruginosa isolates. METHODS: The combination was analyzed by means of the hollow-fiber infection model in three selected carbapenemase-producing P. aeruginosa isolates that were representative of the three most common XDRP. aeruginosa high-risk clones (ST175, ST111, ST235) responsible for global nosocomial infection outbreaks. RESULTS: The three isolates were nonsusceptible to CZA and nonsusceptible to aztreonam. In the dynamic hollow-fiber infection model, the combination of CZA plus aztreonam exerts a bactericidal effect on the isolates, regardless of their resistance mechanism and demonstrates synergistic interactions against three isolates, achieving a bacterial reduction of 5.07 log10 CFU/ml, 5.2 log10 CFU/ml and 4 log10 CFU/ml, respectively. CONCLUSION: The combination of CZA and aztreonam significantly enhanced the in vitro efficacy against XDR P. aeruginosa isolates compared to each monotherapy. This improvement suggests that the combination could serve as a feasible treatment alternative for infections caused by carbapenemase-producing XDR P. aeruginosa, especially in scenarios where no other treatment options are available.

Practical Application of Aztreonam-Avibactam as a Treatment Strategy for Ambler Class B Metallo-ß-Lactamase Producing Enterobacteriaceae.

Carbapenem-resistant Enterobacteriaceae infections are a considerable challenge for clinicians. In recent years, novel antibiotic options have resulted in a tremendous advance in medical therapy; however, current treatment options are primarily effective for resistance derived from serine-based carbapenemases. The Ambler class B metallo-ß-lactamases (MBLs) remain a critical challenge with decidedly fewer effective options. One intriguing option for these MBL pathogens is the combination of ceftazidime-avibactam with aztreonam. While clinical experience with this regimen is limited, in vitro studies are promising, and limited case reports describe success with this regimen; however, significant challenges preclude widespread adoption of this novel treatment regimen. A systemic literature review was performed to offer recommendations based on current evidence for a practical strategy on how to best integrate the use of aztreonam with avibactam combination therapy.

Mediastinitis caused by an NDM-1 Escherichia coli in a child with Dacron Sano shunt after pulmonary atresia with ventricular septal defect surgery treated with combination of aztreonam-avibactam.

Carbapenem-resistant Enterobacterales are being reported increasingly and cause nosocomial infections, which may include postoperative mediastinitis. This paper reports a case of postoperative mediastinitis caused by an Escherichia coli NDM-1 carbapenemase producer in a 13-month-old boy with DiGeorge syndrome. The infection was managed with surgical debridement and antibiotherapy with aztreonam, ceftazidime-avibactam and IV fosfomycin for 6 weeks. The evolution was favourable, without relapse over 10 weeks of follow-up.

Treatment of a challenging NDM and OXA-48-producing Klebsiella pneumoniae causing skin and soft tissue infection and exhibiting resistance to the combination of Ceftazidime-Avibactam and Aztreonam: A case report.

Carbapenem-resistant Enterobacterales (CRE) pose a significant public health concern. CRE could be carbapenamse producers or non-producers. In the Kingdom of Saudi Arabia, bla OXA-48 and bla NDM represent the majority of carbapenemase isolates. There are very limited treatment options for carbapenemase-producing CRE caused by bla NDM. Ceftazidime-avibactam plus aztreonam (CZA-ATM) or cefiderocol as monotherapy are considered the treatment of choice for these infections. Here, we report a case of a 70-year-old man presented with surgical site infection of above knee amputation stump. The cultures revealed carbapenem-resistant Klebsiella pneumoniae positive for bla NDM and bla OXA-48 resistant to CZA-ATM therapy and intermediate susceptibility to tigecycline. He was started on CZA-ATM both adjusted for renal function, and high dose tigecycline with daily wound dressing and irrigation. By day 20 of the antibiotic regimens, he had clinical and microbiological cure based on repeated wound cultures. This case identifies a rare incidence of CRE skin and soft tissue infection positive for bla NDM and bla OXA-48 resistant to CZA-ATM in a background of limited targeted options, but successfully treated with CZA-ATM and high-dose tigecycline. Such therapeutic approach might be useful in few circumstances when no other antibiotic options are available to treat extensively drug-resistant Klebsiella pneumoniae.

Synergistic Combination of Aztreonam and Ceftazidime-Avibactam-A Promising Defense Strategy against OXA-48 + NDM Klebsiella pneumoniae in Romania.

With the increasing burden of carbapenem-resistant Klebsiella pneumoniae (CR-Kp), including high rates of healthcare-associated infections, treatment failure, and mortality, a good therapeutic strategy for attacking this multi-resistant pathogen is one of the main goals in current medical practice and necessitates the use of novel antibiotics or new drug combinations. OBJECTIVES: We reviewed the clinical and microbiological outcomes of seven patients treated at the "Agrippa Ionescu" Clinical Emergency Hospital between October 2023 and January 2024, aiming to demonstrate the synergistic activity of the ceftazidime-avibactam (C/A) plus aztreonam (ATM) combination against the co-producers of blaNDM + blaOXA-48-like CR-Kp. MATERIAL AND METHODS: Seven CR-Kp with blaNDM and blaOXA-48 as resistance mechanisms were tested. Seven patients treated with C/A + ATM were included. The synergistic activity of C/A + ATM was proven through double-disk diffusion in all seven isolates. Resistance mechanisms like KPC, VIM, OXA-48, NDM, IMP, and CTX-M were assessed through immunochromatography. RESULTS: With a mean of nine days of treatment with the synergistic combination C/A + ATM, all patients achieved clinical recovery, and five achieved microbiological recovery. CONCLUSIONS: With the emerging co-occurrence of blaOXA-48 and blaNDM among Kp in Romania, the combination of C/A and ATM could be a promising therapeutic option.