Artificial intelligence-clinical decision support system for enhanced infectious disease management: Accelerating ceftazidime-avibactam resistance detection in Klebsiella pneumoniae.

BACKGROUND: Effective and rapid diagnostic strategies are required to manage antibiotic resistance in Klebsiella pneumonia (KP). This study aimed to design an artificial intelligence-clinical decision support system (AI-CDSS) using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and machine learning for the rapid detection of ceftazidime-avibactam (CZA) resistance in KP to improve clinical decision-making processes. METHODS: Out of 107,721 bacterial samples, 675 specimens of KP with suspected multi-drug resistance were selected. These specimens were collected from a tertiary hospital and four secondary hospitals between 2022 and 2023 to evaluate CZA resistance. We used MALDI-TOF MS and machine learning to develop an AI-CDSS with enhanced speed of resistance detection. RESULTS: Machine learning models, especially light gradient boosting machines (LGBM), exhibited an area under the curve (AUC) of 0.95, indicating high accuracy. The predictive models formed the core of our newly developed AI-CDSS, enabling clinical decisions quicker than traditional methods using culture and antibiotic susceptibility testing by a day. CONCLUSIONS: The study confirms that MALDI-TOF MS, integrated with machine learning, can swiftly detect CZA resistance. Incorporating this insight into an AI-CDSS could transform clinical workflows, giving healthcare professionals immediate, crucial insights for shaping treatment plans. This approach promises to be a template for future anti-resistance strategies, emphasizing the vital importance of advanced diagnostics in enhancing public health outcomes.

Therapeutic insights: Use of ceftazidime-avibactam in pediatric patients.

BACKGROUND: The increasing worldwide prevalence of multidrug-resistant (MDR) bacteria underscores the pressing demand for innovative therapeutic solutions. Ceftazidime-avibactam (CAZ-AVI) represents a promising new drug combination that has received approval for specific infection types. However, there is limited information regarding its application in pediatric patients. METHODS: This study investigates the effectiveness and adverse reactions associated with CAZ-AVI treatment in pediatric patients with life-threatening infections caused by MDR pathogens. The study was conducted at a tertiary children's hospital between December, 2021 and July, 2023. RESULTS: A total of 21 patients with life-threatening infections caused by MDR pathogens were enrolled in the study. All patients had underlying medical conditions: 10 had cerebral palsy, four had congenital neurometabolic disease, two had Nieman-Pick disease, two had cystic fibrosis, two had primary immunodeficiency, and one had leukemia. Among these, 12 patients had tracheostomies. Eight patients received CAZ- AVI monotherapy, and 13 patients received combination therapy. Microbiological eradication was achieved in 18 patients (85.7%), and a clinical response was observed in 20 patients (95.2%). Two patients (9.5%) experienced relapse with the same bacteria. One patient developed anaphylaxis, and one patient had elevated creatine phosphokinase levels that normalized following discontinuation of treatment. One patient died during the study period due to gastrointestinal bleeding. CONCLUSIONS: Ceftazidime-avibactam may be a promising new drug option for the treatment of life-threatening infections caused by MDR Gram-negative microorganisms in pediatric patients. However, further studies with larger case series are needed to further evaluate the efficacy and safety of CAZ-AVI in this population.

Ceftazidime-Avibactam as a Salvage Treatment for Severely Infected Immunosuppressed Children.

Background: Multidrug-resistant Gram-negative bacteria (MDR-GNB) are becoming increasingly common around the world, with carbapenems frequently serving as a last resort but being threatened by the growing incidence of carbapenemase-producing bacteria. Ceftazidime-avibactam (CAZ/AVI) is a potential agent against MDR-GNB but with limited clinical experience, particularly in critically ill immunosuppressed children. Methods: This study analyzed the use of CAZ/AVI as salvage treatment in severely infected immunosuppressed children from September 2019 to July 2022. Patients with confirmed GNB infection who received CAZ/AVI were matched with patients who received other antibiotics. Results: Twenty-five critically ill immunosuppressed children treated with CAZ/AVI were included. The majority had hematologic diseases. All patients presented with sepsis in all 30 courses. Septic shock presented in 36.7% of these courses. The primary sites of infection included bloodstream infection (20.0%), skin and skin structure infection (20.0%), intra-abdominal infection (13.3%) and hospital-acquired pneumonia (10.0%). Twelve of the 25 (48.0%) patients had positive microbiological cultures, mainly Pseudomonas aeruginosa and Klebsiella pneumoniae, including 5 carbapenem-resistant GNB-infected cases. Fifteen (50.0%) courses presented clinical improvement. For the initial course of each patient, the clinical response rate of the GNB recovered group was significantly higher than that of the group without GNB recovery (66.7% vs 23.1%, P = 0.047). The 14-day and 30-day mortality rates were 24.0% and 28.0%, respectively, which were significantly correlated with the absence of GNB recovery (P = 0.004 and 0.024, respectively) and hospital-acquired pneumonia as the primary site of infection (P = 0.001 and 0.006, respectively). There was no significant difference in major outcomes between patients who received CAZ/AVI and matched patients who received other antibiotics. Conclusion: CAZ/AVI could be considered a salvage strategy for immunosuppressed children with confirmed GNB infection. Caution should be taken when CAZ/AVI is applied to these patients in the absence of GNB recovery.

Estimating the value of new antibiotic treatment strategies in Zhejiang province, China: cost-effectiveness analysis based on a validated dynamic model.

OBJECTIVES: This analysis aims to better reflect the value of new antibiotic treatment strategies, thereby informing clinical antibiotic use, antimicrobial reimbursement and/or hospital formulary decision-making in China. DESIGN: We adapted a published and validated dynamic disease transmission and cost-effectiveness model to evaluate the clinical and economic outcomes of introducing a new antibiotic, ceftazidime/avibactam (CAZ-AVI) for treating resistant infections in Zhejiang province, China. Outcomes were assessed over a 10-year infectious period and an annual discount rate of 5%. Costs were extracted from the hospital's Health Information System (HIS) and obtained after data cleaning, aggregation and discounting. SETTING: The Chinese healthcare system perspective. PARTICIPANTS: 10 905 patients in a Chinese tier-3 hospital from 2018 to 2021 with any of the three common infections (complicated intra-abdominal infection (cIAI), hospital-acquired/ventilator-associated pneumonia (HAP/VAP) and infections with limited treatment options (LTO)) caused by three common resistant pathogens (Escherichia coli, Klebsiella spp. and Pseudomonas aeruginosa). INTERVENTIONS: (1) Current treatment strategy (piperacillin-tazobactam (pip/taz) and meropenem); (2) CAZ-AVI at the third line; (3) CAZ-AVI at the second line; (4) CAZ-AVI at the first line; (5) CAZ/AVI first line, two lines diversified (i.e., equal pip/taz and CAZ-AVI at the first line; meropenem at the last line) and (6) CAZ/AVI first line, all-lines diversified. PRIMARY OUTCOME MEASURES: Quality-adjusted life years (QALYs) lost, hospitalisation costs and incremental net monetary benefit (INMB) were used to assess cost-effectiveness. RESULTS: Over 10 years, the introduction of CAZ-AVI to the current treatment strategy led to lower hospitalisation costs and more QALYs across all five treatment strategies, with between 68 284 and 78 571 QALYs gained whilst saving up to US$236.37 for each additional QALY gained. The INMB of introducing CAZ-AVI is estimated up to US$3 550 811 878. CONCLUSIONS: Introducing CAZ-AVI had a positive impact on clinical and economic outcomes for treating antimicrobial resistance, and diversifying the antibiotics use early in the treatment might yield the best benefits.

Failure of ceftazidime/avibactam experimental therapy in the treatment of Klebsiella pneumoniae ST11 co-producing NDM-1 and OXA-48 carbapenemases infection.

Carbapenem-resistant organisms (CRO) represent a significant threat because of their widespread in hospital settings, difficult-to-treat, and association with high morbidity and mortality rates. Data on the efficacy of ceftazidime/avibactam (CAZ-AVI) among patients infected with CRO in Iran are lacking. Herein, we report a case of a 91-year-old man with infection caused by extensively drug-resistant ST11 co-harbouring blaNDM and blaOXA-48-like strain from seven isolates. During ICU hospitalization, 10 different antibiotics were prescribed to the patient, and CAZ-AVI was experimentally prescribed in combination with tobramycin and tigecycline to the patient for the first time in the teaching hospitals of Isfahan City. The patient died on the 56th day of hospitalization. The present study revealed that the use of CAZ-AVI should be limited to targeted therapy after susceptibility results and minimum inhibitory concentration values are available to the treating clinicians and not be used for empirical therapy of patients with an infection caused by CRO, underscoring the urgent need for stringent policies for antibiotic stewardship to preserve the activity of novel ß-lactam/ß-lactamase inhibitors.

Evolution of blaKPC Under the Pressure of Carbapenems and Ceftazidime/Avibactam in a Patient With Persistent Bacteremia Caused by Klebsiella pneumoniae.

A 30-year-old Korean man with myelodysplastic syndrome admitted hospital due to undifferentiated fever and recurrent skin lesions. He received combination therapy with high doses of meropenem, tigecycline and amikacin, yielding carbapenem resistant Klebsiella pneumoniae (CRKP) harboring K. pneumoniae carbapenemase (KPC)-2 from blood cultures on hospital day (HD) 23. Ceftazidime/avibactam was started at HD 37 and CRKP was eradicated from blood cultures after 5 days. However, ceftazidime/avibactam-resistant CRKP carrying KPC-44 emerged after 26 days of ceftazidime/avibactam treatment and then ceftazidime/avibactam-resistant, carbapenem-susceptible K. pneumoniae carrying KPC-135 was isolated on HD 65. The 3-D homology of KPC protein showed that hot spot changes in the omega loop could be attributed to ceftazidime/avibactam resistance and loss of carbapenem resistance. Whole genome sequencing of serial isolates supported that phenotypic variation was due to clonal evolution than clonal replacement. The treatment regimen was changed from CAZ/AVI to meropenem-based therapy (meropenem 1 g iv q 8 hours and amikacin 600 mg iv per day) starting with HD 72. CAZ/AVI-susceptible CRKP was presented again from blood cultures on HD 84, and the patient expired on HD 85. This is the first Korean report on the acquisition of ceftazidime/avibactam resistance through the emergence of blaKPC variants.

Change in Klebsiella pneumoniae susceptibility profile after the arrival of ceftazidime-avibactam in an Argentinean intensive care unit: a new ecological landscape.

OBJECTIVE: Ceftazidime-avibactam (CZA) is a good option for Gram-negative bacilli infections that produce carbapenemase Classes A (especially blaKPC) and D (blaOXA). However, it is unknown whether it would have an impact on metallo-ß-lactamases (blaMBL) selection. The aim of the study was to compare carbapenem and CZA Klebsiella pneumoniae (KPN) susceptibility profiles for a period of two years following the introduction of CZA. METHODS: The study was conducted in a 36-bed adult ICU of a tertiary hospital in Buenos Aires, Argentina. Antimicrobial consumption was expressed as days of treatment per 100 patients-day (DOT). RESULTS: A total of 123 KPN strains in the first year and 172 in the second year were analyzed. An alarming decrease in carbapenem susceptibility was detected in the second year (OR 0.5 [0.3-0.8] p<.001). In parallel, there was a decrease in CZA susceptibility (OR 0.5 [0.3-0.9] p<.05). These findings were linked to a rise in blaMBL-KPN (32.1% vs. 45.1%, OR 1.7 [1.1-2.9], p <.04) during the second year. This new KPN susceptibility profile promoted an increment in CZA (1.0 DOT vs. 6.6 DOT, OR 6.6 [4.9-9.1] p<.001) and aztreonam (0.3 DOT vs. 4.1 DOT, OR 16.3 [9.1-29.3] p<.001) consumption. Thus, there was a decrease in carbapenem prescription (17.8 DOT vs. 15.4 DOT, OR 0.8 [0.8-0.9] p<.001). CONCLUSIONS: There was an escalation of blaMBL-KPN rate two years after CZA introduction, leading to a decrease in CZA and carbapenem susceptibility and an increase in CZA and aztreonam prescriptions.

Ceftazidime-avibactam resistance determination in carbapenem-resistant Klebsiella pneumoniae infections before its use in practice.

INTRODUCTION: To ensure the appropriate usage of ceftazidime-avibactam (CAZ-AVI), recently introduced in our hospital, we aimed to determine susceptibility rates, enzyme analysis, and clonal relationship among strains, together with clinical data. METHODOLOGY: Between June 1 and September 30, 2021, demographic and microbiological data of the patients were recorded. In the obtained samples, meropenem and colistin minimal inhibitory concentration (MIC) levels, carbapenem resistance genes, and the clonal relationship were studied by molecular methods. CAZ-AVI was not used in any of the patients. RESULTS: 140 carbapenem-resistant Klebsiella pneumoniae were isolated from 57 patients. Resistance to CAZ-AVI was found in 76 (54.3%) strains. Out of 57 patients, 31 (54.4%) isolates could be reached. Meropenem MIC level was ≥ 32 µg/mL in 26 (83.9%), and colistin MIC level was ≥ 4 µg/mL in 17 (54.8%) isolates. Enzyme analysis revealed NDM in 20 (64.5%), OXA-48 in 17 (54.8%), and KPC in seven (22.6%). NDM + OXA-48 was determined in 10 (32.2%) strains. NDM was determined in all CAZ-AVI resistant strains, OXA-48 in 16.1% (2/5) strains. Seven genotypes were detected. The largest cluster was genotype 3 clusters (11 isolates). Of 31 patients, 22 (71.0%) died. CAZ-AVI was susceptible in one of the patients who survived and four who died. CONCLUSIONS: Before using a new antibiotic, each center should determine the basal data and phenotypic/genotypic resistance ratios specific to that antibiotic. While a high NDM rate and low CAZ-AVI sensitivity limit the use of the drug in our center, it is clear that CAZ-AVI use in sensitive strains will decrease mortality.

Difficult to treat Pseudomonas: successful salvage therapy with cefepime-zidebactam.

Carbapenem-resistant Pseudomonas aeruginosa (CRPa) infection is extremely challenging to manage. Cefepime-zidebactam is a novel combination that can be considered for salvage therapy when no other antimicrobials are susceptible. A 15-y-old boy presented with 56% thermal burns, followed by skin and soft tissue infection, secondary bacteraemia, complicated parapneumonic effusion and endophthalmitis due to CRPa, which was not susceptible to any of the routinely available antibiotics. He was treated with cefepime-zidebactam for 45 d, with which he recovered.

A Systematic Review of the Pharmacokinetics and Pharmacodynamics of Novel Beta-Lactams and Beta-Lactam with Beta-Lactamase Inhibitor Combinations for the Treatment of Pneumonia Caused by Carbapenem-Resistant Gram-Negative Bacteria.

BACKGROUND: Novel beta-lactams show activity against many multidrug-resistant Gram-negative bacteria that cause severe lung infections. Understanding pharmacokinetic/pharmacodynamic characteristics of these agents may help optimise outcomes in the treatment of pneumonia. OBJECTIVES: To describe and appraise studies that report pulmonary pharmacokinetic and pharmacodynamic data of cefiderocol, ceftazidime/avibactam, ceftolozane/tazobactam, imipenem/cilastatin/relebactam and meropenem/vaborbactam. METHODS: MEDLINE (PubMed), Embase, Web of Science and Scopus libraries were used for the literature search. Pulmonary population pharmacokinetic and pharmacokinetic/pharmacodynamic studies on adult patients receiving cefiderocol, ceftazidime/avibactam, ceftolozane/tazobactam, imipenem/cilastatin/relebactam, and meropenem/vaborbactam published in peer-reviewed journals were included. Two independent authors screened, reviewed and extracted data from included articles. A reporting guideline for clinical pharmacokinetic studies (ClinPK statement) was used for bias assessment. Relevant outcomes were included, such as population pharmacokinetic parameters and probability of target attainment of dosing regimens. RESULTS: Twenty-four articles were included. There was heterogeneity in study methods and reporting of results, with diversity across studies in adhering to the ClinPK statement checklist. Ceftolozane/tazobactam was the most studied agent. Only two studies collected epithelial lining fluid samples from patients with pneumonia. All the other phase I studies enrolled healthy subjects. Significant population heterogeneity was evident among available population pharmacokinetic models. Probabilities of target attainment rates above 90% using current licensed dosing regiments were reported in most studies. CONCLUSIONS: Although lung pharmacokinetics was rarely described, this review observed high target attainment using plasma pharmacokinetic data for all novel beta-lactams. Future studies should describe lung pharmacokinetics in patient populations at risk of carbapenem-resistant pathogen infections.

Clinical outcomes in patients infected with ertapenem-only-resistant Enterobacterales versus multi-carbapenem-resistant Enterobacterales.

BACKGROUND: Use of anti-carbapenem-resistant Enterobacterales (anti-CRE) agents such as ceftazidime/avibactam has been associated with improved clinical outcome in cohorts that primarily include patients infected with CRE that are resistant to meropenem (MCRE). OBJECTIVES: To clarify whether patients with CRE resistant to ertapenem but susceptible to meropenem (ertapenem-only-resistant Enterobacterales; EORE) benefit from therapy with anti-CRE agents. METHODS: Patients treated for CRE infection in hospitals in the USA between 2016 and 2019 and enrolled in the CRACKLE-2 study were included. The primary outcome was the desirability of outcome ranking (DOOR) assessed at 30 days after index cultures. RESULTS: The EORE group included 213 patients and the MCRE group included 643. The demographics were similar between the groups except for the patients' race and origin before admission. The MCRE group received anti-CRE agents for definitive therapy significantly more frequently compared with the EORE group (30% versus 5% for ceftazidime/avibactam). We did not observe a significant difference between the groups in the adjusted DOOR probability of a more desirable outcome for a randomly selected patient in the EORE group compared with the MCRE group (52.5%; 95% CI, 48.3%-56.7%). The MCRE group had a similar proportion of patients who died at 30 days (26% versus 21%) and who were discharged to home (29% versus 40%), compared with the EORE group. CONCLUSIONS: Patients with clinical EORE infection rarely received anti-CRE agents, but attained similar outcomes compared with patients with MCRE infection. The findings support current IDSA treatment guidance for meropenem- or imipenem-based therapy for treatment of EORE infections.

Tracking emergence and outbreak of Klebsiella pneumoniae co-producing NDM-1 and KPC-2 after sulfamethoxazole-trimethoprim treatment: Insights from genetic analysis.

The co-production of KPC and NDM carbapenemases in carbapenem-resistant Klebsiella pneumoniae (CRKP) complicates clinical treatment and increases mortality rates. The emergence of KPC-NDM CRKP is believed to result from the acquisition of an NDM plasmid by KPC CRKP, especially under the selective pressure of ceftazidime-avibactam (CZA). In this study, a CRKP-producing KPC-2 (JNP990) was isolated from a patient at a tertiary hospital in Shandong Province, China. Following sulfamethoxazole-trimethoprim (SXT) treatment, the isolate evolved into a strain that co-produces KPC and NDM (JNP989), accompanied by resistance to SXT (minimum inhibitory concentration >2/38 µg/mL) and CZA (dd ≤14 mm). Whole-genome sequencing and S1 nuclease pulsed-field gel electrophoresis revealed that JNP989 acquired an IncC plasmid (NDM plasmid) spanning 197 kb carrying sul1 and blaNDM-1 genes. The NDM plasmid could be transferred successfully into Escherichia coli J53 at a conjugation frequency of (8.70±2.47) × 10-4. The IncFⅡ/IncR plasmid carrying the blaKPC-2 gene in JNP990 could only be transferred in the presence of the NDM plasmid at a conjugation frequency of (1.93±0.41) × 10-5. Five CRKP strains with the same resistance pattern as JNP989, belonging to the same clone as JNP989, with sequence type 11 were isolated from other patients in the same hospital. Two strains lost resistance to CZA due to the loss of the blaNDM-1-carrying fragment mediated by insertion sequence 26. Plasmid stability testing indicated that the IncC plasmid was more stable than the blaNDM-1 genes in the hosts. This study describes the evolution of KPC-NDM CRKP and its spread in hospitalized patients following antibiotic treatment, highlighting the severity of the spread of resistance.

In vivo emergence of cefiderocol and ceftazidime/avibactam cross-resistance in KPC-producing Klebsiella pneumoniae following ceftazidime/avibactam -based therapies.

We described the emergence of ceftazidime/avibactam and cefiderocol cross-resistance in patients with KPC-producing Klebsiella pneumoniae infections. All strains with ceftazidime/avibactam and cefiderocol cross-resistance showed point mutations on KPC Ω-loop. Taken together, our results indicate that prolonged exposure to ceftazidime/avibactam can confer cross-resistance to ceftazidime/avibactam and cefiderocol.

Using host-mimicking conditions and a murine cutaneous abscess model to identify synergistic antibiotic combinations effective against Pseudomonas aeruginosa.

Antibiotic drug combination therapy is critical for the successful treatment of infections caused by multidrug resistant pathogens. We investigated the efficacy of ß-lactam and ß-lactam/ß-lactamase inhibitor combinations with other antibiotics, against the hypervirulent, ceftazidime/avibactam resistant Pseudomonas aeruginosa Liverpool epidemic strain (LES) B58. Although minimum inhibitory concentrations in vitro differed by up to eighty-fold between standard and host-mimicking media, combinatorial effects only marginally changed between conditions for some combinations. Effective combinations in vitro were further tested in a chronic, high-density murine infection model. Colistin and azithromycin demonstrated combinatorial effects with ceftazidime and ceftazidime/avibactam both in vitro and in vivo. Conversely, while tobramycin and tigecycline exhibited strong synergy in vitro, this effect was not observed in vivo. Our approach of using host-mimicking conditions and a sophisticated animal model to evaluate drug synergy against bacterial pathogens represents a promising approach. This methodology may offer insights into the prediction of combination therapy outcomes and the identification of potential treatment failures.

Clinical outcomes and risk factors for mortality in recipients with carbapenem-resistant gram-negative bacilli infections after kidney transplantation treated with ceftazidime-avibactam: a retrospective study.

Background: Ceftazidime-avibactam is a treatment option for carbapenem-resistant gram-negative bacilli (CR-GNB) infections. However, the risk factors associated with ceftazidime-avibactam (CAZ-AVI) treatment failure in kidney transplant (KT) recipients and the need for CAZ-AVI-based combination therapy remain unclear. Methods: From June 2019 to December 2023, a retrospective observational study of KT recipients with CR-GNB infection treated with CAZ-AVI was conducted, with the primary outcome being 30-day mortality and secondary outcomes being clinical cure, microbiological cure, and safety. Risk factors for 30-day mortality and clinical failure were also investigated. Results: A total of 81 KT recipients treated with CAZ-AVI were included in this study. Forty recipients (49.4%) received CAZ-AVI monotherapy, with a 30-day mortality of 22.2%. The clinical cure and microbiological cure rates of CAZ/AVI therapy were 72.8% and 66.7%, respectively. CAZ-AVI alone or in combination with other medications had no effect on clinical cure or 30-day mortality. Multivariate logistic regression analysis revealed that a higher Acute Physiology and Chronic Health Evaluation (APACHE) II score (odds ratio [OR]: 4.517; 95% confidence interval [CI]: 1.397-14.607; P = 0.012) was an independent risk factor for 30-day mortality. Clinical cure was positively associated with the administration of CAZ-AVI within 48 hours of infection onset (OR: 11.009; 95% CI: 1.344-90.197; P=0.025) and negatively associated with higher APACHE II scores (OR: 0.700; 95% CI: 0.555-0.882; P=0.002). Four (4.9%) recipients experienced recurrence within 90 days after the initial infection, 3 (3.7%) recipients experienced CAZ-AVI-related adverse events, and no CAZ-AVI resistance was identified. Conclusion: CAZ-AVI is an effective medication for treating CR-GNB infections following kidney transplantation, even as monotherapy. Optimization of CAZ/AVI therapy (used within 48 hours of infection onset) is positively associated with potential clinical benefit. Further larger-scale studies are needed to validate these findings.

Outcomes of 23 patients diagnosed with New Delhi metallo-beta-lactamase (NDM)-producing Klebsiella pneumoniae infection treated with ceftazidime/avibactam and aztreonam at a single center in Poland.

PURPOSE: Amongst all etiologic hospital-acquired infection factors, K. pneumoniae strains producing New Delhi metallo-ß-lactamase (KP-NDM) belong to pathogens with the most effective antibiotic resistance mechanisms. Clinical guidelines recommend using ceftazidime/avibactam with aztreonam (CZA + AT) as the preferred option for NDM-producing Enterobacterales. However, the number of observations on such treatment regimen is limited. This retrospective study reports the clinical and microbiological outcomes of 23 patients with KP-NDM hospital-acquired infection treated with CZA + AT at a single center in Poland. METHODS: The isolates were derived from the urine, lungs, blood, peritoneal cavity, wounds, and peritonsillar abscess. In microbiological analysis, mass spectrometry for pathogen identification, polymerase chain reaction, or an immunochromatographic assay for detection of carbapenemase, as well as VITEK-2 system, broth microdilution, and microdilution in agar method for antimicrobial susceptibility tests were used, depending of the pathogens' nature. CZA was administered intravenously (IV) at 2.5 g every eight hours in patients with normal kidney function, and aztreonam was administered at 2 g every eight hours IV. Such dosage was modified when renal function was reduced. RESULTS: KP-NDM was eradicated in all cases. Four patients (17.4%) died: three of them had a neoplastic disease, and one - a COVID-19 infection. CONCLUSION: The combination of CZA + AT is a safe and effective therapy for infections caused by KP-NDM, both at the clinical and microbiological levels. The synergistic action of all compounds resulted in a good agreement between the clinical efficacy of CZA + AT and the results of in vitro susceptibility testing.

In vitro and in vivo activity of ceftazidime/avibactam and aztreonam alone or in combination against mcr-9, serine- and metallo-ß-lactamases-co-producing carbapenem-resistant Enterobacter cloacae complex.

PURPOSE: Enterobacteriaceae carrying mcr-9, in particularly those also co-containing metallo-ß-lactamase (MBL) and TEM type ß-lactamase, present potential transmission risks and lack adequate clinical response methods, thereby posing a major threat to global public health. The aim of this study was to assess the antimicrobial efficacy of a combined ceftazidime/avibactam (CZA) and aztreonam (ATM) regimen against carbapenem-resistant Enterobacter cloacae complex (CRECC) co-producing mcr-9, MBL and TEM. METHODS: The in vitro antibacterial activity of CZA plus ATM was evaluated using a time-kill curve assay. Furthermore, the in vivo interaction between CZA plus ATM was confirmed using a Galleria mellonella (G. mellonella) infection model. RESULTS: All eight clinical strains of CRECC, co-carrying mcr-9, MBL and TEM, exhibited high resistance to CZA and ATM. In vitro time-kill curve analysis demonstrated that the combination therapy of CZA + ATM exerted significant bactericidal activity against mcr-9, MBL and TEM-co-producing Enterobacter cloacae complex (ECC) isolates with a 100% synergy rate observed in our study. Furthermore, in vivo survival assay using Galleria mellonella larvae infected with CRECC strains co-harboring mcr-9, MBL and TEM revealed that the CZA + ATM combination significantly improved the survival rate compared to the drug-treatment alone and untreated control groups. CONCLUSION: To our knowledge, this study represents the first report on the in vitro and in vivo antibacterial activity of CZA plus ATM against CRECC isolates co-harboring mcr-9, MBL and TEM. Our findings suggest that the combination regimen of CZA + ATM provides a valuable reference for clinicians to address the increasingly complex antibiotic resistance situation observed in clinical microorganisms.

Characterization of Acinetobacter baumannii-calcoaceticus complex isolates and microbiological outcome for patients treated with sulbactam-durlobactam in a phase 3 trial (ATTACK).

Acinetobacter baumannii-calcoaceticus complex (ABC) causes severe, difficult-to-treat infections that are frequently antibiotic resistant. Sulbactam-durlobactam (SUL-DUR) is a targeted ß-lactam/ß-lactamase inhibitor combination antibiotic designed to treat ABC infections, including those caused by multidrug-resistant strains. In a global, pathogen-specific, randomized, controlled phase 3 trial (ATTACK), the efficacy and safety of SUL-DUR were compared to colistin, both dosed with imipenem-cilastatin as background therapy, in patients with serious infections caused by carbapenem-resistant ABC. Results from ATTACK showed that SUL-DUR met the criteria for non-inferiority to colistin for the primary efficacy endpoint of 28-day all-cause mortality with improved clinical and microbiological outcomes compared to colistin. This report describes the characterization of the baseline ABC isolates from patients enrolled in ATTACK, including an analysis of the correlation of microbiological outcomes with SUL-DUR MIC values and the molecular drivers of SUL-DUR resistance.

Evolution, control and success of combination therapy with Ampicilin-sulbactam/Ceftazidime-Avibactam during a Carbapenem-Resistant Acinetobacter baumannii outbreak in burn Intensive Care Unit.

We present our findings on interpatient transmission, epidemic control measures, and the outcomes of a series of ten critically ill burn patients who were either colonized or infected with carbapenem-resistant Acinetobacter baumannii (CRAB). None of the five infected patients achieved clinical cure, and all experienced relapses. Microbiological failure was observed in 40% of the infected patients. The isolated CRAB strains were found to carry blaOXA-23 and armA resistance genes. Despite the lack of clinical cure, all five infected patients survived and were discharged from the Burn Intensive Care Unit.