Mycobacterium abscessus is a difficult-to-treat, multidrug-resistant human pathogen. Relebactam has been shown to inhibit M. abscessus β-lactamase (BLAMab) and increase the activity of imipenem and amoxicillin. We present two cases of lung infection due to M. abscessus, one caused by M. abscessussubsp. massiliense and the other by subsp. abscessus. Both strains showed moderate sensitivity to imipenem, and the second strain was also resistant to macrolides. A multidrug antibiotic regimen was administered in both cases, which included imipenem/cilastatin/relebactam adjusted to the estimated glomerular filtration rate (eGFR) and amoxicillin for three months. The regimen was well tolerated and both patients improved both clinically and radiologically after the first phase of treatment. The results of our patients indicate that the combination of imipenem/cilastatin/relebactam and amoxicillin could be used in the future in difficult infections by M. abscessus.

UNASSIGNED: Real-life experience with imipenem/cilastatin/relebactam (IMI/REL) for the treatment of KPC-producing Klebsiella pneumoniae complex (KPC-Kp) and difficult-to-treat resistance (DTR) Pseudomonas aeruginosa (DTR-PA) infections is herein described.
UNASSIGNED: Adult patients with KPC-Kp or DTR-PA infections who received ≥48 h of IMI/REL were included. Clinical and microbiological outcomes were retrieved through the medical records. Primary outcome was clinical cure. Secondary outcomes included mortality from infection onset and adverse effects attributable to IMI/REL.
UNASSIGNED: We included 10 patients with different infections caused by DTR-PA (n = 4), KPC-Kp [n = 5, of which 3 ceftazidime/avibactam-resistant (CTV-R KPC-Kp), 2 CTV susceptible (CTV-S KPC-Kp)] or both DTR-PA/KPC-Kp (n = 1) successfully treated with IMI/REL: 3 hospital-acquired pneumonia, 1 ventilator-associated pneumonia, 2 skin and soft tissue infections, 1 osteomyelitis, 2 bloodstream infections, 1 complicated urinary tract infection. Clinical cure was achieved in all cases. No patients died and no side effect were reported.
UNASSIGNED: We reported the preliminary real-life experience on the successful and safe use of IMI/REL for the treatment of KPC-Kp or DTR-PA complicated infections, including pneumonia and bone infections.

(1) Background: Infections caused by multidrug-resistant (MDR) bacteria represent one of the major global public health problems of the 21st century. Beta-lactam antibacterial agents are commonly used to treat infections due to Gram-negative pathogens. New β-lactam/β-lactamase inhibitor combinations are urgently needed. Combining relebactam (REL) with imipenem (IMI) and cilastatin (CS) can restore its activity against many imipenem-nonsusceptible Gram-negative pathogens. (2) Methods: we performed a systematic review of the studies reporting on the use of in vivo REAL/IPM/CS. (3) Results: A total of eight studies were included in this review. The primary diagnosis was as follows: complicated urinary tract infection (n = 234), complicated intra-abdominal infections (n = 220), hospital-acquired pneumonia (n = 276), and ventilator-associated pneumonia (n = 157). Patients with normal renal function received REL/IPM/CS (250 mg/500 mg/500 mg). The most frequently reported AEs occurring in patients treated with imipenem/cilastatin plus REL/IPM/CS were nausea (11.5%), diarrhea (9.8%), vomiting (9.8%), and infusion site disorders (4.0%). Treatment outcomes in these high-risk patients receiving REL/IPM/CS were generally favorable. A total of 70.6% of patients treated with REL/IPM/CS reported a favorable clinical response at follow-up. (4) Conclusions: this review indicates that REL/IPM/CS is active against important MDR Gram-negative organisms.

Bacterial resistance surveillance is one of the main outputs of microbiological laboratories and its results are important part of antimicrobial stewardship (AMS). In this study, the susceptibility of specific bacteria to selected antimicrobial agents was tested. The susceptibility of 90 unique isolates of pathogens of critical priority obtained from clinically valid samples of ICU patients in 2017-2021 was tested. 50% of these fulfilled difficult-to-treat resistance (DTR) criteria and 50% were susceptible to all antibiotics included in the definition. 10 Enterobacterales strains met DTR criteria, and 2 (20%) were resistant to colistin (COL), 2 (20%) to cefiderocol (FCR), 7 (70%) to imipenem/cilastatin/relebactam (I/R), 3 (30%) to ceftazidime/avibactam (CAT) and 5 (50%) to fosfomycin (FOS). For Enterobacterales we also tested aztreonam/avibactam (AZA) for which there are no breakpoints yet. The highest MIC of AZA observed was 1 mg/l, MIC range in the susceptible cohort was 0.032-0.064 mg/l and in the DTR cohort (incl. class B beta-lactamase producers) it was 0.064-1 mg/l. Two (13.3%) isolates of Pseudomonas aeruginosa (15 DTR strains) were resistant to COL, 1 (6.7%) to FCR, 13 (86.7%) to I/R, 5 (33.3%) to CAT, and 5 (33.3%) to ceftolozane/tazobactam. All isolates of Acinetobacter baumannii with DTR were susceptible to COL and FCR, and at the same time resistant to I/R and ampicillin/sulbactam. New antimicrobial agents are not 100% effective against DTR. Therefore, it is necessary to perform susceptibility testing of these antibiotics, use the data for surveillance (including local surveillance) and conform to AMS standards.

We assessed 160 patients who received imipenem/cilastatin/relebactam for ≥2 days. At treatment initiation, the median Charlson Comorbidity Index was 5, 45% were in the intensive care unit, and 19% required vasopressor support. The in-hospital mortality rate was 24%. These data advance our understanding of real-world indications and outcomes of imipenem/cilastatin/relebactam use.

UNASSIGNED: Gram-negative bacteria is a global public health problem. Treatment options include novel beta-lactamase inhibitors.
UNASSIGNED: The objective of this study was to collect information on the efficacy and safety of novel β-lactamase inhibitor combinations such as imipenem-cilastatin/relebactam (IMI/REL).
UNASSIGNED: In order to comprehensively evaluate the clinical, microbiological, and adverse events outcomes, a meta-analysis was conducted on clinical trials comparing novel β-lactamase inhibitor combinations with existing comparator therapies.
UNASSIGNED: Four studies comprising 948 patients were included in the analysis. IMI/REL therapy demonstrated similar clinical responses to comparators across various treatment visits, including discontinuation of intravenously administered therapy visits [DCIV, RR = 1.00 (0.88, 1.12)], early follow-up visits [EFU, RR = 1.00 (0.89, 1.14)], late follow-up visits [LFU, RR = 1.00 (0.88, 1.13)]. Moreover, no significant difference in the microbiologic response of MITT patients was observed between IMI/REL and comparators across DCIV [RR = 0.99 (0.89, 1.11)], EFU [RR = 1.01 (0.95, 1.07)], and LFU visits [RR = 1.00 (90.94, 1.07)]. In terms of safety, therapy with IMI/REL and comparators exhibited similar risks of at least one adverse event (AE), drug-related AEs, and discontinuation due to AEs. The incidence of serious AEs (SAEs) was significantly lower in the IMI/REL group compared to the comparison groups. The predominant AEs were gastrointestinal disorders, with no significant difference observed between the IMI/REL group and comparators.
UNASSIGNED: The clinical and microbiologic response to IMI/REL in the treatment of bacterial infection was comparable to that of the comparator. Furthermore, the incidence of AEs and the tolerability of IMI/REL were similar among the comparators. Based on these findings, IMI/REL can be considered as a viable alternative treatment option.

Imipenem/cilastatin/relebactam is approved for the treatment of serious gram-negative bacterial infections in adults. This study assessed the pharmacokinetics (PK), safety, and tolerability of a single dose of imipenem/cilastatin/relebactam (with a fixed 2:1 ratio of imipenem/cilastatin to relebactam, and with a maximum dose of 15 mg/kg imipenem and 15 mg/kg cilastatin [≤500 mg imipenem and ≤500 mg cilastatin] and 7.5 mg/kg relebactam [≤250 mg relebactam]) in children with confirmed/suspected gram-negative bacterial infections receiving standard-of-care antibacterial therapy. In this phase 1, noncomparative study (ClinicalTrials.gov identifier, NCT03230916), PK parameters from 46 children were analyzed using both population modeling and noncompartmental analysis. The PK/pharmacodynamic (PD) target for imipenem was percent time of the dosing interval that unbound plasma concentration exceeded the minimum inhibitory concentration (%fT>MIC) of ≥30% (MIC = 2 mcg/mL). For relebactam, the PK/PD target was a free drug area under the plasma concentration-time curve (AUC) normalized to MIC (at 2 mcg/mL) of ≥8.0 (equivalent to an AUC from time zero extrapolated to infinity of ≥20.52 mcg·h/mL). Safety was assessed up to 14 days after drug infusion. For imipenem, the ranges for the geometric mean %fT>MIC and maximum concentration (Cmax ) across age cohorts were 56.5%-93.7% and 32.2-38.2 mcg/mL, respectively. For relebactam, the ranges of the geometric mean Cmax and AUC from 0 to 6 hours across age cohorts were 16.9-21.3 mcg/mL and 26.1-55.3 mcg·h/mL, respectively. In total, 8/46 (17%) children experienced ≥1 adverse events (AEs) and 2/46 (4%) children experienced nonserious AEs that were deemed drug related by the investigator. Imipenem and relebactam exceeded plasma PK/PD targets; single doses of imipenem/cilastatin/relebactam were well tolerated with no significant safety concerns identified. These results informed imipenem/cilastatin/relebactam dose selection for further pediatric clinical evaluation.

Aim: This study evaluates the cost-effectiveness of imipenem/cilastatin/relebactam (IMI/REL) for treating hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) in an \'early adjustment prescribing scenario\'. Methods: An economic model was constructed to compare two strategies: continuation of empiric piperacillin/tazobactam (PIP/TAZ) versus early adjustment to IMI/REL. A decision tree was used to depict the hospitalization period, and a Markov model used to capture long-term outcomes. Results: IMI/REL generated more quality-adjusted life years than PIP/TAZ, at an increased cost per patient. The incremental cost-effectiveness ratio of $17,529 per QALY is below the typical US willingness-to-pay threshold. Conclusion: IMI/REL may represent a cost-effective treatment for payers and a valuable option for clinicians, when considered alongside patient risk factors, local epidemiology, and susceptibility data.

BACKGROUND: Imipenem/cilastatin/relebactam (IMI/REL), a combination β-lactam antibiotic (imipenem) with a novel β-lactamase inhibitor (relebactam), is an efficacious and well-tolerated option for the treatment of hospitalized patients with gram-negative (GN) bacterial infections caused by carbapenem-non-susceptible (CNS) pathogens. This study examines cost-effectiveness of IMI/REL vs. colistin plus imipenem (CMS + IMI) for the treatment of infection(s) caused by confirmed CNS pathogens.
METHODS: We developed an economic model comprised of a decision-tree depicting initial hospitalization, and a Markov model projecting long-term health and economic impacts following discharge. The decision tree, informed by clinical data from RESTORE-IMI 1 trial, modeled clinical outcomes (mortality, cure rate, and adverse events including nephrotoxicity) in the two comparison scenarios of IMI/REL versus CMS + IMI for patients with CNS GN infection. Subsequently, a Markov model translated these hospitalization stage outcomes (i.e., death or uncured infection) to long-term consequences such as quality-adjusted life years (QALYs). Sensitivity analyses were conducted to test the model robustness.
RESULTS: IMI/REL compared to CMS + IMI demonstrated a higher cure rate (79.0% vs. 52.0%), lower mortality (15.2% vs. 39.0%), and reduced nephrotoxicity (14.6% vs. 56.4%). On average a patient treated with IMI/REL vs. CMS + IMI gained additional 3.7 QALYs over a lifetime. Higher drug acquisition costs for IMI/REL were offset by shorter hospital length of stay and lower AE-related costs, which result in net savings of $11,015 per patient. Sensitivity analyses suggested that IMI/REL has a high likelihood (greater than 95%) of being cost-effective at a US willingness-to-pay threshold of $100,000-150,000 per QALY.
CONCLUSIONS: For patients with confirmed CNS GN infection, IMI/REL could yield favorable clinical outcomes and may be cost-saving-as the higher IMI/REL drug acquisition cost is offset by reduced nephrotoxicity-related cost-for the US payer compared to CMS + IMI.

Pathogen-focused, randomized, controlled trials (PF-RCT) are important in the fight against carbapenem-resistant (CR) Gram-negative infections. Some recently approved antibiotics and older generic antibiotics with activity against CR Gram-negative bacteria were investigated in PF-RCTs in a variety of infections.
We searched Pubmed, Cochrane database and international clinical trial databases for PF-RCTs for the period between 2005 and 2020 and compared the study designs, patient populations, infection types, pathogens, and Day-28 all-cause mortality (ACM).
PF-RCTs are particularly challenging to quantitatively assess and compare due to the heterogeneity in infection types, pathogens, CR mechanism, inclusion/exclusion criteria, and endpoints. Data interpretation is further complicated by lack of formal statistical analysis plans and/or non-inferiority design, and limited power across most PF-RCTs. The studies with new antibiotics (i.e. plazomicin, meropenem/vaborbactam, cefiderocol) ranked lower regarding feasibility, with relatively small sample sizes (analyzed: 37-118) versus the comparative effectiveness studies of older generic drugs (analyzed: 94-406). ACM ranged between 11.8% and 40% for CR Enterobacterales, 17.7% and 57.4% for CR Acinetobacter spp., and 20.0% and 30.8% for CR Pseudomonas aeruginosa. The information gathered must be considered carefully alongside the study limitations and caution should be exercised when making direct comparisons across trials.PLAIN LANGUAGE SUMMARYNew antibiotics to treat multidrug-resistant Gram-negative bacterial infections are needed because antimicrobial resistance has become a global threat. In recent years, several pathogen-focused, randomized, controlled clinical trials were conducted to test new antibiotics or combinations of older generic antibiotics in the fight against resistant bacteria. However, these trials were exceptionally challenging and most of them enrolled relatively few patients. These studies were highly heterogeneous in terms of species, antibiotics, infection site, mechanism of resistance, endpoints and patient factors. In these trials, all-cause mortality at Day 28 or Day 30 were numerically lower with the new antibiotics in infections caused by carbapenem-resistant (CR) Enterobacterales. However, in the trials which investigated CR Acinetobacter spp. infections, there was no reduction in all-cause mortality at Day 28 or Day 30 with combinations of older generic antibiotics compared with colistin monotherapy. Limited information was available for CR Pseudomonas aeruginosa. More pathogen-focused, randomized, controlled clinical trials with more feasible design and higher patient numbers are needed to demonstrate clinical benefit in drug-resistant infections.