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.

Treatment-emergent cefiderocol resistance in carbapenem-resistant Acinetobacter baumannii is associated with insertion sequence ISAba36 in the siderophore receptor pirA.

We report the emergence of cefiderocol resistance in a blaOXA-72 carbapenem-resistant Acinetobacter baumannii isolate from a sacral decubitus ulcer. Cefiderocol was initially used; however, a newly approved sulbactam-durlobactam therapy with source control and flap coverage was successful in treating the infection. Laboratory investigation revealed cefiderocol resistance mediated by ISAba36 insertion into the siderophore receptor pirA.

Sulbactam-durlobactam susceptibility test method development and quality control ranges for MIC and disk diffusion tests.

Sulbactam-durlobactam is a ß-lactam/ß-lactamase inhibitor combination developed to treat hospital-acquired and ventilator-associated bacterial pneumonia caused by Acinetobacter baumannii-calcoaceticus complex (ABC). Durlobactam is a diazabicyclooctane ß-lactamase inhibitor with potent activity against Ambler classes A, C, and D serine ß-lactamases and restores sulbactam activity against multidrug-resistant ABC. Studies were conducted to establish sulbactam-durlobactam antimicrobial susceptibility testing methods for both broth microdilution minimal inhibitory concentration (MIC) and disk diffusion tests as well as quality control (QC) ranges. To establish the MIC test method, combinations of sulbactam and durlobactam were evaluated using a panel of genetically characterized A. baumannii isolates which were categorized as predicted to be susceptible or resistant based on the spectrum of ß-lactamase inhibition by durlobactam. MIC testing with doubling dilutions of sulbactam with a fixed concentration of 4 µg/mL of durlobactam resulted in the greatest discrimination of the pre-defined susceptible and resistant strains. Similarly, the sulbactam/durlobactam 10/10 µg disk concentration showed the best discrimination as well as correlation with the MIC test. A. baumannii NCTC 13304 was selected for QC purposes because it assesses the activity of both sulbactam and durlobactam with clear endpoints. Multi-laboratory QC studies were conducted according to CLSI M23 Tier 2 criteria. A sulbactam-durlobactam broth MIC QC range of 0.5/4-2/4 µg/mL and a zone diameter QC range of 24-30 mm were determined for A. baumannii NCTC 13304 and have been approved by CLSI. These studies will enable clinical laboratories to perform susceptibility tests with accurate and reproducible methods.

Sulbactam-durlobactam: A Step Forward in Treating Carbapenem-Resistant Acinetobacter baumannii (CRAB) Infections.

Antimicrobial resistance in gram-negative pathogens, such as Acinetobacter baumannii, is a serious threat to human health. Sulbactam-durlobactam, a unique ß-lactam and a ß-lactamase inhibitor combination, is a novel agent targeted against carbapenem-resistant A. baumannii. This supplement provides a summary of the development of SUL-DUR, discussing its unique features and role in treating infections caused by CRAB pathogens.

Pathogen-Targeted Clinical Development to Address Unmet Medical Need: Design, Safety, and Efficacy of the ATTACK Trial.

There is a crucial need for novel antibiotics to stem the tide of antimicrobial resistance, particularly against difficult to treat gram-negative pathogens like Acinetobacter baumannii-calcoaceticus complex (ABC). An innovative approach to addressing antimicrobial resistance may be pathogen-targeted development programs. Sulbactam-durlobactam (SUL-DUR) is a ß-lactam/ß-lactamase inhibitor combination antibiotic that is being developed to specifically target drug-resistant ABC. The development of SUL-DUR culminated with the Acinetobacter Treatment Trial Against Colistin (ATTACK) trial, a global, randomized, active-controlled phase 3 clinical trial that compared SUL-DUR with colistin for treating serious infections due to carbapenem-resistant ABC. SUL-DUR met the primary noninferiority endpoint of 28-day all-cause mortality. Furthermore, SUL-DUR had a favorable safety profile with a statistically significant lower incidence of nephrotoxicity compared with colistin. If approved, SUL-DUR could be an important treatment option for infections caused by ABC, including carbapenem-resistant and multidrug-resistant strains. The development program and the ATTACK trial highlight the potential for pathogen-targeted development programs to address the challenge of antimicrobial resistance.

In Vitro Activity of Sulbactam-Durlobactam against Global Isolates of Acinetobacter baumannii-calcoaceticus Complex Collected from 2016 to 2021.

Sulbactam-durlobactam is a ß-lactam-ß-lactamase inhibitor combination designed to treat serious Acinetobacter baumannii-calcoaceticus complex (ABC) infections, including carbapenem-non-susceptible and multidrug-resistant (MDR) isolates. The current study characterized the in vitro activity of sulbactam-durlobactam against a collection of 5,032 ABC clinical isolates collected in 33 countries across the Asia/South Pacific region, Europe, Latin America, the Middle East, and North America from 2016 to 2021. The sulbactam-durlobactam MIC50 and MIC90 were 1 and 2 µg/mL, respectively, for all ABC isolates tested. The addition of durlobactam (at a fixed concentration of 4 µg/mL) to sulbactam decreased its MIC50 by 8-fold (from 8 to 1 µg/mL) and its MIC90 by 32-fold (from 64 to 2 µg/mL) for all ABC isolates. The in vitro activity of sulbactam-durlobactam was maintained across individual ABC species, years, global regions of collection, specimen sources, and resistance phenotypes, including MDR and extensively drug-resistant (XDR) isolates. At 4 µg/mL (preliminary sulbactam-durlobactam susceptible MIC breakpoint), sulbactam-durlobactam inhibited 98.3% of all ABC isolates and >96% of sulbactam-, imipenem-, ciprofloxacin-, amikacin-, and minocycline-non-susceptible isolates; as well as colistin-resistant, MDR, and XDR isolates. Most imipenem-non-susceptible ABC isolates (96.8%, 2,488/2,570) were carbapenem-resistant A. baumannii (CRAB); 96.9% (2,410/2,488) of CRAB isolates were sulbactam-durlobactam-susceptible. More than 80% of ABC isolates had sulbactam-durlobactam MIC values that were ≥2 doubling-dilutions (4-fold) lower than sulbactam alone. Only 1.7% (84/5,032) of ABC isolates from 2016 to 2021 had sulbactam-durlobactam MIC values of >4 µg/mL. Of the 84 isolates, 94.0% were A. baumannii, 4.8% were A. pittii, and 1.2% were A. nosocomialis. In summary, sulbactam-durlobactam demonstrated potent antibacterial activity against a 2016 to 2021 collection of geographically diverse clinical isolates of ABC isolates, including carbapenem-non-susceptible and MDR isolates.

Extensively Drug-Resistant Acinetobacter baumannii Nosocomial Pneumonia Successfully Treated with a Novel Antibiotic Combination.

Extremely drug-resistant (XDR) Acinetobacter baumannii causes challenging nosocomial infections. We report the case of a patient with XDR A. baumannii pneumonia and septic shock successfully treated with cefiderocol and a novel antibiotic obtained via expanded access protocol. With focused research and drug development efforts, the poor outcomes associated with these infections may be mitigated.

Sulbactam-durlobactam for the treatment of Acinetobacter baumannii-calcoaceticus complex.

INTRODUCTION: Infections with Acinetobacter baumannii-calcoaceticus complex (ABC) pose difficulty for clinicians given a limited arsenal of effective antimicrobials. Sulbactam/durlobactam provides a novel treatment option for patients experiencing hospital- or ventilator-acquired pneumonia with susceptible strains. AREAS COVERED: This review provides a comprehensive discussion of sulbactam/durlobactam, including basic characteristics, in vitro activity, and clinical trial data supporting its use for the treatment of ABC. Manufacturer's data, published literature to date, and conference data are utilized in this review. EXPERT OPINION: Sulbactam/durlobactam offers clinicians a new and effective treatment option for resistant ABC infection. Sulbactam, when combined with durlobactam, displays enhanced potency against ABC isolates, which has translated into positive clinical outcomes observed in clinical trials and post-marketing case studies. Although overall treatment indications and clinical experience are limited to date, sulbactam/durlobactam offers a familiar and favorable safety profile in comparison with alternative agents. Factors associated with use of combination antibiotic therapy, availability of commercial drug susceptibility testing, and cost-effectiveness are all currently key considerations for sulbactam/durlobactam use.

Clinical Outcomes for Patients With Monomicrobial vs Polymicrobial Acinetobacter baumannii-calcoaceticus Complex Infections Treated With Sulbactam-Durlobactam or Colistin: A Subset Analysis From a Phase 3 Clinical Trial.

Background: In a previous study, the efficacy and safety of sulbactam-durlobactam vs colistin for the treatment of patients with carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex (CRABC) infections were evaluated in a randomized controlled phase 3 trial. Both arms were dosed on a background of imipenem-cilastatin to treat coinfecting gram-negative pathogens. Thirty-six percent of infections in the primary efficacy population were polymicrobial. Methods: A subset analysis was performed to compare clinical and microbiological outcomes at test of cure (7 ± 2 days after the last dose) for patients with monomicrobial and polymicrobial CRABC infections. Minimal inhibitory concentrations of antibiotics against baseline isolates were determined by broth microdilution according to Clinical and Laboratory Standards Institute methodology. Results: Clinical cure, 28-day all-cause mortality, and microbiological outcomes were similar for patients in the sulbactam-durlobactam treatment arm with monomicrobial or polymicrobial A baumannii-calcoaceticus infections. Patients in the colistin arm with monomicrobial CRABC infections had higher mortality rates with worse clinical and microbiological outcomes as compared with those with polymicrobial infections. For patients who received sulbactam-durlobactam, imipenem susceptibility of coinfecting gram-negative pathogens trended with clinical benefit for patients with polymicrobial A baumannii-calcoaceticus infections. When tested in vitro, durlobactam restored imipenem susceptibility to the majority of coinfecting gram-negative pathogens from the sulbactam-durlobactam arm. This phenotype appeared to be related to the clinical outcome in 13 of 15 evaluable cases. Conclusions: These results suggest that the use of sulbactam-durlobactam plus a carbapenem could be an effective approach to treat polymicrobial infections that include CRABC, but additional clinical data are needed to demonstrate efficacy.

In vitro antibacterial activity of sulbactam-durlobactam in combination with other antimicrobial agents against Acinetobacter baumannii-calcoaceticus complex.

Combinations of the ß-lactam/ß-lactamase inhibitor sulbactam-durlobactam and seventeen antimicrobial agents were tested against strains of Acinetobacter baumannii in checkerboard assays. Most combinations resulted in indifference with no instances of antagonism. These results suggest sulbactam-durlobactam antibacterial activity against A. baumannii is unlikely to be affected if co-dosed with other antimicrobial agents.

Potentially effective antimicrobial treatment for pneumonia caused by isolates of carbapenem-resistant and extensively drug-resistant Acinetobacter baumannii complex species: what can we expect in the future?

INTRODUCTION: Acinetobacter baumannii complex (Abc) is currently a significant cause of difficult-to-treat pneumonia. Due to the high prevalence rates of carbapenem- and extensively drug-resistant (CR, XDR) phenotypes, limited antibiotic options are available for the effective treatment of pneumonia caused by CR/XDR-Abc. AREAS COVERED: In vitro susceptibility data, relevant pharmacokinetic profiles (especially the penetration ratios from plasma into epithelial-lining fluid), and pharmacodynamic indices of key antibiotics against CR/XDR-Abc are reviewed. EXPERT OPINION: Doubling the routine intravenous maintenance dosages of conventional tigecycline (100 mg every 12 h) and minocycline (200 mg every 12 h) might be recommended for the effective treatment of pneumonia caused by CR/XDR-Abc. Nebulized polymyxin E, novel parenteral rifabutin BV100, and new polymyxin derivatives (SPR206, MRX-8, and QPX9003) could be considered supplementary combination options with other antibiotic classes. Regarding other novel antibiotics, the potency of sulbactam-durlobactam (1 g/1 g infused over 3 h every 6 h intravenously) combined with imipenem-cilastatin, and the ß-lactamase inhibitor xeruborbactam, is promising. Continuous infusion of full-dose cefiderocol is likely an effective treatment regimen for CR/XDR-Abc pneumonia. Zosurabalpin exhibits potent anti-CR/XDR-Abc activity in vitro, but its practical use in clinical therapy remains to be evaluated. The clinical application of antimicrobial peptides and bacteriophages requires validation.

Case report: Successful treatment of OXA-23 Acinetobacter baumannii neurosurgical infection and meningitis with sulbactam-durlobactam combination therapy.

Meningitis caused by Acinetobacter species is a rare complication of neurosurgical procedures, although it is associated with high morbidity and mortality. Carbapenem-resistant Acinetobacter is particularly difficult to treat, considering the limited selection and tolerability of effective antimicrobials. Sulbactam-durlobactam was approved by the FDA in 2023 for treatment of hospital-acquired and ventilator-associated pneumonia due to susceptible strains of Acinetobacter, including carbapenem-resistant Acinetobacter baumannii. Here, we present a case of carbapenem-resistant Acinetobacter baumannii neurosurgical infection and meningitis successfully treated with sulbactam-durlobactam combination therapy.

Antibiotic Treatment of Carbapenem-Resistant Acinetobacter baumannii Infections in View of the Newly Developed ß-Lactams: A Narrative Review of the Existing Evidence.

It is estimated that antimicrobial resistance (AMR) is responsible for nearly 5 million human deaths worldwide each year and will reach 10 million by 2050. Carbapenem-resistant Acinetobacter baumannii (CRAB) infections represent the fourth-leading cause of death attributable to antimicrobial resistance globally, but a standardized therapy is still lacking. Among the antibiotics under consideration, Sulbactam/durlobactam seems to be the best candidate to replace current back-bone agents. Cefiderocol could play a pivotal role within combination therapy regimens. Due to toxicity and the pharmacokinetics/pharmacodynamics (PK/PD) limitations, colistin (or polymyxin B) should be used as an alternative agent (when no other options are available). Tigecycline (or minocycline) and fosfomycin could represent suitable partners for both NBLs. Randomized clinical trials (RCTs) are needed to better evaluate the role of NBLs in CRAB infection treatment and to compare the efficacy of tigecycline and fosfomycin as partner antibiotics. Synergism should be tested between NBLs and "old" drugs (rifampicin and trimethoprim/sulfamethoxazole). Huge efforts should be made to accelerate pre-clinical and clinical studies on safer polymyxin candidates with improved lung activity, as well as on the iv rifabutin formulation. In this narrative review, we focused the antibiotic treatment of CRAB infections in view of newly developed ß-lactam agents (NBLs).

Sulbactam-durlobactam: a ß-lactam/ß-lactamase inhibitor combination targeting Acinetobacter baumannii.

Sulbactam-durlobactam is a pathogen-targeted ß-lactam/ß-lactamase inhibitor combination that has been approved by the US FDA for the treatment of hospital-acquired and ventilator-associated bacterial pneumonia caused by susceptible isolates of Acinetobacter baumannii-calcoaceticus complex (ABC) in patients 18 years of age and older. Sulbactam is a penicillin derivative with antibacterial activity against Acinetobacter but is prone to hydrolysis by ß-lactamases encoded by contemporary isolates. Durlobactam is a diazabicyclooctane ß-lactamase inhibitor with activity against Ambler classes A, C and D serine ß-lactamases that restores sulbactam activity both in vitro and in vivo against multidrug-resistant ABC. Sulbactam-durlobactam is a promising alternative therapy for the treatment of serious Acinetobacter infections, which can have high rates of mortality.

Sulbactam­durlobactam: a drug for treating lung infectionsAcinetobacter is a type of bacteria. One type, called CRAB, causes serious infections and can be fatal. CRAB is very hard to treat because most drugs no longer work. Sulbactam­durlobactam (SUL-DUR) is a drug that can kill CRAB. The US FDA approved SUL-DUR in May of 2023 for treating lung infections (pneumonia) caused by CRAB. This article explains how SUL-DUR works. Use of SUL-DUR and other drugs to treat these types of infections are discussed. In conclusion, SUL-DUR is a promising therapy for serious infections caused by CRAB.

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.

Friends or foes? Novel antimicrobials tackling MDR/XDR Gram-negative bacteria: a systematic review.

Gram-negative bacteria have been one of the most studied classes in the field of microbiology, especially in the context of globally alarming antimicrobial resistance levels to these pathogens over the course of the past decades. With high numbers of these microorganisms being described as multidrug-resistant (MDR), or even extended-drug-resistant (XDR) bacteria, specialists in the field have been struggling to keep up with higher prevalence of difficult-to-treat infections caused by such superbugs. The FDA approval of novel antimicrobials, such as cefiderocol (FDC), ceftolozane/tazobactam (C/T), ceftazidime/avibactam (CZA), imipenem/relebactam (IMR), sulbactam/durlobactam (SUL-DUR) and phase 3 clinical trials' results of aztreonam/avibactam (ATM-AVI) has proven that, while all these substances provide encouraging efficacy rates, antibiotic resistance keeps up with the pace of drug development. Microorganisms have developed more extensive mechanisms of resistance in order to target the threat posed by these novel antimicrobials, thus equiring researchers to be on a constant lookout for other potential drug candidates and molecule development. However, these strategies require a proper understanding of bacterial resistance mechanisms to gain a comprehensive outlook on the issue. The present review aims to highlight these six antibiotic agents, which have brought hope to clinicians during the past decade, discussing general properties of these substances, as well as mechanisms and patterns of resistance, while also providing a short overview on further directions in the field. Systematic review registration: https://www.crd.york.ac.uk/prospero/#searchadvanced, Identifier CRD42024505832.

Novel Antibiotics for Gram-Negative Nosocomial Pneumonia.

Nosocomial pneumonia, including hospital-acquired pneumonia and ventilator-associated pneumonia, is the leading cause of death related to hospital-acquired infections among critically ill patients. A growing proportion of these cases are attributed to multi-drug-resistant (MDR-) Gram-negative bacteria (GNB). MDR-GNB pneumonia often leads to delayed appropriate treatment, prolonged hospital stays, and increased morbidity and mortality. This issue is compounded by the increased toxicity profiles of the conventional antibiotics required to treat MDR-GNB infections. In recent years, several novel antibiotics have been licensed for the treatment of GNB nosocomial pneumonia. These novel antibiotics are promising therapeutic options for treatment of nosocomial pneumonia by MDR pathogens with certain mechanisms of resistance. Still, antibiotic resistance remains an evolving global crisis, and resistance to novel antibiotics has started emerging, making their judicious use crucial to prolong their shelf-life. This article presents an up-to-date review of these novel antibiotics and their current role in the antimicrobial armamentarium. We critically present data for the pharmacokinetics/pharmacodynamics, the in vitro spectrum of antimicrobial activity and resistance, and in vivo data for their clinical and microbiological efficacy in trials. Where possible, available data are summarized specifically in patients with nosocomial pneumonia, as this cohort may exhibit 'critical illness' physiology that affects drug efficacy.

In vitro activity of cefiderocol against European Pseudomonas aeruginosa and Acinetobacter spp., including isolates resistant to meropenem and recent ß-lactam/ß-lactamase inhibitor combinations.

Carbapenem-resistant Pseudomonas aeruginosa and Acinetobacter spp. represent major threats and have few approved therapeutic options. Non-|fermenting Gram-negative isolates were collected from hospitalized inpatients from 49 sites in 6 European countries between 01 January 2020 and 31 December 2020 and underwent susceptibility testing against cefiderocol and ß-lactam/ß-lactamase inhibitor combinations. Meropenem-resistant (MIC >8 mg/L), cefiderocol-susceptible isolates were analyzed by PCR, and cefiderocol-resistant isolates were analyzed by whole-genome sequencing to identify resistance mechanisms. Overall, 1,451 (950 P. aeruginosa; 501 Acinetobacter spp.) isolates were collected, commonly from the respiratory tract (42.0% and 39.3%, respectively). Cefiderocol susceptibility was higher than |ß|-|l|a|c|t|a|m|/|ß|-|l|a|c|t|a|mase| inhibitor combinations against P. aeruginosa (98.9% vs 83.3%-91.4%), and P. |aeruginosa resistant to meropenem (n = 139; 97.8% vs 12.2%-59.7%), ß-lactam/ß-lactamase inhibitor combinations (93.6%-98.1% vs 10.7%-71.8%), and both meropenem and ceftazidime-avibactam (96.7% vs 5.0%-||45.0%) or |ceftolozane-tazobactam (98.4% vs 8.1%-54.8%), respectively. Cefiderocol and sulbactam-durlobactam susceptibilities were high against Acinetobacter spp. (92.4% and 97.0%) and meropenem-resistant Acineto|bacter |spp. (n = 227; 85.0% and 93.8%) but lower against sulbactam-durlobactam- (n |= 15; 13.3%) and cefiderocol- (n = 38; 65.8%) resistant isolates, respectively. Among meropenem-resistant P. aeruginosa and Acinetobacter spp., the most common ß-||lactamase genes were metallo-ß-lactamases [30/139; blaVIM-2 (15/139)] and oxacillinases [215/227; blaOXA-23 (194/227)], respectively. Acquired ß-lactamase genes were identified in 1/10 and 32/38 of cefiderocol-resistant P. aeruginosa and Acinetobacter spp., and pirA-like or piuA mutations in 10/10 and 37/38, respectively. Conclusion: cefiderocol susceptibility was high against P. aeruginosa and Acinetobacter spp., including meropenem-resistant isolates and those resistant to recent ß-lactam/ß-lactamase inhibitor combinations common in first-line treatment of European non-fermenters. IMPORTANCE: This was the first study in which the in vitro activity of cefiderocol and non-licensed ß-lactam/ß-lactamase inhibitor combinations were directly compared against Pseudomonas aeruginosa and Acinetobacter spp., including meropenem- and ß-lactam/ß-lactamase inhibitor combination-resistant isolates. A notably large number of European isolates were collected. Meropenem resistance was defined according to the MIC breakpoint for high-dose meropenem, ensuring that data reflect antibiotic activity against isolates that would remain meropenem resistant in the clinic. Cefiderocol susceptibility was high against non-fermenters, and there was no apparent cross resistance between cefiderocol and ß-lactam/ß-lactamase inhibitor combinations, with the exception of sulbactam-durlobactam. These results provide insights into therapeutic options for infections due to resistant P. aeruginosa and Acinetobacter spp. and indicate how early susceptibility testing of cefiderocol in parallel with ß-lactam/ß-lactamase inhibitor combinations will allow clinicians to choose the effective treatment(s) from all available options. This is particularly important as current treatment options against non-fermenters are limited.

In Vivo Emergence of Pandrug-Resistant Acinetobacter baumannii Strain: Comprehensive Resistance Characterization and Compassionate Use of Sulbactam-Durlobactam.

The treatment of patients with infection secondary to carbapenem-resistant Acinetobacter baumannii with emerging cefiderocol resistance remains challenging and unclear. We present a case of in vivo emergence of pandrug-resistant A baumannii that was successfully treated with the compassionate use of investigational sulbactam-durlobactam-based antibiotic regimen. We also performed a longitudinal genomic analysis of the bacterial isolates and showed the development of resistance and genetic mutations over time.

Cefiderocol and Sulbactam-Durlobactam against Carbapenem-Resistant Acinetobacter baumannii.

Infections caused by carbapenem-resistant Acinetobacter baumannii (CRAB) remain a clinical challenge due to limited treatment options. Recently, cefiderocol, a novel siderophore cephalosporin, and sulbactam-durlobactam, a bactericidal ß-lactam-ß-lactamase inhibitor combination, have been approved by the Food and Drug Administration for the treatment of A. baumannii infections. In this review, we discuss the mechanisms of action of and resistance to cefiderocol and sulbactam-durlobactam, the antimicrobial susceptibility of A. baumannii isolates to these drugs, as well as the clinical effectiveness of cefiderocol and sulbactam/durlobactam-based regimens against CRAB. Overall, cefiderocol and sulbactam-durlobactam show an excellent antimicrobial activity against CRAB. The review of clinical studies evaluating the efficacy of cefiderocol therapy against CRAB indicates it is non-inferior to colistin/other treatments for CRAB infections, with a better safety profile. Combination treatment is not associated with improved outcomes compared to monotherapy. Higher mortality rates are often associated with prior patient comorbidities and the severity of the underlying infection. Regarding sulbactam-durlobactam, current data from the pivotal clinical trial and case reports suggest this antibiotic combination could be a valuable option in critically ill patients affected by CRAB infections, in particular where no other antibiotic appears to be effective.