Sulbactam–durlobactam for infections caused by Acinetobacter baumannii–calcoaceticus complex – Authors' reply

We thank Simone Giuliano and colleagues for their comments and feedback on our Article disclosing results from the ATTACK trial, a multicentre, randomised, active-controlled, phase 3, non-inferiority clinical trial comparing the efficacy comparing the efficacy and safety of sulbactam–durlobactam versus colistin in patients with serious infections caused by carbapenem-resistant Acinetobacter baumannii–calcoaceticus complex (ABC).1Kaye KS Shorr AF Wunderink RG et al.Efficacy and safety of sulbactam–durlobactam versus colistin for the treatment of patients with serious infections caused by Acinetobacter baumannii–calcoaceticus complex: a multicentre, randomised, active-controlled, phase 3, non-inferiority clinical trial (ATTACK).Lancet Infect Dis. 2023; (published online May 11.)https://doi.org/10.1016/S1473-3099(23)00184-6PubMed Google Scholar Sulbactam–durlobactam is a targeted antibiotic combination of sulbactam, a β-lactam antibacterial with intrinsic activity against ABC, and durlobactam, a β-lactamase inhibitor, with activity against Ambler class A, C, and D serine β-lactamases.2Noguchi JK Gill MA Sulbactam: a β-lactamase inhibitor.Clin Pharm. 1988; 7: 37-51PubMed Google Scholar, 3Durand-Réville TF Guler S Comita-Prevoir J et al.ETX2514 is a broad-spectrum β-lactamase inhibitor for the treatment of drug-resistant Gram-negative bacteria including Acinetobacter baumannii.Nat Microbiol. 2017; 217104Crossref PubMed Scopus (165) Google Scholar In the ATTACK trial, all patients received imipenem–cilastatin as background therapy to treat non-ABC, co-infecting pathogens.1Kaye KS Shorr AF Wunderink RG et al.Efficacy and safety of sulbactam–durlobactam versus colistin for the treatment of patients with serious infections caused by Acinetobacter baumannii–calcoaceticus complex: a multicentre, randomised, active-controlled, phase 3, non-inferiority clinical trial (ATTACK).Lancet Infect Dis. 2023; (published online May 11.)https://doi.org/10.1016/S1473-3099(23)00184-6PubMed Google Scholar As Giuliano and colleagues indicate, sulbactam in combination with a carbapenem has been proposed for the treatment of carbapenem-resistant A baumannii (CRAB) on the premise that this treatment would result in the saturation of penicillin-binding proteins (PBPs). Consistent with this proposal, current treatment guidance from the Infectious Diseases Society of America recommends sulbactam-based combination therapy for the treatment of moderate and severe CRAB infections. However, the superiority of combination therapy has not been shown.4Tamma PD Aitken SL Bonomo RA Mathers AJ van Duin D Clancy CJ IDSA 2023 guidance on the treatment of antimicrobial resistant Gram-negative infections.https://www.idsociety.org/practice-guideline/amr-guidance/Date: 2023Date accessed: June 13, 2023Google Scholar As durlobactam is a β-lactamase inhibitor, it has the capacity to protect both sulbactam and imipenem from degradation by the β-lactamases typically encoded by contemporary clinical isolates of CRAB.3Durand-Réville TF Guler S Comita-Prevoir J et al.ETX2514 is a broad-spectrum β-lactamase inhibitor for the treatment of drug-resistant Gram-negative bacteria including Acinetobacter baumannii.Nat Microbiol. 2017; 217104Crossref PubMed Scopus (165) Google Scholar Giudliano and colleagues suggest this activity has the potential to confound the interpretation of sulbactam–durlobactam efficacy in the ATTACK trial and that we should assess any contributions of imipenem to sulbactam–durlobactam activity. Our preclinical studies show that sulbactam–durlobactam does not need to be combined with imipenem to treat infections caused by CRAB isolates with sulbactam–durlobactam minimum inhibitory concentration (MIC) values of 4 μg/mL or less (ie, the susceptibility breakpoint).5US Food and Drug AdministrationFDA-recognized antimicrobial susceptibility test interpretive criteria.https://www.fda.gov/drugs/development-resources/fda-recognized-antimicrobial-susceptibility-test-interpretive-criteriaDate: 2023Date accessed: June 13, 2023Google Scholar Efficacy studies of murine neutropenic thigh and lung models of infection with CRAB isolates show more than 2·5 log10 reductions in colony forming units per g relative to the starting inoculum in the presence of sulbactam–durlobactam without imipenem.3Durand-Réville TF Guler S Comita-Prevoir J et al.ETX2514 is a broad-spectrum β-lactamase inhibitor for the treatment of drug-resistant Gram-negative bacteria including Acinetobacter baumannii.Nat Microbiol. 2017; 217104Crossref PubMed Scopus (165) Google Scholar Simulations of clinical regimens of sulbactam–durlobactam in hollow-fibre and one-compartment infection models also show that bactericidal activity against CRAB strains with MICs of 4 μg/mL or less is achieved and that the addition of imipenem does not contribute to this activity.6Tanudra A McLeod SM Miller A Tommasi R O'Donnell JP Sulbactam–durlobactam (SUL–DUR) in vitro dose response studies with and without imipenem or meropenem against carbapenemase-producing Acinetobacter baumannii utilizing the hollow-fiber infection model.https://www.entasistx.com/application/files/8616/5096/5758/ECCMID_2022_HFIM_Final.pdfDate: 2022Date accessed: July 4, 2023Google Scholar, 7O'Donnell JP Bhavnani SM The pharmacokinetics/pharmacodynamic relationship of durlobactam in combination with sulbactam in in vitro and in vivo infection model systems versus Acinetobacter baumannii–calcoaceticus complex.Clin Infect Dis. 2023; 76: S202-S209Crossref PubMed Scopus (4) Google Scholar Furthermore, we have profiled the in-vitro activity of sulbactam, durlobactam, and imipenem alone and in different combinations. The activity of single, double, and triple combinations of sulbactam, durlobactam, and imipenem against baseline ABC isolates from the ATTACK trial show that sulbactam–durlobactam is the component driving activity (table).8McLeod SM, Carter N, Miller A. In vitro susceptibility of Acinetobacter baumannii–calcoaceticus complex (ABC) to sulbactam–durlobactam in combination with a carbapenem. Copenhagen, Denmark: 33rd European Congress of Clinical Microbiology and Infectious Diseases, 2023; poster presentation P2126.Google Scholar The MIC50 value was 2 μg/mL for sulbactam–durlobactam and 1 μg/mL for the triple combination of imipenem–sulbactam–durlobactam; the MIC90 value was 4 μg/mL for sulbactam–durlobactam and 4 μg/mL for imipenem–sulbactam–durlobactam. These results are supported by checkerboard studies against ten different A baumannii isolates in which indifference between sulbactam–durlobactam and imipenem was seen primarily, with only one instance of synergy.9Carter N McLeod SM Shapiro A Miller A In vitro activity of sulbactam–durlobactam in combination with other antimicrobial agents.https://www.entasistx.com/application/files/1516/5531/8278/Microbe_2022_SUL-DUR_combination_poster_final2.pdfDate: 2022Date accessed: July 4, 2023Google Scholar These data indicate that imipenem does not provide a meaningful contribution to sulbactam–durlobactam activity against sulbactam–durlobactam-susceptible isolates.TableIn-vitro susceptibility of 175 baseline Acinetobacter baumannii–calcoaceticus complex isolates from the ATTACK trialMIC rangeMIC50MIC90Single agentsSulbactam0·25 μg/mL to >64 μg/mL32 μg/mL64 μg/mLDurlobactam0·25 μg/mL to >64 μg/mL64 μg/mL>64 μg/mLImipenem0·12 μg/mL to >64 μg/mL64 μg/mL>64 μg/mLDouble combinationsSulbactam plus 4 μg/mL durlobactam0·25 μg/mL to 32 μg/mL2 μg/mL4 μg/mLImipenem plus 4 μg/mL durlobactam0·12 μg/mL to 64 μg/mL16 μg/mL32 μg/mLSulbactam–imipenem (1:1)0·12 μg/mL to 64 μg/mL16 μg/mL32 μg/mLTriple combinationSulbactam–imipenem (1:1) plus 4 μg/mL durlobactam0·12 μg/mL to 16 μg/mL1 μg/mL4 μg/mLMIC=minimum inhibitory concentration. Open table in a new tab MIC=minimum inhibitory concentration. Although we appreciate the suggestion by Giuliano and colleagues that ATTACK trial data should be analysed for treatment of non-ABC, Gram-negative organisms by imipenem–sulbactam–durlobactam, only approximately 30% of patients had polymicrobial infections1Kaye KS Shorr AF Wunderink RG et al.Efficacy and safety of sulbactam–durlobactam versus colistin for the treatment of patients with serious infections caused by Acinetobacter baumannii–calcoaceticus complex: a multicentre, randomised, active-controlled, phase 3, non-inferiority clinical trial (ATTACK).Lancet Infect Dis. 2023; (published online May 11.)https://doi.org/10.1016/S1473-3099(23)00184-6PubMed Google Scholar and this trial was not designed to evaluate efficacy versus non-ABC, co-infecting pathogens. Results from the ATTACK trial show the safety and efficacy of sulbactam–durlobactam for the treatment of hospital-acquired and ventilator-associated bacterial pneumonia caused by susceptible strains of ABC. Individual treatment approaches will need to be established on a case-by-case basis on the basis of the clinical condition of each patient, microbiological findings, and local bacterial-susceptibility profiles. KSK was a member of the Data Safety Monitoring Committee for the ATTACK trial; has received consulting fees from Entasis Therapeutics, Merck, Shionogi, Qpex Biopharma, GlaxoSmithKline, MicuRx Pharmaceuticals, AbbVie, Johnson & Johnson, Venatorx Pharmaceuticals, and Allecra Therapeutics; and owns stock options in Merck. At the time of the ATTACK trial, SMM, JPO’D, and DA were employees of Entasis Therapeutics. SMM, JPO’D, and DA are currently employees of Innoviva Specialty Therapeutics, an affiliate of Entasis Therapeutics.