Nomogram Based on Clinical Characteristics to Predict 28-Day Mortality Among Patients with CRAB-BSI.

BACKGROUND: The drug resistance of carbapenem-resistant Acinetobacter baumannii bloodstream infections (CRAB-BSI), especially hospital-acquired infections, has promoted their rapid and vast spread. It is necessary to use reliable methods to establish better prediction models. According to Cox proportional hazards regression, a nomogram was established. METHODS: A retrospective cohort study among patients who were diagnosed with CRAB-BSI was performed from January 2020 to December 2022. Univariate and multivariate Cox proportional hazards regression analyses were used to determine independent prognostic factors regarding CRAB-BSI. Then, nomograms were used to calculate the area under the curve (AUC), C-index, and calibration curve to determine the predictive accuracy and dis-criminability. Decision curve analysis (DCA) was employed to further confirm the clinical effectiveness of the nomogram. RESULTS: A total of 98 cases were included in the comparison between the 28-day mortality group consisting of 32 patients and the 28-day survival group with 66 patients. The use of cefoperazone-sulbactam was significantly higher among patients who survived than among those who died. Univariable analysis revealed that factors such as primary diagnosis, time to inadequate antimicrobial therapy, and high serum creatinine and procalcitonin (PCT) levels were more prevalent in the mortality group. However, only primary diagnosis, time to inadequate antimicrobial therapy, and high PCT levels emerged as statistically significant risk factors for death in multivariate analysis and were used to construct the nomogram. The nomogram validation exhibited excellent performance. CONCLUSIONS: The nomogram was sufficiently accurate to predict the risk and prognostic factors of CRAB-BSI, allowing for individualized clinical decisions for future clinical work. The cefoperazone-sulbactam did have an effect, but more studies are needed to interpret it.

In vitro activity of sulbactam-durlobactam against colistin-resistant and/or cefiderocol-non-susceptible, carbapenem-resistant Acinetobacter baumannii collected in U.S. hospitals.

The activity of a novel ß-lactamase inhibitor combination, sulbactam-durlobactam (SUL-DUR), was tested against 87 colistin-resistant and/or cefiderocol-non-susceptible carbapenem-resistant Acinetobacter baumannii clinical isolates collected from U.S. hospitals between 2017 and 2019. Among them, 89% and 97% were susceptible to SUL-DUR and imipenem plus SUL-DUR, with MIC50/MIC90 values of 2 µg/mL/8 µg/mL and 1 µg/mL/4 µg/mL, respectively. The presence of amino acid substitutions in penicillin-binding protein 3, including previously reported A515V or T526S, was associated with SUL-DUR non-susceptibility.

I n vitro pharmacokinetics/pharmacodynamics of the ß-lactamase inhibitor, durlobactam, in combination with sulbactam against Acinetobacter baumannii-calcoaceticus complex.

Infections caused by Acinetobacter baumannii are increasingly multidrug resistant and associated with high rates of morbidity and mortality. Sulbactam is a ß-lactamase inhibitor with intrinsic antibacterial activity against A. baumannii. Durlobactam is a non-ß-lactam ß-lactamase inhibitor with an extended spectrum of activity compared to other inhibitors of its class. In vitro pharmacodynamic infection models were undertaken to establish the pharmacokinetic/pharmacodynamic (PK/PD) index and magnitudes associated with sulbactam and durlobactam efficacy and to simulate epithelial lining fluid (ELF) exposures at clinical doses to understand sulbactam-durlobactam activity with and without co-administration of a carbapenem. Hollow fiber infection models (HFIMs) and one-compartment systems were used to identify the PK/PD indices and exposure magnitudes associated of 1-log10 and 2-log10 colony-forming unit (CFU)/mL reductions. Sulbactam and durlobactam demonstrated PK/PD drivers of % time above the minimum inhibition concentration (%T > MIC) and area under the plasma concentration-time curve from time 0 to 24 h (AUC0-24)/MIC, respectively. Against a sulbactam-susceptible strain, sulbactam %T > MIC of 71.5 and 82.0 were associated with 1-log10 and 2-log10 CFU/mL reductions, respectively, in the HFIM. Against a non-susceptible strain, durlobactam restored the activity of sulbactam with an AUC0-24/MICs of 34.0 and 46.8 using a polysulfone cartridge to achieve a 1-log10 and 2-log10 CFU/mL reduction. These magnitudes were reduced to 13.8 and 24.2, respectively, using a polyvinylidene fluoride cartridge with a membrane pore size of 0.1 µm. In the one-compartment model, durlobactam AUC0-24/MIC to achieve 1-log10 and 2-log10 CFU/mL reduction were 7.6 and 33.4, respectively. Simulations of clinical ELF exposures in the HFIM showed cidal activity at MICs ≤4 µg/mL. Penicillin binding protein 3 mutant strains with MICs of 8 µg/mL may benefit from the addition of a carbapenem at clinical exposures.

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.

Molecular drivers of resistance to sulbactam-durlobactam in contemporary clinical isolates of Acinetobacter baumannii.

Acinetobacter baumannii-calcoaceticus complex (ABC) causes severe infections that are difficult to treat due to pre-existing antibiotic resistance. Sulbactam-durlobactam (SUL-DUR) is a targeted ß-lactam/ß-lactamase inhibitor combination antibiotic designed to treat serious infections caused by Acinetobacter, including multidrug- and carbapenem-resistant strains. In a recent global surveillance study of 5,032 ABC clinical isolates collected from 2016 to 2021, less than 2% of ABC isolates had SUL-DUR MIC values >4 µg/mL. Molecular characterization of these isolates confirmed the primary drivers of resistance are metallo-ß-lactamases or penicillin-binding protein 3 (PBP3) mutations, as previously described. In addition, this study shows that certain common PBP3 variants, such as A515V, are insufficient to confer sulbactam resistance and that the efflux of durlobactam by AdeIJK is likely to play a role in a subset of strains.

In vitro synergy of the combination of sulbactam-durlobactam and cefepime at clinically relevant concentrations against A. baumannii, P. aeruginosa and Enterobacterales.

BACKGROUND: Sulbactam-durlobactam is a potent combination active against Acinetobacter baumannii; however, it lacks activity against other nosocomial pathogens. Cefepime is a common first-line therapy for hospital/ventilator-associated pneumonia caused by Gram-negative pathogens including Pseudomonas aeruginosa and Enterobacterales. With increasing resistance to cefepime, and the significant proportion of polymicrobial nosocomial infections, effective therapy for infections caused by Acinetobacter baumannii, P. aeruginosa and Enterobacterales is needed. This study investigated the in vitro synergy of sulbactam-durlobactam plus cefepime against relevant pathogens. METHODS: Static time-kills assays were performed in duplicate against 14 cefepime-resistant isolates (A. baumannii, n = 4; P. aeruginosa, n = 4; Escherichia coli, n = 3; Klebsiella pneumoniae, n = 3). One WT K. pneumoniae isolate was included. Antibiotic concentrations simulated the free-steady state average concentration of clinically administered doses in patients. RESULTS: Sulbactam-durlobactam alone showed significant activity against A. baumannii consistent with the MIC values. Sulbactam-durlobactam plus cefepime showed synergy against one A. baumannii isolate with an elevated MIC to sulbactam-durlobactam (32 mg/L). Against all P. aeruginosa isolates, synergy was observed with sulbactam-durlobactam plus cefepime. For the Enterobacterales, one E. coli isolate demonstrated synergy while the others were indifferent due to significant kill from sulbactam-durlobactam alone. The combination of sulbactam-durlobactam plus cefepime showed synergy against one of the K. pneumoniae and additive effects against the other two K. pneumoniae tested. No antagonism was observed in any isolates including the WT strain. CONCLUSIONS: Synergy and no antagonism was observed with a combination of sulbactam-durlobactam and cefepime; further in vivo pharmacokinetic/pharmacodynamics data and clinical correlation are necessary to support our findings.

Heterogeneity in M. tuberculosis ß-lactamase inhibition by Sulbactam.

For decades, researchers have elucidated essential enzymatic functions on the atomic length scale by tracing atomic positions in real-time. Our work builds on possibilities unleashed by mix-and-inject serial crystallography (MISC) at X-ray free electron laser facilities. In this approach, enzymatic reactions are triggered by mixing substrate or ligand solutions with enzyme microcrystals. Here, we report in atomic detail (between 2.2 and 2.7 Å resolution) by room-temperature, time-resolved crystallography with millisecond time-resolution (with timepoints between 3 ms and 700 ms) how the Mycobacterium tuberculosis enzyme BlaC is inhibited by sulbactam (SUB). Our results reveal ligand binding heterogeneity, ligand gating, cooperativity, induced fit, and conformational selection all from the same set of MISC data, detailing how SUB approaches the catalytic clefts and binds to the enzyme noncovalently before reacting to a trans-enamine. This was made possible in part by the application of singular value decomposition to the MISC data using a program that remains functional even if unit cell parameters change up to 3 Å during the reaction.

Investigation of three common centrifugation protocols for platelet-rich fibrin (PRF) as a bio-carrier for ampicillin/sulbactam: a prospective trial.

OBJECTIVES: Different platelet-rich fibrin (PRF) protocols exist and are known to differ in resulting mechanical and bioactive properties. Centrifugation parameters may also influence drug release, in particular antibiotics, when using PRF as a bio-carrier. We thus evaluated three common protocols regarding effects on the bio-carrier properties. MATERIALS AND METHODS: In a prospective trial comprising 33 patients, we compared different protocols for PRF as a bio-carrier for ampicillin/sulbactam (SAM). Blood samples were taken shortly after a single dose of ampicillin/sulbactam (2 g/1 g) was administered to patients intravenously. PRF was obtained by centrifugation and three protocols were used: protocol A (1300 rpm, 8 min, RCF-max = 208 g), B (2300 rpm, 12 min, RCF-max = 652 g), and C (1500 rpm, 14 min, RCF-max = 276 g). The antibacterial activity of PRF was investigated against five oral species in vitro, based on agar diffusion methodology. RESULTS: The study demonstrates that a single dose of SAM is sufficient to reach high concentrations in PRF in all protocols (150 µg/ml), which is comparable to the plasma SAM concentration. Antibacterial activity was inferred from the diameter of inhibition zones seen in agar diffusion tests using PRF discs. Protocol B resulted in the largest inhibition zones. One-way ANOVA revealed statistically improved results for protocol B for some bacteria. CONCLUSIONS: The study provides valuable data on PRF antibiotic enrichment, notably SAM. A single dose of SAM is sufficient to reach clinically relevant concentrations in PRF. CLINICAL RELEVANCE: These findings potentially extend the application of PRF, for example in patients with osteonecrosis of the jaw or in oral surgery (e.g., stick bone).

Sulbactam/Durlobactam: First Approval.

Sulbactam/durlobactam (XACDURO®), is a co-packaged antibacterial product that has been developed by Entasis Therapeutics Inc. for the treatment of infections caused by Acinetobacter baumannii-calcoaceticus complex (ABC). Coadministration of durlobactam (a ß-lactamase inhibitor with potent activity against a broad range of serine ß-lactamases) with sulbactam (an established class A ß-lactamase inhibitor with antibacterial activity against A. baumannii) prevents sulbactam degradation by ABC-produced ß-lactamases. In May 2023, sulbactam/durlobactam was approved in the USA for use in patients 18 years of age and older for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) caused by susceptible isolates of ABC. This article summarizes the milestones in the development of sulbactam/durlobactam leading to this first approval for the treatment of infections caused by ABC.

Cefotaxime/sulbactam plus gentamicin as a potential carbapenem- and amikacin-sparing first-line combination for neonatal sepsis in high ESBL prevalence settings.

BACKGROUND: Infection with ESBL-producing Enterobacteriaceae infection is ubiquitous in some neonatal ICUs and increasing levels of antibiotic resistance are a cause for urgent concern. Delineation of bacterial and viral sepsis can be challenging, often leading to patients receiving empirical antibiotics without or whilst waiting for a definitive causal diagnosis. Empirical therapy is often dependent on broad-spectrum 'Watch' antibiotics, contributing to further resistance. METHODS: ESBL-producing Enterobacteriaceae clinical isolates found to have caused neonatal sepsis and meningitis underwent a detailed in vitro screening including susceptibility testing, chequerboard combination analysis and hollow-fibre infection model dynamic analyses using combinations of cefotaxime, ampicillin and gentamicin in combination with ß-lactamase inhibitors. RESULTS: Additivity or synergy was found for all antibiotic combinations against seven Escherichia coli and three Klebsiella pneumoniae clinical isolates. Cefotaxime or ampicillin plus sulbactam combined with gentamicin was able to consistently inhibit the growth of ESBL-producing isolates at typical neonatal doses, and the combination cleared the hollow-fibre infection model system of organisms resistant to each agent alone. The combination of cefotaxime/sulbactam and gentamicin was consistently bactericidal at clinically achievable concentrations (Cmax of 180, 60 and 20 mg/L for cefotaxime, sulbactam and gentamicin, respectively). CONCLUSIONS: The addition of sulbactam to cefotaxime or ampicillin to the typical first-line empirical therapy could obviate the need for carbapenems and amikacin in settings with high ESBL-infection prevalence.

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.

Navigating Available Treatment Options for Carbapenem-Resistant Acinetobacter baumannii-calcoaceticus Complex Infections.

Carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex (CRAB) is one of the top-priority pathogens for new antibiotic development. Unlike other antibiotic-resistant threats, none of the available therapies have been shown to consistently reduce mortality or improve patient outcomes in clinical trials. Antibiotic combination therapy is routinely used in clinical practice; however, the preferred combination has not been defined. This narrative review focuses on evidence-based solutions for the treatment of invasive CRAB infections. We dissect the promise and perils of traditional agents used in combination, such as colistin, sulbactam, and the tetracyclines, and offer clinical pearls based on our interpretation of the available data. Next, we investigate the merits of newly developed ß-lactam agents like cefiderocol and sulbactam-durlobactam, which have demonstrated contrasting results in recent randomized clinical trials. The review concludes with the authors' perspective on the evolving treatment landscape for CRAB infections, which is complicated by limited clinical data, imperfect treatment options, and a need for future clinical trials. We propose that effective treatment for CRAB infections requires a personalized approach that incorporates host factors, the site of infection, pharmacokinetic-pharmacodynamic principles, local molecular epidemiology of CRAB isolates, and careful interpretation of antibiotic susceptibility testing results. In most clinical scenarios, a dose-optimized, sulbactam-based regimen is recommended with the addition of at least one other in vitro active agent. Should sulbactam-durlobactam receive regulatory approval, recommendations will need to be re-evaluated with the most recent evidence.

The Pharmacokinetics/Pharmacodynamic Relationship of Durlobactam in Combination With Sulbactam in In Vitro and In Vivo Infection Model Systems Versus Acinetobacter baumannii-calcoaceticus Complex.

Sulbactam-durlobactam is a ß-lactam/ß-lactamase inhibitor combination currently in development for the treatment of infections caused by Acinetobacter, including multidrug-resistant (MDR) isolates. Although sulbactam is a ß-lactamase inhibitor of a subset of Ambler class A enzymes, it also demonstrates intrinsic antibacterial activity against a limited number of bacterial species, including Acinetobacter, and has been used effectively in the treatment of susceptible Acinetobacter-associated infections. Increasing prevalence of ß-lactamase-mediated resistance, however, has eroded the effectiveness of sulbactam in the treatment of this pathogen. Durlobactam is a rationally designed ß-lactamase inhibitor within the diazabicyclooctane (DBO) class. The compound demonstrates a broad spectrum of inhibition of serine ß-lactamase activity with particularly potent activity against class D enzymes, an attribute which differentiates it from other DBO inhibitors. When combined with sulbactam, durlobactam effectively restores the susceptibility of resistant isolates through ß-lactamase inhibition. The present review describes the pharmacokinetic/pharmacodynamic (PK/PD) relationship associated with the activity of sulbactam and durlobactam established in nonclinical infection models with MDR Acinetobacter baumannii isolates. This information aids in the determination of PK/PD targets for efficacy, which can be used to forecast efficacious dose regimens of the combination in humans.

Durlobactam, a Broad-Spectrum Serine ß-lactamase Inhibitor, Restores Sulbactam Activity Against Acinetobacter Species.

Sulbactam-durlobactam is a pathogen-targeted ß-lactam/ß-lactamase inhibitor combination in late-stage development for the treatment of Acinetobacter infections, including those caused by multidrug-resistant strains. Durlobactam is a member of the diazabicyclooctane class of ß-lactamase inhibitors with broad-spectrum serine ß-lactamase activity. Sulbactam is a first-generation, narrow-spectrum ß-lactamase inhibitor that also has intrinsic antibacterial activity against Acinetobacter spp. due to its ability to inhibit penicillin-binding proteins 1 and 3. The clinical utility of sulbactam for the treatment of contemporary Acinetobacter infections has been eroded over the last decades due to its susceptibility to cleavage by numerous ß-lactamases present in this species. However, when combined with durlobactam, the activity of sulbactam is restored against this problematic pathogen. The following summary describes what is known about the molecular drivers of activity and resistance as well as results from surveillance and in vivo efficacy studies for this novel combination.

Alteration of adeS Contributes to Tigecycline Resistance and Collateral Sensitivity to Sulbactam in Acinetobacter baumannii.

The treatment of extensively drug-resistant (XDR) A. baumannii has emerged as a major problem. Tigecycline (TGC) and sulbactam (SUL) are both effective antibiotics against XDR A. baumannii. Here, we investigated the in-host evolution and mechanism of collateral sensitivity (CS) phenomenon in development of tigecycline resistance accompanied by a concomitant increase of sulbactam susceptibility. A total of four XDR A. baumannii strains were sequentially isolated from the same patient suffering from bacteremia. Core-genome multilocus sequence typing separated all the strains into two clusters. Comparative analysis of isolate pair 1 revealed that multiplication of blaOXA-23 within Tn2006 on the chromosome contributed to the change in the antimicrobial susceptibility phenotype of isolate pair 1. Additionally, we observed the emergence of CS to sulbactam in isolate pair 2, as demonstrated by an 8-fold increase in the TGC MIC with a simultaneous 4-fold decrease in the SUL MIC. Compared to the parental strain Ab-3557, YZM-0406 showed partial deletion in the two-component system sensor adeS. Reconstruction of the adeS mutant in Ab-3557 in situ suggested that TGC resistance and CS to SUL were mainly caused by the mutation of adeS. Overall, our study reported a novel CS combination of TGC and SUL in A. baumannii and further revealed a mechanism of CS attributed to the mutation of adeS. This study provides a valuable foundation for developing effective regimens and sequential combinations of tigecycline and sulbactam against XDR A. baumannii. IMPORTANCE Collateral sensitivity (CS) has become an increasingly common evolutionary trade-off during adaptive bacterial evolution. Here, we report a novel combination of tigecycline (TGC) resistance and CS to sulbactam (SUL) in A. baumannii. TGC and SUL are both effective antibiotics against XDR A. baumannii, and it is essential to reveal the mechanism of CS between TGC and SUL. In our study, the partial deletion of adeS, a two-component system sensor, was confirmed to be the key factor contributing to this CS phenomenon. This study provides a valuable foundation for developing effective regimens and sequential combinations of tigecycline and sulbactam against XDR A. baumannii.

Establishing breakpoints for amoxicillin/clavulanate and ampicillin/sulbactam for rapid antimicrobial susceptibility testing directly from positive blood culture bottles.

Introduction. In 2018, EUCAST released guidelines on rapid antimicrobial susceptibility testing (RAST) directly from positive blood culture bottles for selected bacterial species and antimicrobial agents, but not for the commonly used agents amoxicillin/clavulanate (AMC) and ampicillin/sulbactam (SAM).Hypothesis/Gap statement. This work addresses the Enterobacterales RAST capability gap for betalactam/betalactamase inhibitor combinations.Aim. We aimed to determine RAST breakpoints for AMC and SAM for Escherichia coli and Klebsiella pneumoniae after 4 and 6 h of incubation directly from positive blood cultures.Methodology. Blood culture bottles were spiked with clinical isolates of E. coli (n=89) and K. pneumoniae (n=81). RAST was performed according to EUCAST guidelines and zones were read after 4 and 6 h. Breakpoints were defined to avoid very major errors.Results. The proportion of readable zone diameters after 4 h of incubation were 90.8 % in E. coli and 85.8 % in K. pneumoniae isolates. After 6 h of incubation all zone diameters could be read. The proposed breakpoints for E. coli after 6 h of incubation were ≥16 mm S (susceptible), 14-15 mm ATU (area of technical uncertainty) and <14 mm R (resistant) for AMC; ≥15 mm S, 12-14 mm ATU and <12 mm R for SAM; for K. pneumoniae these were ≥16 mm S, 14-15 mm ATU and <14 mm R for AMC; ≥13 mm S, 12 mm ATU, <12 mm R for SAM. Applying our newly set breakpoints, major errors were infrequent (2.6 %).Conclusion. We propose novel AMC and SAM breakpoints for RAST directly from positive blood cultures for reading after 4 and 6 h of incubation.

Evaluation of combination therapies with colistin in an experimental mouse pneumonia model induced by carbapenem-resistant Acinetobacter baumannii strain.

The treatment options are limited in Acinetobacter baumannii infections. In this study, the effectiveness of colistin monotherapy and combinations of colistin with different antibiotics were investigated in an experimental pneumonia model induced by carbapenem-resistant A. baumannii strain. Mice in the study were divided into five groups as control (no treatment), colistin monotherapy, colistin + sulbactam, colistin + imipenem, and colistin + tigecycline combinations. The modified experimental surgical pneumonia model of Esposito and Pennington was applied to all groups. The presence of bacteria in blood and lung samples was investigated. Results were compared. In blood cultures, while there was no difference between the control and colistin groups, there was a statistical difference between the control and the combination groups (P = 0.029). When the groups were compared in terms of lung tissue culture positivity, there was a statistical difference between the control group and all treatment groups (colistin, colistin + sulbactam, colistin + imipenem, and colistin + tigecycline) (P = 0.026, P < 0.001, P < 0.001, and P = 0.002, respectively). The number of microorganisms that grew in the lung tissue was found to be statistically significantly lower in all treatment groups in comparison with the control group (P = 0.001). Both monotherapy and combination therapies of colistin were found to be effective in the treatment of carbapenem-resistant A. baumannii pneumonia, but the superiority of combination therapies over colistin monotherapy has not been demonstrated.

Enhanced bacterial killing with a combination of sulbactam/minocycline against dual carbapenemase-producing Acinetobacter baumannii.

Carbapenem-resistant Acinetobacter baumannii (CRAB) is often difficult to treat. Considering the current circumstances, there is an unquestionable need for new therapeutic options to treat CRAB infections. In the present study, the synergistic activity of sulbactam-based combination was determined against genetically characterized CRAB isolates. Non-duplicate CRAB isolates (n = 150) recovered from blood culture and endotracheal aspirates were included in this study. The minimum inhibitory concentrations (MICs) of tetracyclines (minocycline, tigecycline, eravacycline) and their comparators (meropenem, sulbactam, cefoperazone/sulbactam, ceftazidime/avibactam, and colistin) were determined using the microbroth dilution method. Six isolates were tested for the synergistic activity of various sulbactam-based combinations using time-kill experiments. Tigecycline and minocycline showed a wide spread of MICs with most isolates in the range of 1 to 16 mg/L. The MIC90 of eravacycline (0.5 mg/L) was four dilutions lower than that of tigecycline (8 mg/L). Minocycline with sulbactam was the most active dual combination against OXA-23 like (n = 2) and NDM with OXA-23 like producers (n = 1), which resulted in ≥ 2 log10 kill. The combination of ceftazidime-avibactam with sulbactam showed ≥ 3 log10 kill against all the three tested OXA-23 like producing CRAB isolates, but showed no activity against dual carbapenemase producers. Sulbactam with meropenem showed ≥ 2 log10 kill against one OXA-23 like producing CRAB isolate. The findings suggest that sulbactam-based combination may confer therapeutic benefits against CRAB infections.

Evaluation of continuous ampicillin/sulbactam infusion in critically ill patients.

Continuous infusion (CI) of beta-lactam-antibiotics may improve pharmacodynamics in critically ill patients, but resulting concentrations have not been studied. Therapeutic drug monitoring is increasingly used to ensure antibiotic concentration. The aim of this study is to evaluate therapeutic ampicillin/sulbactam concentrations of a continuous infusion regimen. METHODS: Medical records of all patients admitted to ICU between January 2019 and December 2020 were retrospectively reviewed. Each patient received a 2/1 g ampicillin/sulbactam loading dose, followed by a continuous infusion of 8/4 g per 24 h. Ampicillin serum concentrations were measured. Main outcomes were reaching of plasma concentrations breakpoint defined by minimum inhibitory concentration (MIC at 8 mg/l) and 4-fold MIC (MIC at 32 mg/l) during steady state of CI. RESULTS: In 50 patients a total of 60 concentration measurements were performed. The first concentration was measured after a median of 29 h (IQR 21-61 h). Mean ampicillin concentration was 62.6 ± 39.1 mg/l. Furthermore, serum concentrations exceeded the defined MIC breakpoint in all measurements (100 %) and were above the 4-fold MIC in 43 analyses (71.1 %). However, patients suffering from acute kidney injury exhibited significant higher serum concentrations (81.1 ± 37.7 mg/l vs. 38.2 ± 24.8 mg/l; p < 0.001). Also, there was a negative correlation between ampicillin serum concentrations and GFR (r = -0.659; p < 0.001). CONCLUSION: The described dosing regimen for ampicillin/sulbactam is safe with respect to the defined MIC breakpoints for ampicillin, and continuous subtherapeutic concentration is unlikely. However, with impaired renal function drug accumulation occurs, and with increased renal clearance, drug levels can be below the 4-fold MIC breakpoint.