Multidrug-resistant Gram-negative clinical isolates with reduced susceptibility/resistance to cefiderocol: which are the best present and future therapeutic alternatives?

PURPOSE: To evaluate the different present and future therapeutic ß-lactam/ß-lactamase inhibitor (BL/BLI) alternatives, namely aztreonam-avibactam, imipenem-relebactam, meropenem-vaborbactam, cefepime-zidebactam, cefepime-taniborbactam, meropenem-nacubactam, and sulbactam-durlobactam against clinical isolates showing reduced susceptibility or resistance to cefiderocol in Enterobacterales, Acinetobacter baumannii, and Pseudomonas aeruginosa. METHODS: MIC values of aztreonam, aztreonam-avibactam, cefepime, cefepime-taniborbactam, cefepime-zidebactam, imipenem, imipenem-relebactam, meropenem, meropenem-vaborbactam, meropenem-nacubactam, sulbactam-durlobactam, and cefiderocol combined with a BLI were determined for 67, 9, and 11 clinical Enterobacterales, P. aeruginosa or A. baumannii isolates, respectively, showing MIC values of cefiderocol being ≥1 mg/L. If unavailable, the respective ß-lactam breakpoints according to EUCAST were used for BL/BLI combinations. RESULTS: For Enterobacterales, the susceptibility rates for aztreonam, cefepime, imipenem, and meropenem were 7.5%, 0%, 10.4%, and 10.4%, respectively, while they were much higher for cefepime-zidebactam (91%), cefiderocol-zidebactam (91%), meropenem-nacubactam (71.6%), cefiderocol-nacubactam (74.6%), and cefiderocol-taniborbactam (76.1%), as expected. For P. aeruginosa isolates, the higher susceptibility rates were observed for imipenem-relebactam, cefiderocol-zidebactam, and meropenem-vaborbactam (56% for all combinations). For A. baumannii isolates, lower susceptibility rates were observed with commercially or under development BL/BLI combos; however, a high susceptibility rate (70%) was found for sulbactam-durlobactam and when cefiderocol was associated to some BLIs. CONCLUSIONS: Zidebactam- and nacubactam-containing combinations showed a significant in vitro activity against multidrug-resistant Enterobacterales clinical isolates with reduced susceptibility to cefiderocol. On the other hand, imipenem-relebactam and meropenem-vaborbactam showed the highest susceptibility rates against P. aeruginosa isolates. Finally, sulbactam-durlobactam and cefiderocol combined with a BLI were the only effective options against A. baumannii tested isolates.

Treatment approaches for severe Stenotrophomonas maltophilia infections.

PURPOSE OF REVIEW: Stenotrophomonas maltophilia is an emerged opportunistic pathogen. Intrinsic multidrug resistance makes treating infections caused by S. maltophilia a great clinical challenge. Herein, we provide an update on the most recent literature on treatment options for severe S. maltophilia infections. RECENT FINDINGS: Trimethoprim-sulfamethoxazole (SXT) is recognized as the first-line therapy for S. maltophilia infections. However, its clinical use is based on good in vitro activity and favorable clinical outcomes, rather than on solid minimum inhibitory concentration (MIC) correlations with pharmacokinetic/pharmacodynamics (PK/PD) and/or clinical outcomes. The same is true for other treatment options like levofloxacin (LVX) and minocycline (MIN). Recent PK/PD studies question the current clinical breakpoints for SXT, LVX, and MIN. Based on this, the latest guidance issued by the Infectious Diseases Society of America (IDSA) recommends using these agents only as part of a combination therapy. Alternatively, novel therapeutic options such as cefiderocol (FDC) and ceftazidime-avibactam plus aztreonam (CZA-ATM) are suggested, based on limited but promising clinical data. SUMMARY: PK/PD data and controlled clinical studies are needed to optimize current treatment options. Presently, combination therapy of SXT, LVX, MIN, or FDC, or monotherapy with CZA-ATM are recommended therapeutic options for severe-to-moderate S. maltophilia infections.

Looking for Stenotrophomonas maltophilia treatment: in vitro activity of ceftazidime/avibactam alone and in combination with aztreonam.

During the Sars-Cov-2 pandemic, Stenotrophomonas maltophilia (S.maltophilia) secondary pulmonary infections have increased, especially in critically ill patients, highlighting the need for new therapeutic options. Trimethoprim-sulfamethoxazole (SXT) is the treatment of choice but the increase of resistant strains or adverse drug reactions limited its clinical use. Recently ceftazidime/avibactam (CZA) has been approved for the treatment of multi drug resistant (MDR) Gram-negative bacteria infections, including hospital acquired pneumonia. The aim of this study was to evaluate the in vitro activity of ceftazidime/avibactam (CZA) alone and in combination with aztreonam (ATM) against S. maltophilia clinical isolates by E-test method. Susceptibility of SXT and levofloxacin (LEV) was also investigated. Our results showed 22% of resistance to CZA, 2% to SXT and 26% to LEV. CZA in combination with ATM demonstrated synergistic activity against 86% of the strains, including all those resistant to CZA. The combination of CZA with ATM provides a new therapeutic option for the treatment of severe respiratory infections in critically ill patients.

Combinational Effect of Selected Medicinal Plants and Antibiotics Against Pathogenic Bacteria.

<b>Background and Objective:</b> The emergence of antibiotic resistance is a primary global health concern. As a result, there is an urgent need for new strategies to combat antibiotic-resistant bacteria. One of these essential strategies is the combination of medicinal plants and antibiotics as an alternative to using antibiotics alone which was the objective of this article. <b>Materials and Methods:</b> Nine plant materials were collected from different Egypt localities and then extracted by water. Water extracts were filtered and added with Mueller-Hinton agar during preparation. Nine test bacteria and 13 standard antibiotics were used in the disc diffusion sensitivity method. <b>Results:</b> The activity of Amikacin was increased when combined with most different plant extracts against <i>Escherichia coli</i> while antagonistic against <i>Pseudomonas aeruginosa</i>. Aztreonam, Ceftriaxone, Gentamicin and Nalidixic acid antibiotics showed antagonistic or indifferent effects when combined with most different plant extracts against <i>E. coli</i>, <i>Klebsiella pneumonia</i> and <i>P. aeruginosa</i>. The synergistic effect was achieved in Aztreonam when combined with all plant extracts, while Nalidixic acid showed antagonistic when combined with most plant extracts against <i>Proteus mirabilis</i>. The antagonistic effect was achieved in Aztreonam, Ceftriaxone and Nalidixic acid when combined with <i>Achillea fragrantissima</i>, <i>Artemisia monosperma</i> and <i>Leptadenia pyrotechnica</i>, also Aztreonam with <i>Lycium shawii</i> extract against <i>Salmonella typhimurium</i>. The <i>A. fragrantissima</i> and <i>A. monosperma</i> increase the activity of Novobiocin and Vancomycin against <i>Bacillus cereus</i> and Ampicillin and Cefazolin against <i>Staphylococcus aureus</i> but Novobiocin activity increased with most plant extracts against <i>S. aureus</i>. <b>Conclusion:</b> The combinations of antibiotics with the extracts of medicinal plants displayed varying degrees of effects, synergistic, antagonistic and indifferent according to antibiotic type, plant extract and test organism.

Optimal treatment of ceftazidime-avibactam and aztreonam-avibactam against bloodstream infections or lower respiratory tract infections caused by extensively drug-resistant or pan drug-resistant (XDR/PDR) Pseudomonas aeruginosa.

Objective: To evaluate the efficacy of ceftazidime-avibactam (CZA) and aztreonam-avibactam (AZA) against bloodstream infections (BSIs) or lower respiratory tract infections (LRTIs) - caused by extensive drug-resistant or pan drug-resistant (XDR/PDR) Pseudomonas aeruginosa. Method: The two-fold dilution method was used to determine the minimum inhibitory concentrations (MICs) of CZA/AZA against XDR/PDR P. aeruginosa. Whole-genome sequencing was used to analyze the resistance determinants of each isolate. Monte Carlo simulations (MCSs) were used to evaluate the probability of target attainment (PTA) and the cumulative fraction of response (CFR) of each CZA/AZA dosing regimen via traditional infusion (TI)/optimized two-step-administration therapy (OTAT). Results: We found that XDR/PDR P. aeruginosa may carry some rare MBLs (e.g.: IND-6, SLB-1, THIN-B). P. aeruginosa isolates producing IMP-45, VIM-1, or VIM-2 were inhibited by AZA at a concentration of 2 to 8 mg/L. All isolates producing IND-6 plus other serine ß-lactamases were high-level resistant to CZA/AZA (MICs >64 mg/L). All simulated dosing regimens of CZA/AZA against BSIs-causing XDR/PDR P. aeruginosa achieved 100% PTA when the MIC was ≤32 mg/L. Conclusion: AZA has been considered as an option for the treatment of infections caused by XDR/PDR P. aeruginosa producing IMP-45, VIM-1, or VIM-2. OTAT with sufficient pharmacodynamic exposure may be an optimal treatment option for XDR/PDR P. aeruginosa with a high-level MIC of CZA/AZA.

Bloodstream infections due to Carbapenem-Resistant Enterobacteriaceae in hematological patients: assessment of risk factors for mortality and treatment options.

PURPOSE: Bloodstream infection (BSI) caused by Carbapenem-Resistant Enterobacteriaceae (CRE) are associated with poor outcomes in hematological patients. The aim of this study was to identify risk factors for mortality and evaluate the value of epidemiological feature of carbapenemases in guiding antimicrobial treatment options. METHODS: Hematological patients with monomicrobial CRE BSI between January 2012 and April 2021 were included. The primary outcome was all-cause mortality 30 days after BSI onset. RESULTS: A total of 94 patients were documented in the study period. Escherichia coli was the most common Enterobacteriaceae, followed by Klebsiella pneumoniae. 66 CRE strains were tested for carbapenemase genes, and 81.8% (54/66) were positive, including NDM (36/54), KPC (16/54), IMP (1/54). Besides, one E. coli isolate was found to express both NDM and OXA-48-like genes. Overall, 28 patients received an antimicrobial treatment containing ceftazidime-avibactam (CAZ-AVI), of which 21 cases were combined with aztreonam. The remaining 66 patients were treated with other active antibiotics (OAAs). The 30-day mortality rate was 28.7% (27/94) for all patients, and was only 7.1% ((2/28) for patients treated with CAZ-AVI. In multivariate analysis, the presence of septic shock at BSI onset (OR 10.526, 95% CI 1.376-76.923) and pulmonary infection (OR 6.289, 95% CI 1.351-29.412) were independently risk factors for 30-day mortality. Comparing different antimicrobial regimens, CAZ-AVI showed a significant survive benefit than OAAs (OR 0.068, 95% CI 0.007-0.651). CONCLUSION: CAZ-AVI-containing regimen is superior to OAAs for CRE BSI. As the predominance of blaNDM in our center, we recommend the combination with aztreonam when choose CAZ-AVI.

Treatment strategies for OXA-48-like and NDM producing Klebsiella pneumoniae infections.

INTRODUCTION: OXA-48 and NDM are amongst the most prevalent carbapenemase types associated with Klebsiella pneumoniae worldwide, with an increase in their prevalence in recent years. Knowledge on the treatment of carbapenem-resistant Klebsiella pneumoniae (CRKP) comes from KPC-producing CRKP with limited data available for OXA-48-like and NDM producers. Our aim is to review the literature on the treatment of OXA-48-like and NDM-producing CRKP with the goal of providing an update on the available antibiotic treatment strategies, particularly in light of changing carbapenemase epidemiology and increasing antimicrobial resistance. AREAS COVERED: We reviewed studies looking at the antibiotic treatment and outcome of OXA-48-like and/or NDM-producing CRKP. EXPERT OPINION: The best available treatment option for OXA-48 producers is ceftazidime-avibactam, where available and when the price permits its use. Colistin remains as the second-line option if in vitro susceptibility is demonstrated with an appropriate method. There is not enough evidence to support the use of meropenem-containing combination therapies for meropenem-resistant OXA-48 producers. Treatment of NDM producers is an unmet need. Ceftazidime-avibactam and aztreonam combination or cefiderocol can be used for NDM producers, where available. Higher cefiderocol MICs against NDM producers is concerning. Aztreonam-avibactam provides hope for the treatment of NDM producers.

Validated Preclinical Mouse Model for Therapeutic Testing against Multidrug-Resistant Pseudomonas aeruginosa Strains.

The rise in infections caused by antibiotic-resistant bacteria is outpacing the development of new antibiotics. The ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) are a group of clinically important bacteria that have developed resistance to multiple antibiotics and are commonly referred to as multidrug resistant (MDR). The medical and research communities have recognized that, without new antimicrobials, infections by MDR bacteria will soon become a leading cause of morbidity and death. Therefore, there is an ever-growing need to expedite the development of novel antimicrobials to combat these infections. Toward this end, we set out to refine an existing mouse model of pulmonary Pseudomonas aeruginosa infection to generate a robust preclinical tool that can be used to rapidly and accurately predict novel antimicrobial efficacy. This refinement was achieved by characterizing the virulence of a panel of genetically diverse MDR P. aeruginosa strains in this model, by both 50% lethal dose (LD50) analysis and natural history studies. Further, we defined two antibiotic regimens (aztreonam and amikacin) that can be used as comparators during the future evaluation of novel antimicrobials, and we confirmed that the model can effectively differentiate between successful and unsuccessful treatments, as predicted by in vitro inhibitory data. This validated model represents an important tool in our arsenal to develop new therapies to combat MDR P. aeruginosa strains, with the ability to provide rapid preclinical evaluation of novel antimicrobials and support data from clinical studies during the investigational drug development process. IMPORTANCE The prevalence of antibiotic resistance among bacterial pathogens is a growing problem that necessitates the development of new antibiotics. Preclinical animal models are important tools to facilitate and speed the development of novel antimicrobials. Successful outcomes in animal models not only justify progression of new drugs into human clinical trials but also can support FDA decisions if clinical trial sizes are small due to a small population of infections with specific drug-resistant strains. However, in both cases the preclinical animal model needs to be well characterized and provide robust and reproducible data. Toward this goal, we have refined an existing mouse model to better predict the efficacy of novel antibiotics. This improved model provides an important tool to better predict the clinical success of new antibiotics.

Ceftazidime-Avibactam plus Aztreonam for the Treatment of Infections by VIM-Type-Producing Gram-Negative Bacteria.

This is a retrospective single-center study of 24 patients who received ceftazidime-avibactam plus aztreonam (CZA/ATM) for the treatment of VIM-type-producing Gram-negative bacillus (GNB) infections. The bacteria isolated were Enterobacterales in 22 patients and Pseudomonas aeruginosa in 2. Sixteen out of 19 isolates showed synergistic activity. Two patients presented clinical failure at day 14, and the 30-day mortality was 17% (4/24). CZA/ATM could be considered an alternative therapy for VIM-type-producing GNB infections.

Development of Resistance to Eravacycline by Klebsiella pneumoniae and Collateral Sensitivity-Guided Design of Combination Therapies.

The evolution of bacterial antibiotic resistance is exhausting the list of currently used antibiotics and endangers those in the pipeline. The combination of antibiotics is a promising strategy that may suppress resistance development and/or achieve synergistic therapeutic effects. Eravacycline is a newly approved antibiotic that is effective against a variety of multidrug-resistant (MDR) pathogens. However, the evolution of resistance to eravacycline and strategies to suppress the evolution remain unexplored. Here, we demonstrated that a carbapenem-resistant Klebsiella pneumoniae clinical isolate quickly developed resistance to eravacycline, which is mainly caused by mutations in the gene encoding the Lon protease. The evolved resistant mutants display collateral sensitivities to ß-lactam/ß-lactamase inhibitor (BLBLI) combinations aztreonam/avibactam and ceftazidime-avibactam. Proteomic analysis revealed upregulation of the multidrug efflux system AcrA-AcrB-TolC and porin proteins OmpA and OmpU, which contributed to the increased resistance to eravacycline and susceptibility to BLBLIs, respectively. The combination of eravacycline with aztreonam/avibactam or ceftazidime-avibactam suppresses resistance development. We further demonstrated that eravacycline-resistant mutants evolved from an NDM-1-containing K. pneumoniae strain display collateral sensitivity to aztreonam/avibactam, and the combination of eravacycline with aztreonam/avibactam suppresses resistance development. In addition, the combination of eravacycline with aztreonam/avibactam or ceftazidime-avibactam displayed synergistic therapeutic effects in a murine cutaneous abscess model. Overall, our results revealed mechanisms of resistance to eravacycline and collateral sensitivities to BLBLIs and provided promising antibiotic combinations in the treatment of multidrug-resistant K. pneumoniae infections. IMPORTANCE The increasing bacterial antibiotic resistance is a serious threat to global public health, which demands novel antimicrobial medicines and treatment strategies. Eravacycline is a newly approved antibiotic that belongs to the tetracycline antibiotics. Here, we found that a multidrug-resistant Klebsiella pneumoniae clinical isolate rapidly developed resistance to eravacycline and the evolved resistant mutants displayed collateral sensitivity to antibiotics aztreonam/avibactam and ceftazidime-avibactam. We demonstrated that the combination of eravacycline with aztreonam/avibactam or ceftazidime-avibactam repressed resistance development and improved the treatment efficacies. We also elucidated the mechanisms that contribute to the increased resistance to eravacycline and susceptibility to aztreonam/avibactam and ceftazidime-avibactam. This work demonstrated the mechanisms of antibiotic resistance and collateral sensitivity and provided a new therapeutically option for effective antibiotic combinations.

Susceptibility of Burkholderia cepacia Complex to Ceftazidime/Avibactam and Standard Drugs of Treatment for Cystic Fibrosis Patients.

Burkholderia cepacia complex (Bcc) in airways of patients with cystic fibrosis (CF) is associated with an increased morbidity and mortality. A huge range of intrinsic antimicrobial resistances challenges the treatment of Bcc infections. The aim was to assess the susceptibility of Bcc to ceftazidime/avibactam and standard drugs for the treatment for CF patients and to determine the respective genomic determinants of resistance. Bcc isolates (n = 64) from a prospective multicenter study of CF airway pathogens (2004-2020, Germany) were subjected to broth microdilution and minimal inhibitory concentrations were interpreted with European Committee on Antimicrobial Susceptibility Testing and Clinical & Laboratory Standards Institute breakpoints. A synergism between aztreonam and avibactam was tested using ceftazidime/avibactam disks with or without aztreonam. Plasmids and chromosomes of all isolates were screened for antimicrobial resistance genes. The highest susceptibility rate was detected for trimethoprim/sulfamethoxazole (83%), followed by ceftazidime/avibactam (78%), ceftazidime (53%), levofloxacin (39%) and meropenem (27%). The median inhibition zone diameters of ceftazidime-avibactam and ceftazidime/avibactam plus aztreonam were equal. This was in line with the absence of known class B metallo-ß-lactamases in any of the isolates. The majority of isolates carried blapenA (98%) and blaampC (86%). Trimethoprim/sulfamethoxazole and ceftazidime/avibactam showed high susceptibility rates. Aztreonam in combination with ceftazidime/avibactam had no synergistic effect in our Bcc isolates.

Antimicrobial effects of Melaleuca alternifolia (tea tree) essential oil against biofilm-forming multidrug-resistant cystic fibrosis-associated Pseudomonas aeruginosa as a single agent and in combination with commonly nebulized antibiotics.

Broth microdilution assays were used to determine minimum inhibitory concentrations (MICs) and fractional inhibitory concentration indices (FICIs) of tea tree oil (TTO), tobramycin, colistin and aztreonam (ATM) against clinical cystic fibrosis-associated Pseudomonas aeruginosa (CFPA) isolates (n = 20). The minimum biofilm eradication concentration (MBEC) and fractional biofilm eradication concentration index (FBECI) were also determined using a similar microbroth dilution checkerboard assay, with biofilms formed using the MBEC device® . TTO was effective at lower concentrations against multidrug-resistant (MDR) CFPA isolates (n = 3) in a biofilm compared to in a planktonic state (MBEC 18·7-fold lower than MIC). CFPA within biofilm was less susceptible to ATM, colistin and tobramycin compared to planktonic cells (MBEC 6·3-fold, 9·3-fold, and 2·1-fold higher than MIC respectively). All combinations of essential oil and antibiotic showed indifferent relationships (FICI 0·52-1·72) when tested against planktonic MDR CFPA isolates (n = 5). Against CFPA isolates (n = 3) in biofilm, combinations of TTO/aztreonam and TTO/colistin showed indifferent relationships (mean FBECI 0·85 and 0·60 respectively), whereas TTO/tobramycin showed a synergistic relationship (mean FBECI 0·42). The antibiofilm properties of TTO and the synergistic relationship seen between TTO and tobramycin against CFPA in vitro make inhaled TTO a promising candidate as a potential therapeutic agent.

Successful treatment of Verona integron-encoded metallo-ß-lactamase-producing Klebsiella pneumoniae infection using the combination of ceftazidime/avibactam and aztreonam.

The case of a female who had an accident that caused an open fracture is reported. During hospitalisation, Verona integron-encoded metallo-ß-lactamase (VIM)-producing Klebsiella pneumoniae was isolated. Antimicrobial susceptibility testing revealed resistance to ß-lactam antibiotics, quinolones, trimethoprim/sulfamethoxazole, and susceptibility to tigecycline, colistin, fosfomycin and aminoglycosides. Synergistic activity of ceftazidime-avibactam and aztreonam was proved in vitro and a combined therapy with tigecycline was started. Combination with aminoglycosides was ruled out as it was not described in the literature and also in order to avoid side effects. Colistin was rejected because of its nephrotoxicity profile. The antibiotic treatment was assessed by a multidisciplinary team with a pharmacist who closely monitored adverse effects and interactions with other drugs. The total duration of this combination was 25 days, without any adverse events reported. Fourteen weeks after the accident the patient was discharged. After 2 months of follow-up neither relapses nor reinfections have been reported.

In Vitro Evaluation of the Activity of Aztreonam-Avibactam against 341 Recent Clinical Isolates of Anaerobes.

Aztreonam-avibactam is under clinical development for multidrug-resistant Gram-negative infections. We evaluated in vitro activity against 341 recent clinical isolates. The addition of avibactam to aztreonam had no effect on the anaerobic activity of aztreonam. IMPORTANCE This work shows that aztreonam-avibactam lacks activity against anaerobic organisms.

Evaluation of Susceptibility Testing Methods for Aztreonam and Ceftazidime-Avibactam Combination Therapy on Extensively Drug-Resistant Gram-Negative Organisms.

Carbapenem-resistant Enterobacterales (CRE) and Pseudomonas aeruginosa (CR-PA) producing metallo-ß-lactamases (MBLs) cause severe nosocomial infections with no defined treatment. The combination of aztreonam (ATM) with ceftazidime-avibactam (CZA) is a potential therapeutic option, but there is no approved, feasible testing method for use in clinical laboratories to assess the activity of two antimicrobials in combination. Here, we evaluate the performance of four ATM-CZA combination testing methods, as follows: broth disk elution (DE), disk stacking (DS), strip stacking (SS), and strip crossing (SX). We used 10 clinical, representative Enterobacterales and 6 P. aeruginosa isolates harboring MBL, Guiana extended-spectrum beta-lactamase (GES), or non-MBL enzymes. Four of these isolates were from clinical cases treated by ATM-CZA. All CRE producing NDM and CR-PA producing GES that were resistant to ATM and CZA alone were susceptible to the ATM-CZA combination. P. aeruginosa generating NDM or VIM remained resistant to ATM-CZA, likely due to non-ß-lactamase mechanisms, and all other isolates were susceptible to ATM or CZA alone. The most accurate, precise, and reproducible methods of low complexity were disc elution and both strip methods (SX and SS) using MIC test strips (MTS) , all with 100% sensitivity and specificity, followed by Etest with SX (95.83% sensitivity, 100% specificity) and SS (87.5% sensitivity, 100% specificity). DS had the lowest performance. DE is particularly valuable in low-resource settings that routinely use disks. MTS yielded higher categorical agreements by SX (94%) and SS (84%), relative to Etest by SX (90%) and SS (82%). P. aeruginosa results yielded the majority of the errors. These methods may allow laboratories to inform clinical decision making like combination therapy for severe infections caused by extensively drug-resistant Enterobacterales.

Successful Treatment of Klebsiella pneumoniae NDM Sepsis and Intestinal Decolonization with Ceftazidime/Avibactam Plus Aztreonam Combination in a Patient with TTP Complicated by SARSCoV-2 Nosocomial Infection.

Carbapenem-resistant Enterobacteriaceae (CRE) are a serious public health threat. Infections due to these organisms are associated with significant morbidity and mortality. Among them, metallo-ß-lactamases (MBLs)-producing Klebsiella pneumoniae are of global concern today. The ceftazidime/avibactam combination and the ceftazidime/avibactam + aztreonam combination currently represent the most promising antibiotic strategies to stave off these kinds of infections. We describe the case of a patient affected by thrombotic thrombocytopenic purpura (TTP) admitted in our ICU after developing a hospital-acquired SarsCoV2 interstitial pneumonia during his stay in the hematology department. His medical conditions during his ICU stay were further complicated by a K. Pneumoniae NDM sepsis. To our knowledge, the patient had no risk factors for multidrug-resistant bacteria exposure or contamination during his stay in the hematology department. During his stay in the ICU, we treated the sepsis with a combination therapy of ceftazidime/avibactam + aztreonam. The therapy solved his septic state, allowing for a progressive improvement in his general condition. Moreover, we noticed that the negativization of the hemocultures was also associated to a decontamination of his known rectal colonization. The ceftazidime/avibactam + aztreonam treatment could not only be a valid therapeutic option for these kinds of infections, but it could also be considered as a useful tool in selected patients' intestinal decolonizations.

Management of serious infections caused by metallo ß-lactamases with or without OXA-48-like expressing Enterobacterales with aztreonam and ceftazidime/avibactam combination: Dosing strategy for better clinical outcome.

Serious infections caused by MBLs with or without OXA-48-like expressing Enterobacterales remain challenging to treat. Since aztreonam is stable to MBLs, it can be combined with ceftazidime/avibactam to protect against concurrently expressed ESBLs and class C ß-lactamases in MBL pathogens. However, in the light of dose-limiting hepatotoxicity of aztreonam, short half life of avibactam, significant protein binding of aztreonam, appropriate dosing and method of administration to optimize PK/PD and toxicodynamics for this combination is being debated. Based on in-vitro PK/PD studies, simultaneous administration of 6/1.5 g of ceftazidime/avibactam and 8 g of aztreonam per day has been recently suggested.

Activity of aztreonam in combination with ceftazidime-avibactam against serine- and metallo-ß-lactamase-producing Pseudomonas aeruginosa.

Existing data support the combination of aztreonam and ceftazidime-avibactam against serine-ß-lactamase (SBL)- and metallo-ß-lactamase (MBL)-producing Enterobacterales, although there is a paucity of data against SBL- and MBL-producing Pseudomonas aeruginosa. In this study, 5 SBL- and MBL-producing P. aeruginosa (1 IMP, 4 VIM) were evaluated against aztreonam and ceftazidime-avibactam alone and in combination via broth microdilution and time-kill analyses. All 5 isolates were nonsusceptible to aztreonam, aztreonam-avibactam, and ceftazidime-avibactam. Combining aztreonam with ceftazidime-avibactam at subinhibitory concentrations produced synergy and restored bactericidal activity in 4/5 (80%) isolates tested. These results suggest that the combination of aztreonam and ceftazidime-avibactam may be a viable treatment option against SBL- and MBL-producing P. aeruginosa.

Treatment of invasive IMP-4 Enterobacter cloacae infection in transplant recipients using ceftazidime/avibactam with aztreonam: A case series and literature review.

Infections caused by carbapenemase-producing Enterobacteriaceae (CPE) are an emerging threat in both solid organ and stem cell transplant recipients. Invasive CPE infections in transplant recipients are associated with a high mortality, often due to limited therapeutic options and antibacterial toxicities. One of the most therapeutically challenging group of CPE are the metallo-ß-lactamase (MBL)-producing Gram-negative bacteria, which are now found worldwide, and often need treatment with older, highly toxic antimicrobial regimens. Newer ß-lactamase inhibitors such as avibactam have well-established activity against certain carbapenemases such as Klebsiella pneumoniae carbapenemases (KPC), but have no activity against MBL-producing organisms. Conversely, aztreonam has activity against MBL-producing organisms but is often inactivated by other co-existing ß-lactamases. Here, we report four cases of invasive MBL-CPE infections in transplant recipients caused by IMP-4-producing Enterobacter cloacae who were successfully treated with a new, mechanism-driven antimicrobial combination of ceftazidime/avibactam with aztreonam. This novel antimicrobial combination offers a useful treatment option for high-risk patients with CPE infection, with reduced drug interactions and toxicity.