avibactam and Gram-Negative-Bacterial-Infections

Avibactam, a potent non-β lactam β-lactamase inhibitor, was recently approved in the USA for combination use with ceftazidime, a cephalosporin antibiotic drug. The addition of avibactam potentiates the antimicrobial drug ceftazidime, which otherwise would have been susceptible to β-lactamases produced by variety of Gram negative pathogens. The focus of this review was to provide clinical pharmacokinetic data of avibactam to cover absorption, distribution, metabolism, and excretion aspects including any potential for avibactam to show drug-drug interactions in the clinic. Based on the review of the data, the pharmacokinetics of avibactam was generally stationary in the studied dosing regimen. The elimination half-life (approximately 1.4- 3.2 h) and volume of distribution at steady state (15.4-26.3 L) were found similar across the studies and therefore, provided the complementary pharmacokinetic attributes for combination use with ceftazidime. Renal excretion was the major pathway for the clearance of avibactam. In summary, any degree of renal dysfunction is expected to alter the pharmacokinetics of avibactam - this consideration should be factored in dosage adjustments while dosing in patients with renal impairment. Concomitant drugs that may influence renal mechanism of elimination of avibactam should be avoided and/or monitored for any impact on the pharmacokinetics of avibactam.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; Ceftazidime; Dose-Response Relationship, Drug; Drug Combinations; Drug Interactions; Drug Resistance, Bacterial; Gram-Negative Bacterial Infections; Half-Life; Humans; Intestinal Absorption; Intestinal Elimination; Kidney; Renal Elimination; Tissue Distribution

With the current carbapenem-resistant organism crisis, conventional approaches to optimizing pharmacokinetic-pharmacodynamic parameters are frequently inadequate, and traditional salvage agents (eg, colistin, tigecycline, etc) confer high toxicity and/or have low efficacy. However, several β-lactam agents with activity against carbapenem-resistant organisms were approved recently by the US Food and Drug Administration, and more are anticipated to be approved in the near future. The primary goal of this review is to assist infectious disease practitioners with preferentially selecting 1 agent over another when treating patients infected with a carbapenem-resistant organism. However, resistance to some of these antibiotics has already developed. Antibiotic stewardship programs can ensure that they are reserved for situations in which other options are lacking and are paramount for the survival of these agents.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Aztreonam; Boronic Acids; Carbapenems; Cefiderocol; Ceftazidime; Cephalosporins; Cilastatin, Imipenem Drug Combination; Drug Combinations; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Heterocyclic Compounds, 1-Ring; Meropenem; Tazobactam

During the last decade infections caused by MDR Gram-negative bacteria (GNB) have become increasingly prevalent. Because of their high morbidity and mortality rates, these infections constitute a serious threat to public health worldwide. Ceftazidime/avibactam is a new approved agent combining ceftazidime and a novel β-lactamase inhibitor with activity against various β-lactamases produced by MDR GNB. Avibactam has a spectrum of inhibition of class A and C β-lactamases, including ESBLs, AmpC and Klebsiella pneumoniae carbapenemase (KPC) enzymes. Thus, combination with this inhibitor expands ceftazidime's spectrum of activity to MDR Enterobacteriaceae and Pseudomonas aeruginosa strains. In Phase II clinical trials of patients with complicated intra-abdominal infections and complicated urinary tract infections ceftazidime/avibactam exhibited clinical efficacy comparable to those of meropenem and imipenem/cilastatin, respectively. A Phase III clinical trial confirmed the efficacy of ceftazidime/avibactam in patients with MDR Enterobacteriaceae and P. aeruginosa infections. Microbiological surveillance studies, in vivo animal models of infection and pharmacokinetic/pharmacodynamic target attainment analyses are also discussed, to assess the potential role of this new drug in the treatment of infections caused by MDR GNB.

Topics: Animals; Anti-Bacterial Agents; Azabicyclo Compounds; Bacterial Proteins; beta-Lactamase Inhibitors; beta-Lactamases; Ceftazidime; Clinical Trials as Topic; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Intraabdominal Infections; Klebsiella pneumoniae; Mice; Microbial Sensitivity Tests; Urinary Tract Infections

As the incidence of Gram-negative bacterial infections for which few effective treatments remain increases, so does the contribution of drug-hydrolyzing β-lactamase enzymes to this serious clinical problem. This review highlights recent advances in β-lactamase inhibitors and focuses on agents with novel mechanisms of action against a wide range of enzymes. To this end, we review the β-lactamase inhibitors currently in clinical trials, select agents still in preclinical development, and older therapeutic approaches that are being revisited. Particular emphasis is placed on the activity of compounds at the forefront of the developmental pipeline, including the diazabicyclooctane inhibitors (avibactam and MK-7655) and the boronate RPX7009. With its novel reversible mechanism, avibactam stands to be the first new β-lactamase inhibitor brought into clinical use in the past 2 decades. Our discussion includes the importance of selecting the appropriate partner β-lactam and dosing regimens for these promising agents. This "renaissance" of β-lactamase inhibitors offers new hope in a world plagued by multidrug-resistant (MDR) Gram-negative bacteria.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; Drug Resistance, Multiple, Bacterial; Enzyme Inhibitors; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests

New Delhi metallo-β-lactamase (NDM-1) is a novel broad spectrum carbapenemase with ability to inactivate all β-lactams except aztreonam. However, most of the NDM-1-producers also produce aztreonam hydrolysing-β-lactamases thereby making these pathogens absolutely resistant to all β-lactams. The bla(NDM-1) gene encodes a 27.5 kDa protein of 269 amino acids. It shares very little identity with other metallo-β-lactamases. Maximum identity has been observed to VIM-1/VIM-2 (32.4%). This mini-review is an update of the scientific literature for the said enzyme. Following the recommendation of David livermore, we further propose to combine "aztreonam" and "inhibitor of the most frequently encountered aztreonam hydrolysing-β-lactamases in a given setting" as a possible strategy against NDM-1-producers. The inhibitor should be 'versatile' as well, i.e. it should have the ability to inhibit most of the variants of aztreonam hydrolysing-β-lactamases prevalent in the concerned setting. We strongly recommend surveillance studies using aztreonam/NXL-104-combination against NDM-1-producing pathogens in different geographical regions across the globe.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Aztreonam; Bacterial Proteins; beta-Lactamase Inhibitors; beta-Lactamases; beta-Lactams; Biotransformation; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Enzyme Inhibitors; Global Health; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Molecular Targeted Therapy; Sulbactam

Increasing prevalence of infections caused by antimicrobial-resistant gram-negative bacteria represents a global health crisis, and while several novel therapies that target various aspects of antimicrobial resistance have been introduced in recent years, few are currently approved for children. Ceftazidime-avibactam is a novel β-lactam β-lactamase inhibitor combination approved for adults and children 3 months and older with complicated intra-abdominal infection, and complicated urinary tract infection or hospital-acquired ventilator-associated pneumonia (adults only in the United States) caused by susceptible gram-negative bacteria. Extensive population pharmacokinetic (PK) data sets for ceftazidime and avibactam obtained during the adult clinical development program were used to iteratively select, modify, and validate the approved adult dosage regimen (2,000-500 mg by 2-hour intravenous (IV) infusion every 8 hours (q8h), with adjustments for renal function). Following the completion of one phase I (NCT01893346) and two phase II ceftazidime-avibactam studies (NCT02475733 and NCT02497781) in children, adult PK data sets were updated with pediatric PK data. This paper describes the development of updated combined adult and pediatric population PK models and their application in characterizing the population PK of ceftazidime and avibactam in children, and in dose selection for further pediatric evaluation. The updated models supported the approval of ceftazidime-avibactam pediatric dosage regimens (all by 2-hour IV infusion) of 50-12.5 mg/kg (maximum 2,000-500 mg) q8h for those ≥6 months to 18 years old, and 40-10 mg/kg q8h for those ≥3 to 6 months old with creatinine clearance > 50 mL/min/1.73 m

Topics: Adolescent; Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; Ceftazidime; Child; Child, Preschool; Drug Combinations; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Infant; Intraabdominal Infections; Male; Pneumonia, Ventilator-Associated; Probability; Urinary Tract Infections

Therapeutic drug monitoring (TDM) of β-lactams in critically ill patients has been correlated with better clinical outcomes. Evidence on TDM of newer β-lactams such as ceftazidime/avibactam administered by continuous infusion (CI) is very limited.. To describe our experience with TDM of ceftazidime/avibactam and pharmacokinetic/pharmacodynamic (PK/PD) target attainment in patients with MDR bacterial infections. Clinical outcomes of ceftazidime/avibactam administered by CI were also assessed.. Patients treated with ceftazidime/avibactam administered by CI and undergoing TDM of ceftazidime plasma concentrations were included. Blood samples were obtained as part of the TDM program. The PK/PD therapeutic target of ceftazidime/avibactam was defined as 100%fT > 4 × MIC of the causative pathogen, and 100%fT > 10 × MIC was considered overexposure. Dose changes were made according to the TDM results.. Thirty-one patients were included. Ceftazidime/avibactam total daily doses ranged from 1 g/0.25 g to 6 g/1.5 g. Twenty-six patients (83.9%) achieved a 100%fT > 4 × MIC, 15 (48.4%) of which were overexposed (100%fT > 10 × MIC). Dose reduction was suggested in 16/28 (57.1%) patients and dose maintenance in 12/28 (42.9%). Overall clinical cure was observed in 21 (67.7%) patients, and 18 of these (85.7%) achieved a 100%fT > 4 × MIC.. Administering ceftazidime/avibactam by CI enabled the desired PK/PD target to be achieved in a large proportion of patients, even at lower doses than those recommended for a 2 h extended infusion. We suggest that the use of CI with TDM may be a useful tool for reducing initial doses, which could help to reduce antimicrobial-related adverse effects and treatment costs.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Ceftazidime; Drug Combinations; Drug Monitoring; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests

The 68-year-old patient presented with fever, general malaise and physical weakness in neutropenia during a known relapse of acute myeloid leukaemia after allogeneic stem cell transplantation.. Due to immune suppression, an empiric antibiotic therapy with piperacillin/tazobactam was started. The 4MRGN screening was positive. For this reason, therapy was switched empirically to ceftazidime/avibactam plus colistin. A tongue ulcer with abscess formation and phlegmonous soft tissue reaction was revealed as the focus of the infection. Several microbiological probes including a blood culture discovered. Die Vorstellung der 68-jährigen Patientin erfolgte bei hohem Fieber, allgemeinem Unwohlseisn und körperlicher Schwäche in der Neutropenie bei Rezidiv einer akuten myeloischen Leukämie nach allogener Stammzelltransplantation.. Aufgrund der bestehenden Immundefizienz wurde eine kalkulierte antibiotische Therapie mit Piperacillin/Tazobactam begonnen. Bei positivem 4MRGN-Screening wurde diese kalkuliert auf Colistin und Ceftazidim/Avibactam umgestellt. Diagnostiziert wurde ein Zungenulkus mit Abszessbildung und phlegmonöser Weichteilreaktion. In mehreren mikrobiologischen Proben, inklusive einer Blutkultur, gelang der Nachweis eines. Vierfach multiresistente gramnegative Bakterien (4MRGN) sind aufgrund ihrer Resistenz gegenüber 4 bakterizid wirkenden Hauptantibiotikagruppen (Acylureidopenicilline, Cephalosporine der 3. Generation, Carbapeneme, Fluorchinolone) nur schwer therapierbar. Der vorliegende Fall zeigt für Cefiderocol eine gute klinische Wirksamkeit – auch bei Erregern, die gegen Antibiotika wie Colistin und Ceftazidim/Avibactam resistent sind und er verdeutlicht, wie wichtig eine antibiogrammgerechte Therapie ist.

Topics: Aged; Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamases; Cefiderocol; Ceftazidime; Cephalosporins; Colistin; Communicable Diseases; Drug Combinations; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Klebsiella pneumoniae; Microbial Sensitivity Tests; Neoplasm Recurrence, Local; Neutropenia

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Ceftazidime; Drug Combinations; Drug Monitoring; Gram-Negative Bacterial Infections; Humans

Limited data on clinical and microbiological efficacy, patient mortality, and other associated factors are available for ceftazidime/avibactam (CAZ/AVI)-based regimens for carbapenem-resistant Gram-negative bacteria (CR-GNB). This study aimed to assess these issues retrospectively using multicenter data.. This multicenter study included CR-GNB infected patients treated with CAZ/AVI-based regimens for more than three days. Patient characteristics, bacterial culture reports, drug-sensitivity test results, and antibiotic use, including CAZ/AVI use, were extracted from the patient's clinical records. The clinical and microbiological efficacy of the combined drug regimen and patient mortality were evaluated according to corresponding definitions. Univariate and multivariate logistic regressions were performed to explore the efficacy and mortality-related factors.. A total of 183 patients with CR-GNB infection were considered for the analysis according to the inclusion and exclusion criteria. After the treatment of CAZ/AVI-based regimens, the clinical efficacy was 75.4 %. The 7-day microbial efficacy and clearance rate after treatment were 43.7 % and 66.0 %, respectively. Moreover, 30-day all-cause and in-hospital mortality were 11.5 % and 14.2 %, respectively. Harboring renal dysfunction (creatinine clearance rate (CCR) of<20 mL/min), cardiovascular diseases, and digestive system diseases were independent risk factors for poor clinical efficacy of CAZ/AVI-based regimens. Bloodstream infection (BSI), patients with the adjusted doses of CAZ/AVI, and CAZ/AVI co-administration with carbapenem were independently associated factors of bacterial clearance by CAZ/AVI-based regimens. Age, total hospital stays, use of mechanical ventilation, and cumulative CAZ/AVI dose were independent factors associated with all-cause mortality.. CAZ/AVI was an effective drug in treating CR-GNB infection. CAZ/AVI that is mostly excreted by the kidney and is accumulated in renal impairment should be renally adjusted. Renal dysfunction and the adjusted dose of CAZ/AVI were associated with efficacy. Clinicians should individualize CAZ/AVI regimen and dose by the level of renal function to achieve optimal efficacy and survival. The efficacy of CAZ/AVI in the treatment of CR-GNB infection, as well as the implementation of individualized precision drug administration of CAZ/AVI according to patients' different infection sites, renal function, bacterial types, bacterial resistance mechanisms, blood concentration monitoring and other conditions need to be further studied in multicenter.

Topics: Anti-Bacterial Agents; Bacterial Infections; Carbapenems; Ceftazidime; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Kidney Diseases; Microbial Sensitivity Tests; Retrospective Studies

To compare the effectiveness of ceftazidime/avibactam (CAZ/AVI) and polymyxin B against carbapenem-resistant Gram-negative bacteria (CRGNB) infections in western China.. The medical records of patients with CRGNB infections in this hospital from 2018-2022 were retrospectively reviewed. The data included demographic characteristics, laboratory results, antibiotic strategies and clinical outcomes.. A total of 378 patients with CRGNB infections were enrolled, including 112 patients in the CAZ/AVI group and 266 patients in the polymyxin B group. The most common pathogen was carbapenem-resistant Klebsiella pneumoniae (44.44%). The rates of treatment failure at 28 days (65.04% vs. 45.54%; P = 0.000) and 28-day in-hospital mortality (20.30% vs. 9.82%; P = 0.014) in the polymyxin B group were higher than those in the CAZ/AVI group. Multivariable analysis revealed that multiple organ dysfunction syndrome (OR 2.730; P = 0.017), acute renal failure (OR 2.595; P = 0.020), higher Charlson comorbidity index (CCI) (OR 1.184; P = 0.011) and Acute Physiology And Chronic Health Evaluation (APACHE) Ⅱ scores (OR 1.149; P = 0.000) were independent risk factors for treatment failure, whereas CAZ/AVI therapy (OR 0.333; P = 0.002) had a protective effect. Multivariate Cox regression analysis revealed that CCI ≥ 5 and APACHE II score ≥ 15 were associated with a higher 28-day in-hospital mortality rate (P < 0.001).. CAZ/AVI therapy was associated with treatment success among patients with CRGNB infection. However, CAZ/AVI therapy did not improve 28-day in-hospital survival compared with polymyxin B. The CCI ≥ 5 and APACHE II score ≥ 15 affected 28-day in-hospital mortality of CRGNB-infected patients.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Carbapenems; Ceftazidime; Drug Combinations; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Polymyxin B; Retrospective Studies

Stenotrophomonas maltophilia is a Gram-negative, opportunistic pathogen associated with a high morbidity and mortality rate. We report our clinical experience in treating a patient with infected pancreatic necrosis caused by multidrug-resistant (MDR) S. maltophilia with a novel drug combination.. A 65-year-old male with history of type II diabetes was admitted with acute pancreatitis, voluminous ascites, and signs of sepsis after undergoing an echo-endoscopy procedure with pancreas biopsy to investigate a Wirsung duct dilatation. Retroperitoneal fluid culture revealed S. maltophilia resistant to colistin and with intermediate susceptibility to trimethoprim-sulfamethoxazole and levofloxacin. The synergy between aztreonam (ATM) and ceftazidime/avibactam (CZA) was demonstrated using the combined disk pre-diffusion test.. There are sparse data providing guidance on the optimal regimen against MDR S. maltophilia infections. Although in this case a surgical excision was essential, combination of ATM and CZA provided effective synergistic antimicrobial treatment with clinical cure of severe acute pancreatitis infected with S. maltophilia. The combined disk pre-diffusion test with ATM and CZA requires no special equipment and can be routinely performed in clinical microbiology labs. Combination of ATM with CZA should be considered for cases of MDR S. maltophilia infections with limited treatment options.

Topics: Acute Disease; Aged; Anti-Bacterial Agents; Aztreonam; Ceftazidime; Diabetes Mellitus, Type 2; Drug Combinations; Gram-Negative Bacterial Infections; Humans; Male; Microbial Sensitivity Tests; Pancreatitis; Stenotrophomonas maltophilia

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Ceftazidime; Drug Combinations; Drug Monitoring; Gram-Negative Bacterial Infections; Humans

Antimicrobial resistance remains a serious and growing threat to public health, both globally and in the UK, leading to diminishing effectiveness of antimicrobials. Despite a clear need for new antimicrobials, the clinical pipeline is insufficient, driven by high research and development costs and limited expected returns on investment. To counteract this, National Institute for Health and Care Excellence (NICE) and National Health Service (NHS) England have launched a reimbursement mechanism, de-linked from volume of sales, that aims to reduce economic risk by recognising the broader population-level value of antimicrobials. The objective of this study was to quantify the value of ceftazidime-avibactam for treating gram-negative infections in the UK considering some of these broader value elements unique to antimicrobials.. A previously developed dynamic disease transmission and cost-effectiveness model was applied to assess the value of introducing ceftazidime-avibactam to UK treatment practice in the management of gram-negative hospital-acquired infections in line with the licenced indications for ceftazidime-avibactam. Model inputs were parameterised using sources aligned to the UK perspective.. The introduction of ceftazidime-avibactam into a two-line treatment sequence saved over 2300 lives, leading to a gain of 27,600 life years and 22,000 quality-adjusted life years (QALY) at an additional cost of £17 million, over a ten-year transmission period. Ceftazidime-avibactam was associated with a net monetary benefit of £642 million at willingness to pay threshold of £30,000 per QALY; even at a lower threshold of £20,000 per QALY, the net monetary benefit is £422 million.. Increasing the diversity of antimicrobial treatments through the introduction of an additional antimicrobial, in this instance ceftazidime-avibactam, was associated with substantial clinical and economic benefits, when considering broader population-level value. Despite revealing considerable benefits, the value of ceftazidime-avibactam is only partially reflected in this analysis. Further efforts are required to fully operationalise the spectrum, transmission, enablement, diversity and insurance (STEDI) value framework and accurately reflect the population-level value of antimicrobials.

Topics: Anti-Bacterial Agents; Ceftazidime; Cost-Benefit Analysis; Gram-Negative Bacterial Infections; Humans; State Medicine; United Kingdom

This study aimed to assess the efficacy of ceftazidime/avibactam (C/A) in the treatment of infections due to Gram-negative bacteria (GNB) in critically ill patients. A multicentre, retrospective, observational study was conducted in critically ill patients receiving C/A for GNB infections. We evaluated demographic data, localisation and severity of infection, clinical and microbiological outcomes, and mortality. A total of 68 patients received C/A for serious GNB infections. The main infections were respiratory (33.8%), intra-abdominal (22.1%) and urinary tract infections (10.3%); bacteraemia was found in 22 cases (32.4%). Most infections were complicated by septic shock (58.8%) or sepsis (36.8%) and most of them required life-supporting therapies. Enterobacterales (79.4%) and Pseudomonas aeruginosa (19.1%) were the most frequently isolated bacteria; 84.2% of isolates were carbapenem-resistant. Thirty-four patients (50.0%) received C/A in combination with other antimicrobials. Fifty patients (73.5%) presented a favourable clinical response. Microbiological eradication was documented in 25 cases (36.8%). No significant differences were found in clinical response between patients treated with monotherapy or combined therapy (79.4% vs. 67.6%; P = 0.27). Overall intensive care unit (ICU) mortality was 41.2%. Univariate analysis showed that 30-day all-cause mortality was significantly (P < 0.05) associated with bacteraemia, previous corticosteroid use and the need of life-supporting therapies. C/A appears to be an effective therapy for severe infections due to GNB, including carbapenem-resistant isolates, in critically ill patients. C/A combination therapy was not associated with a higher clinical response. Mortality correlated significantly with the presence of bacteraemia, previous corticosteroid use and the need for life-supporting therapies.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Ceftazidime; Critical Illness; Drug Combinations; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Retrospective Studies

The aim of this study was to investigate the clinical characteristics and outcomes of patients with infections caused by multidrug-resistant Gram-negative bacteria (MDR-GNB) treated with ceftazidime/avibactam (CAZ/AVI) during the period September 2019 to June 2020 since CAZ/AVI had been marketed in China.. A total of 20 MDR-GNB-infected patients were retrospectively identified using the electronic medical record system in West China Hospital.. The mean age of the 20 patients was 54.5 ± 17.37 years and 14 (70%) were male. Pneumonia (n = 12; 60%), complicated intra-abdominal infection (n = 10; 50%), and bloodstream infection (n = 7; 35%) were the most common infection sources. Klebsiella pneumoniae (55% 18/33) was the predominant pathogen. The 14-day clinical cure rate was 45%. The 14-day and 30-day mortality rates were 25% and 55%, respectively. No significant difference was found in 30-day mortality between treatment with CAZ/AVI monotherapy and combination regimens (P > 0.05). Three patients suffered from adverse drug reactions such as diarrhoea.. No significant difference was found between the effectiveness of CAZ/AVI in the clinical failure and cure groups as salvage treatment of MDR-GNB infection.

Topics: Adult; Aged; Anti-Bacterial Agents; Azabicyclo Compounds; Ceftazidime; China; Female; Gram-Negative Bacterial Infections; Humans; Male; Middle Aged; Retrospective Studies

β-Lactamases (BLs) are important antibiotic-resistance determinants that significantly compromise the efficacy of valuable β-lactam antibacterial drugs. Thus, combinations with BL inhibitor were developed. Avibactam is the first non-β-lactam BL inhibitor introduced into clinical practice. Ceftazidime-avibactam represents one of the few last-resort antibiotics available for the treatment of infections caused by near-pandrug-resistant bacteria. TRU-1 is a chromosomally encoded AmpC-type BL of Aeromonas enteropelogenes, related to the FOX-type BLs and constitutes a good model for class C BLs. TRU-1 crystals provided ultrahigh-resolution diffraction data for the native enzyme and for its complex with avibactam. A comparison of the native and avibactam-bound structures revealed new details in the conformations of residues relevant for substrate and/or inhibitor binding. Furthermore, a comparison of the TRU-1 and Pseudomonas aeruginosa AmpC avibactam-bound structures revealed two inhibitor conformations that were likely to correspond to two different states occurring during inhibitor carbamylation/recyclization.

Topics: Aeromonas; Amino Acid Sequence; Azabicyclo Compounds; beta-Lactamase Inhibitors; beta-Lactamases; Crystallography, X-Ray; Drug Design; Gram-Negative Bacterial Infections; Humans; Molecular Docking Simulation; Protein Conformation; Sequence Alignment

We conducted a national antimicrobial surveillance study of both gram-positive and gram-negative organisms isolated from hospitalized patients. This report presents data on antimicrobial susceptibility among 4998 organisms collected in China between 2012 and 2014.. The minimum inhibitory concentrations (MICs) and susceptibilities of ceftaroline/avibactam (CPA), ceftazidime/avibactam (CZA) and a range of comparative agents were determined according to guidelines established by the Clinical and Laboratory Standards Institute (CLSI).. The highest overall susceptibility levels for all Enterobacteriaceae during the study period were observed for CPA, CZA, doripenem (DOR), meropenem (MEM), and amikacin (AMK), which were all >90%. However, both CPT and CAZ alone and in combination with avibactam showed low activities for Acinetobacter spp., whereas CPA and CZA exhibited MIC90 values for Pseudomonas aeruginosa that were reduced by 4- and 8-fold, respectively, compared with those of CPT and CAZ. High susceptibilities of Acinetobacter spp. and P. aeruginosa to colistin and P. aeruginosa to AMK were observed. For the gram-positive strains, no significant activity changes were seen for Enterococcus, Staphylococcus, and viridans group streptococci to CPT or CAZ alone or in combination with avibactam, whereas Streptococcus pneumoniae and β-hemolytic Streptococcus showed almost 100% susceptibility to both CPT and CPA.. The addition of 4 mg/L avibactam greatly increased the activities of CPT and CAZ against most Enterobacteriaceae and P. aeruginosa isolates, whereas no significant changes were observed in Acinetobacter spp. or any of the gram-positive strains.

Topics: Acinetobacter; Anti-Bacterial Agents; Azabicyclo Compounds; Ceftaroline; Ceftazidime; Cephalosporins; China; Drug Combinations; Drug Resistance, Multiple, Bacterial; Enterobacteriaceae; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Hospitalization; Humans; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Public Health Surveillance

The activities of the novel β-lactam/non-β-lactam β-lactamase inhibitor combination ceftazidime/avibactam and comparators were evaluated against isolates from pneumonia in hospitalised patients including ventilated patients (PHP, pneumonia not designated as VABP; VABP, pneumonia in ventilated patients). Isolates were from the European-Mediterranean region (EuM), China and the USA collected in the SENTRY Antimicrobial Surveillance Program between 2009 and 2011 inclusive. A total of 2393 organisms from PHP were from the EuM, 888 from China and 3213 from the USA; from VABP patients there were 918, 97 and 692 organisms collected, respectively. Among Enterobacteriaceae from PHP, ceftazidime/avibactam MIC90 values against Escherichia coli ranged from 0.25-0.5mg/L and Klebsiella spp. MIC90 values were 0.5mg/L in each region. Among VABP isolates, MIC90 values for ceftazidime/avibactam against E. coli were 0.25mg/L; for Klebsiella spp. from VABP patients, MIC90 values were similar to those obtained against PHP isolates. The MIC of ceftazidime/avibactam was ≤8mg/L against 92-96% of Pseudomonas aeruginosa isolated from PHP patients. Isolates of P. aeruginosa from VABP patients were of lower susceptibility to all antibacterial agents (e.g. depending on region, meropenem susceptibilities were 51.2-69.4% in contrast to 68.3-76.7% among PHP patients). However, ceftazidime/avibactam inhibited 79.2-95.4% of VABP isolates at an MIC of ≤8mg/L. Acinetobacter spp. were resistant to many agents and only rates of susceptibility to colistin were >90% across all regions both for PHP and VABP isolates. Ceftazidime/avibactam was generally active against a high proportion of isolates resistant to ceftazidime from PHP and VAPB patients.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Ceftazidime; Cross Infection; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Hospitalization; Humans; Microbial Sensitivity Tests; Pneumonia, Bacterial; Respiration, Artificial

Avibactam displays potent inhibition of extended-spectrum, AmpC, KPC and some OXA β-lactamases. We examined the combinations of avibactam with ceftazidime, ceftaroline and aztreonam by the broth microdilution method against Gram-negative bacteria harboring molecularly-characterized β-lactamase genes collected in Toho University, Japan. Bacterial isolates included: Ambler class A β-lactamase-producing Enterobacteriaceae (n = 26); class C β-lactamase-producing Enterobacteriaceae (n = 9) and class D β-lactamase-producing Acinetobacter baumannii (n = 9) and Enterobacteriaceae (n = 3). Ceftazidime-avibactam, ceftaroline-avibactam ands aztreonam-avibactam were active against the strains with an extended-spectrum β-lactamase (ESBL) or AmpC enzymes, but combination with avibactam did not reduce β-lactam MICs against A. baumannii with OXA β-lactamases including carbapenemases, such as OXA-40 and -69.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamases; beta-Lactams; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Japan; Microbial Sensitivity Tests

Recent clinical isolates of key Gram-negative and Gram-positive bacteria were collected in 2012 from hospitalised patients in medical centres in four European countries (France, Germany, Italy and Spain) and were tested using standard broth microdilution methodology to assess the impact of 4 mg/L avibactam on the in vitro activities of ceftazidime, ceftaroline and aztreonam. Against Enterobacteriaceae, addition of avibactam significantly enhanced the level of activity of these antimicrobials. MIC(90) values (minimum inhibitory concentration that inhibits 90% of the isolates) of ceftazidime, ceftaroline and aztreonam for Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Enterobacter aerogenes, Citrobacter freundii and Morganella morganii were reduced up to 128-fold or greater when combined with avibactam. A two-fold reduction in the MIC(90) of ceftazidime to 8 mg/L was noted in Pseudomonas aeruginosa isolates when combined with avibactam, whereas little effect of avibactam was noted on the MIC values of the test compounds when tested against Acinetobacter baumannii isolates. Avibactam had little effect on the excellent activity of ceftazidime, ceftaroline and aztreonam against Haemophilus influenzae. It had no impact on the in vitro activity of ceftazidime and ceftaroline against staphylococci and streptococci. This study demonstrates that addition of avibactam enhances the activities of ceftazidime, ceftaroline and aztreonam against Enterobacteriaceae and P. aeruginosa but not against A. baumannii.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; beta-Lactams; Europe; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Hospitals; Humans; Microbial Sensitivity Tests

The combination of aztreonam plus avibactam is being developed for use in infections caused by metallo-β-lactamase-producing Enterobacteriaceae strains that also produce serine β-lactamases. The in vitro activities of aztreonam-avibactam and comparator antimicrobials were determined against year 2012 and 2013 clinical isolates of Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii using the broth microdilution methodology recommended by the Clinical and Laboratory Standards Institute (CLSI). A total of 28,501 unique clinical isolates were obtained from patients in 190 medical centers within 39 countries. MIC90 values of aztreonam and aztreonam-avibactam against all collected isolates of Enterobacteriaceae (n = 23,516) were 64 and 0.12 μg/ml, respectively, with 76.2% of the isolates inhibited by ≤4 μg/ml of aztreonam (the CLSI breakpoint) and 99.9% of the isolates inhibited by ≤4 μg/ml of aztreonam-avibactam using a fixed concentration of 4 μg/ml of avibactam. The MIC90 was 32 μg/ml for both aztreonam and aztreonam-avibactam against P. aeruginosa (n = 3,766). Aztreonam alone or in combination with avibactam had no in vitro activity against isolates of A. baumannii. PCR and sequencing were used to characterize 5,076 isolates for β-lactamase genes. Aztreonam was not active against most Enterobacteriaceae isolates producing class A or class C enzymes alone or in combination with class B metallo-β-lactamases. In contrast, >99% of Enterobacteriaceae isolates producing all observed Ambler classes of β-lactamase enzymes were inhibited by ≤4 μg/ml aztreonam in combination with avibactam, including isolates that produced IMP-, VIM-, and NDM-type metallo-β-lactamases in combination with multiple serine β-lactamases.

Topics: Acinetobacter baumannii; Anti-Bacterial Agents; Azabicyclo Compounds; Aztreonam; beta-Lactamases; Drug Resistance, Bacterial; Enterobacteriaceae; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Pseudomonas aeruginosa

Ceftazidime-avibactam, aztreonam-avibactam, and comparators were tested by reference broth microdilution against 372 nonrepetitive Gram-negative bacilli (346 unselected plus 26 selected meropenem-nonsusceptible Enterobacteriaceae isolates) collected from 11 teaching hospitals in China in 2011 and 2012. Meropenem-nonsusceptible isolates produced extended-spectrum β-lactamases (ESBLs; e.g., CTX-M-14/3), AmpCs (e.g., CMY-2), and/or carbapenemases (e.g., KPC-2 and NDM-1). Avibactam potentiated the activity of ceftazidime against organisms with combinations of ESBLs, AmpCs, and KPC-2. Aztreonam-avibactam was active against all β-lactamase producers (including producers of NDM-1 and IMP-4/8) except blaOXA-containing Acinetobacter baumannii and some Pseudomonas aeruginosa isolates.

Topics: Azabicyclo Compounds; Aztreonam; beta-Lactamases; Ceftazidime; China; Drug Combinations; Drug Resistance, Bacterial; Enterobacteriaceae; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Hospitals, Teaching; Humans; In Vitro Techniques; Microbial Sensitivity Tests

The activities of the novel β-lactam-β-lactamase inhibitor combination ceftazidime-avibactam and comparator agents were evaluated against a contemporary collection of clinically significant Gram-negative bacilli. Avibactam is a novel non-β-lactam β-lactamase inhibitor that inhibits Ambler class A, C, and some D enzymes. A total of 10,928 Gram-negative bacilli-8,640 Enterobacteriaceae, 1,967 Pseudomonas aeruginosa, and 321 Acinetobacter sp. isolates-were collected from 73 U.S. hospitals and tested for susceptibility by reference broth microdilution methods in a central monitoring laboratory (JMI Laboratories, North Liberty, IA, USA). Ceftazidime was combined with avibactam at a fixed concentration of 4 μg/ml. Overall, 99.8% of Enterobacteriaceae strains were inhibited at a ceftazidime-avibactam MIC of ≤4 μg/ml. Ceftazidime-avibactam was active against extended-spectrum β-lactamase (ESBL)-phenotype Escherichia coli and Klebsiella pneumoniae, meropenem-nonsusceptible (MIC≥2 μg/ml) K. pneumoniae, and ceftazidime-nonsusceptible Enterobacter cloacae. Among ESBL-phenotype K. pneumoniae strains, 61.1% were meropenem susceptible and 99.3% were inhibited at a ceftazidime-avibactam MIC of ≤4 μg/ml. Among P. aeruginosa strains, 96.9% were inhibited at a ceftazidime-avibactam MIC of ≤8 μg/ml, and susceptibility rates for meropenem, ceftazidime, and piperacillin-tazobactam were 82.0, 83.2, and 78.3%, respectively. Ceftazidime-avibactam was the most active compound tested against meropenem-nonsusceptible P. aeruginosa (MIC50/MIC90, 4/16 μg/ml; 87.3% inhibited at ≤8 μg/ml). Acinetobacter spp. (ceftazidime-avibactam MIC50/MIC90, 16/>32 μg/ml) showed high rates of resistance to most tested agents. In summary, ceftazidime-avibactam demonstrated potent activity against a large collection of contemporary Gram-negative bacilli isolated from patients in U.S. hospitals in 2012, including organisms that are resistant to most currently available agents, such as K. pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae and meropenem-nonsusceptible P. aeruginosa.

Topics: Acinetobacter; Anti-Bacterial Agents; Azabicyclo Compounds; Ceftazidime; Drug Combinations; Drug Resistance, Bacterial; Enterobacter cloacae; Enterobacteriaceae; Escherichia coli; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Klebsiella pneumoniae; Microbial Sensitivity Tests; Pseudomonas aeruginosa; United States

The activity of ceftazidime/avibactam and comparator agents was monitored at 73 medical centres across all nine US census bureau regions during 2012.. Bacterial isolates were collected from patients hospitalized with pneumonia, urinary tract infections (UTI), intra-abdominal infections (IAI) and bloodstream infections (BSI). The study protocol predetermined the target numbers of strains for each of the requested bacterial species that sites were to collect. Isolates were determined to be clinically relevant at the medical centre and only one isolate per patient episode was collected.. There were 1466 Gram-negative isolates from BSI, 3245 from pneumonia patients, 501 from IAI and 2356 from UTI. Ceftazidime/avibactam was active against Enterobacteriaceae from each infection type. The MIC90 values for ceftazidime/avibactam against Enterobacteriaceae isolates from BSI, pneumonia patients, IAI or UTI were 0.25 mg/L. The extended-spectrum cephalosporin resistance rates for Escherichia coli were 8.5% (UTI), 10.4% (IAI), 12.7% (BSI) and 17.5% (pneumonia patients). The extended-spectrum cephalosporin resistance rates for Klebsiella spp. were 13.0% (UTI), 13.9% (BSI), 16.3% (IAI) and 19.3% (pneumonia patients). A total of 96.5% of the Pseudomonas aeruginosa isolates from BSI, 95.8% from pneumonia patients, 96.3% from IAI and 98.7% from UTI exhibited a ceftazidime/avibactam MIC of ≤8 mg/L (CLSI susceptible breakpoint for ceftazidime when tested alone against P. aeruginosa). Most tested agents showed limited activity against Acinetobacter baumannii, except for colistin. A total of 31.2% of A. baumannii displayed ceftazidime/avibactam MIC values of ≤8 mg/L.. Ceftazidime/avibactam demonstrated potent broad-spectrum activity against Gram-negative pathogens collected in the USA during 2012 from BSI, pneumonia patients, IAI and UTI.

Topics: Academic Medical Centers; Azabicyclo Compounds; Ceftazidime; Cross Infection; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Intraabdominal Infections; Microbial Sensitivity Tests; Pneumonia; United States; Urinary Tract Infections

For an antibacterial agent to be considered for clinical studies in nosocomial pneumonia (NP), it should be active in the presence of pulmonary surfactant. Furthermore, owing to the common practice of treating such infections with more than one antibacterial agent, it should be free of antagonistic interactions with agents of other classes. The aim of this study was to demonstrate the effect of pulmonary surfactant on the activity of ceftazidime and ceftazidime-avibactam and to determine the interaction (if any) of ceftazidime-avibactam and six antimicrobial agents common in the treatment of NP. Minimum inhibitory concentration (MIC) determination for ceftazidime and ceftazidime-avibactam was performed with and without the presence of four concentrations of bovine pulmonary surfactant, and a chequerboard assay was used to determine any interaction between ceftazidime and ceftazidime-avibactam with tobramycin, levofloxacin, linezolid, vancomycin, tigecycline and colistin. Here we report that the in vitro antimicrobial activity of ceftazidime-avibactam against β-lactamase-producing Gram-negative bacteria remained unaltered in the presence of pulmonary surfactant at concentrations that antagonised the antimicrobial activity of daptomycin. Furthermore, in chequerboard interaction studies, an absence of antagonism was demonstrated between ceftazidime-avibactam and six antimicrobial agents of different classes when tested against aerobic species frequently isolated from NP. The results support the further investigation of ceftazidime-avibactam as a potential treatment for NP caused by susceptible bacteria.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamases; Ceftazidime; Cross Infection; Drug Therapy, Combination; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Minocycline; Pneumonia, Bacterial; Pulmonary Surfactants; Tigecycline; Tobramycin

The in vitro activities of ceftaroline-avibactam, ceftaroline, and comparative agents were determined for a collection of bacterial pathogens frequently isolated from patients seeking care at 15 Canadian hospitals from January 2010 to December 2012. In total, 9,758 isolates were tested by using the Clinical and Laboratory Standards Institute (CLSI) broth microdilution method (document M07-A9, 2012), with MICs interpreted by using CLSI breakpoints (document M100-S23, 2013). Ceftaroline-avibactam demonstrated potent activity (MIC90, ≤ 0.5 μg/ml) against Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Proteus mirabilis, Enterobacter cloacae, Enterobacter aerogenes, Serratia marcescens, Morganella morganii, Citrobacter freundii, and Haemophilus influenzae; >99% of isolates of E. coli, K. pneumoniae, K. oxytoca, P. mirabilis, M. morganii, C. freundii, and H. influenzae were susceptible to ceftaroline-avibactam according to CLSI MIC interpretative criteria for ceftaroline. Ceftaroline was less active than ceftaroline-avibactam against all species of Enterobacteriaceae tested, with rates of susceptibility ranging from 93.9% (P. mirabilis) to 54.0% (S. marcescens). All isolates of methicillin-susceptible Staphylococcus aureus (MIC90, 0.25 μg/ml) and 99.6% of methicillin-resistant S. aureus isolates (MIC90, 1 μg/ml) were susceptible to ceftaroline; the addition of avibactam to ceftaroline did not alter its activity against staphylococci or streptococci. All isolates of Streptococcus pneumoniae (MIC90, 0.03 μg/ml), Streptococcus pyogenes (MIC90, ≤ 0.03 μg/ml), and Streptococcus agalactiae (MIC90, 0.015 μg/ml) tested were susceptible to ceftaroline. We conclude that combining avibactam with ceftaroline expanded its spectrum of activity to include most isolates of Enterobacteriaceae resistant to third-generation cephalosporins, including extended-spectrum β-lactamase (ESBL)- and AmpC-producing E. coli and ESBL-producing K. pneumoniae, while maintaining potent activity against staphylococci and streptococci.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Canada; Ceftaroline; Cephalosporins; Cross Infection; Drug Resistance, Multiple, Bacterial; Drug Synergism; Drug Therapy, Combination; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Microbial Sensitivity Tests; Public Health Surveillance; Retrospective Studies

Although Gram-positive cocci are the most common pathogens in diabetic foot infections, these infections often are polymicrobial. The objective of this study was to assess the efficacy of a simulated human dose of 600 mg ceftaroline fosamil-600 mg avibactam every 8 h as a 1-h infusion in a polymicrobial in vivo murine model. Seven isolates were used (3 methicillin-resistant Staphylococcus aureus [MRSA] isolates, 1 methicillin-susceptible S. aureus [MSSA] isolate, 1 Escherichia coli isolate, 1 Enterobacter cloacae isolate, and 1 Bacteroides fragilis isolate) in various combinations in an immunocompromised polymicrobial tissue infection to assess the efficacy of the simulated regimen. Each infection was comprised of at least one S. aureus isolate with a MIC of 0.25 to 1 μg/ml and one Enterobacteriaceae isolate with a MIC of 1 or 4 μg/ml. Eight of 16 infections also included B. fragilis, with a MIC of 0.5 μg/ml, as a third organism. Efficacy was evaluated after 24 h as the change in log10 CFU from the level of 0-h controls. Efficacy was seen against all isolate combinations, with at least a 1-log kill against Enterobacteriaceae and a minimum of a 2-log kill against S. aureus and B. fragilis isolates. These bacterial reductions correlate with free drug concentration above the MIC (fT>MIC) produced by the humanized regimen of 100, 86, and 56% at MICs of 1, 2, and 4 μg/ml, respectively. The humanized regimen of 600 mg ceftaroline fosamil-600 mg avibactam every 8 h as a 1-h infusion showed predictable efficacy against all infections tested in this model. These data support further clinical investigation of ceftaroline fosamil-avibactam for the treatment of polymicrobial tissue infections.

Topics: Animals; Anti-Bacterial Agents; Azabicyclo Compounds; Bacteroides fragilis; Ceftaroline; Cephalosporins; Coinfection; Drug Administration Schedule; Drug Combinations; Enterobacter cloacae; Escherichia coli; Female; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Immunocompromised Host; Methicillin-Resistant Staphylococcus aureus; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Treatment Outcome

Ceftaroline is a new cephalosporin with broad-spectrum activity against Gram-positive and -negative organisms. The prodrug of ceftaroline, ceftaroline fosamil, combined with the β-lactamase inhibitor avibactam (formerly NXL104), was tested against Enterobacteriaceae strains producing Ambler class A, B, C, and D enzymes, including strains producing multiple enzymes, as well as Pseudomonas aeruginosa, Acinetobacter spp., and methicillin-susceptible and methicillin-resistant Staphylococcus aureus (MRSA) strains. Isolates were collected from 1999 to 2008 from global surveillance programs, and susceptibility testing was performed by reference broth microdilution methods. Ceftaroline-avibactam exhibited potent activity against Enterobacteriaceae producing various β-lactamase types (MIC(90), 0.25 to 2 μg/ml, except for metalloenzymes), including 99 strains carrying multiple enzymes (2 to 4 β-lactamases; MIC(90), 2 μg/ml). All isolates were inhibited by ceftaroline-avibactam at ≤4 μg/ml. Ceftaroline-avibactam (MIC(90), 0.5 to 1 μg/ml) was more active than meropenem (MIC(90), >8 μg/ml) and other comparators when tested against KPC-producing strains. S. aureus strains, including MRSA with four staphylococcal cassette chromosome mec (SCCmec) types, were dominantly (99.1%) inhibited by ceftaroline-avibactam at ≤2 μg/ml, and the ceftaroline MIC was not adversely affected by the addition of the β-lactamase inhibitor (MIC(50/90), 1 and 2 μg/ml for ceftaroline with and without avibactam). Ceftaroline-avibactam demonstrated limited activity against Acinetobacter spp. and P. aeruginosa (MIC(50)s, 32 and 16 μg/ml, respectively). These results document that ceftaroline-avibactam has potent activity against Enterobacteriaceae that produce KPC, various ESBL types (CTX-M types), and AmpC (chromosomally derepressed or plasmid-mediated enzymes), as well as against those producing more than one of these β-lactamase types, and its development as a therapeutic option for the treatment of infections caused by multidrug-resistant Enterobacteriaceae as well as MRSA is warranted.

Topics: Acinetobacter; Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; beta-Lactamases; Ceftaroline; Cephalosporins; Chromosomes, Bacterial; Drug Combinations; Gram-Negative Bacterial Infections; Humans; Isoenzymes; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Plasmids; Pseudomonas aeruginosa; Staphylococcal Infections

Avibactam is a β-lactamase inhibitor that is in clinical development, combined with β-lactam partners, for the treatment of bacterial infections comprising gram-negative organisms. Avibactam is a structural class of inhibitor that does not contain a β-lactam core but maintains the capacity to covalently acylate its β-lactamase targets. Using the TEM-1 enzyme, we characterized avibactam inhibition by measuring the on-rate for acylation and the off-rate for deacylation. The deacylation off-rate was 0.045 min(-1), which allowed investigation of the deacylation route from TEM-1. Using NMR and MS, we showed that deacylation proceeds through regeneration of intact avibactam and not hydrolysis. Other than TEM-1, four additional clinically relevant β-lactamases were shown to release intact avibactam after being acylated. We showed that avibactam is a covalent, slowly reversible inhibitor, which is a unique mechanism of inhibition among β-lactamase inhibitors.

Topics: Acylation; Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamase Inhibitors; beta-Lactamases; Drug Discovery; Gram-Negative Bacterial Infections; Kinetics; Magnetic Resonance Spectroscopy; Mass Spectrometry; Molecular Structure