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Antimicrobial Agents and Chemotherapy Jun 2018Avibactam is a novel non-β-lactam β-lactamase inhibitor that has been approved in the United States and Europe for use in combination with ceftazidime. Combinations of... (Review)
Review
Avibactam is a novel non-β-lactam β-lactamase inhibitor that has been approved in the United States and Europe for use in combination with ceftazidime. Combinations of avibactam with aztreonam or ceftaroline fosamil have also been clinically evaluated. Until recently, there has been very little precedence of which pharmacokinetic/pharmacodynamic (PK/PD) indices and magnitudes are appropriate to use for β-lactamase inhibitors in population PK modeling for analyzing potential doses and susceptibility breakpoints. For avibactam, several preclinical studies using different and models have been conducted to identify the PK/PD index of avibactam and the magnitude of exposure necessary for effect in combination with ceftazidime, aztreonam, or ceftaroline fosamil. The PD driver of avibactam critical for restoring the activity of all three partner β-lactams was found to be time dependent rather than concentration dependent and was defined as the time that the concentration of avibactam exceeded a critical concentration threshold (%T>C). The magnitude of the C and the time that this threshold needed to be exceeded to elicit particular PD endpoints varied depending on the model and the partner β-lactam. This review describes the preclinical studies used to determine the avibactam PK/PD target in combination with its β-lactam partners.
Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Aztreonam; Ceftazidime; Cephalosporins; Microbial Sensitivity Tests; beta-Lactamase Inhibitors
PubMed: 29610208
DOI: 10.1128/AAC.02446-17 -
Antimicrobial Agents and Chemotherapy Oct 2021Carbapenem-resistant (CRE) and Pseudomonas aeruginosa (CR-PA) producing metallo-β-lactamases (MBLs) cause severe nosocomial infections with no defined treatment. The...
Carbapenem-resistant (CRE) and Pseudomonas aeruginosa (CR-PA) producing metallo-β-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 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-β-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
Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Aztreonam; Ceftazidime; Drug Combinations; Microbial Sensitivity Tests; Pseudomonas aeruginosa; beta-Lactamases
PubMed: 34424044
DOI: 10.1128/AAC.00846-21 -
Antibiotics (Basel, Switzerland) Mar 2022Carbapenem antibiotics are the most effective antimicrobials for the treatment of infections caused by the most resistant bacteria. They belong to the category of... (Review)
Review
Carbapenem antibiotics are the most effective antimicrobials for the treatment of infections caused by the most resistant bacteria. They belong to the category of β-lactams that include the penicillins, cephalosporins, monobactams and carbapenems. This class of antimicrobials has a broader spectrum of activity than most other beta-lactams antibiotics and are the most effective against Gram-positive and Gram-negative bacteria. All β-lactams antibiotics have a similar molecular structure: the carbapenems together with the β-lactams. This combination gives an extraordinary stability to the molecule against the enzymes inactivating the β-lactams. They are safe to use and therefore widespread use in many countries has given rise to carbapenem resistance which is a major global public health problem. The carbapenem resistance in some species is intrinsic and consists of the capacity to resist the action of antibiotics with several mechanisms: for the absence of a specific target, or an intrinsic difference in the composition of cytoplasmatic membrane or the inability to cross the outer membrane. In addition to intrinsic resistance, bacteria can develop resistance to antibiotics with several mechanisms that can be gathered in three main groups. The first group includes antibiotics with poor penetration into the outer membrane of bacterium or antibiotic efflux. The second includes bacteria that modify the target of the antibiotics through genetic mutations or post-translational modification of the target. The third includes bacteria that act with enzyme-catalyzed modification and this is due to the production of beta-lactamases, that are able to inactivate carbapenems and so called carbapenemases. In this review, we focus on the mode of action of carbapenem and the mechanisms of carbapenem resistance.
PubMed: 35326884
DOI: 10.3390/antibiotics11030421 -
Intensive Care Medicine Dec 2022Individualising drug dosing using model-informed precision dosing (MIPD) of beta-lactam antibiotics and ciprofloxacin has been proposed as an alternative to standard... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Individualising drug dosing using model-informed precision dosing (MIPD) of beta-lactam antibiotics and ciprofloxacin has been proposed as an alternative to standard dosing to optimise antibiotic efficacy in critically ill patients. However, randomised clinical trials (RCT) on clinical outcomes have been lacking.
METHODS
This multicentre RCT, including patients admitted to the intensive care unit (ICU) who were treated with antibiotics, was conducted in eight hospitals in the Netherlands. Patients were randomised to MIPD with dose and interval adjustments based on monitoring serum drug levels (therapeutic drug monitoring) combined with pharmacometric modelling of beta-lactam antibiotics and ciprofloxacin. The primary outcome was ICU length of stay (LOS). Secondary outcomes were ICU mortality, hospital mortality, 28-day mortality, 6-month mortality, delta sequential organ failure assessment (SOFA) score, adverse events and target attainment.
RESULTS
In total, 388 (MIPD n = 189; standard dosing n = 199) patients were analysed (median age 64 [IQR 55-71]). We found no significant differences in ICU LOS between MIPD compared to standard dosing (10 MIPD vs 8 standard dosing; IRR = 1.16; 95% CI 0.96-1.41; p = 0.13). There was no significant difference in target attainment before intervention at day 1 (T1) (55.6% MIPD vs 60.9% standard dosing; p = 0.24) or at day 3 (T3) (59.5% vs 60.4%; p = 0.84). There were no significant differences in other secondary outcomes.
CONCLUSIONS
We could not show a beneficial effect of MIPD of beta-lactam antibiotics and ciprofloxacin on ICU LOS in critically ill patients. Our data highlight the need to identify other approaches to dose optimisation.
Topics: Humans; Middle Aged; Critical Illness; beta-Lactams; Ciprofloxacin; Intensive Care Units; Anti-Bacterial Agents; Monobactams
PubMed: 36350354
DOI: 10.1007/s00134-022-06921-9 -
Clinical Infectious Diseases : An... Oct 2021The development of novel broad-spectrum antibiotics, with efficacy against both gram-positive and gram-negative bacteria, has the potential to enhance treatment options... (Randomized Controlled Trial)
Randomized Controlled Trial
Ceftobiprole Compared With Vancomycin Plus Aztreonam in the Treatment of Acute Bacterial Skin and Skin Structure Infections: Results of a Phase 3, Randomized, Double-blind Trial (TARGET).
BACKGROUND
The development of novel broad-spectrum antibiotics, with efficacy against both gram-positive and gram-negative bacteria, has the potential to enhance treatment options for acute bacterial skin and skin structure infections (ABSSSIs). Ceftobiprole is an advanced-generation intravenous cephalosporin with broad in vitro activity against gram-positive (including methicillin-resistant Staphylococcus aureus) and gram-negative pathogens.
METHODS
TARGET was a randomized, double-blind, active-controlled, parallel-group, multicenter, phase 3 noninferiority study that compared ceftobiprole with vancomycin plus aztreonam. The Food and Drug Administration-defined primary efficacy endpoint was early clinical response 48-72 hours after treatment initiation in the intent-to-treat (ITT) population and the European Medicines Agency-defined primary endpoint was investigator-assessed clinical success at the test-of-cure (TOC) visit. Noninferiority was defined as the lower limit of the 95% CI for the difference in success rates (ceftobiprole minus vancomycin/aztreonam) >-10%. Safety was assessed through adverse event and laboratory data collection.
RESULTS
In total, 679 patients were randomized to ceftobiprole (n = 335) or vancomycin/aztreonam (n = 344). Early clinical success rates were 91.3% and 88.1% in the ceftobiprole and vancomycin/aztreonam groups, respectively, and noninferiority was demonstrated (adjusted difference: 3.3%; 95% CI: -1.2, 7.8). Investigator-assessed clinical success at the TOC visit was similar between the 2 groups, and noninferiority was demonstrated for both the ITT (90.1% vs 89.0%) and clinically evaluable (97.9% vs 95.2%) populations. Both treatment groups displayed similar microbiological success and safety profiles.
CONCLUSIONS
TARGET demonstrated that ceftobiprole is noninferior to vancomycin/aztreonam in the treatment of ABSSSIs, in terms of early clinical response and investigator-assessed clinical success at the TOC visit.
CLINICAL TRIALS REGISTRATION
NCT03137173.
Topics: Anti-Bacterial Agents; Aztreonam; Cephalosporins; Double-Blind Method; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Methicillin-Resistant Staphylococcus aureus; Skin Diseases, Bacterial; Treatment Outcome; Vancomycin
PubMed: 32897367
DOI: 10.1093/cid/ciaa974 -
The New Microbiologica Feb 2023Cefditoren is an oral third-generation cephalosporin with a large spectrum activity against Gram-negative and Gram-positive bacteria which are reported to be responsible... (Review)
Review
Cefditoren is an oral third-generation cephalosporin with a large spectrum activity against Gram-negative and Gram-positive bacteria which are reported to be responsible for respiratory tract and skin and skin structure infections. In this work we reviewed the pharmacodynamics, pharmacokinetics, and the main clinical indications of cefditoren. Similarly to other beta-lactams, cefditoren is a time-dependent antibiotic, and its "best" PK/PD target is probably 40% dosing interval time > 4- 5-fold MIC and 40-70% dosing interval time > 4- 5-fold MIC for bacteriostatic and bactericidal effect, respectively. In fasting patients oral bioavailability is low and increases when the drug is taken with food. This cephalosporin has significant bactericidal activity against S. pneumoniae (both penicillin-susceptible and penicillin-resistant strains), S. pyogenes, H. Influenzae and M. catarrhalis, as well as methicillin-susceptible S. aureus (MSSA). Regarding Enterobacterales, cefditoren has very low MICs90 against K. pneumoniae andE. coli but is not active against AmpC-, ESBL- and carbapenemase-producer' strains. Licensed indications are treatment of exacerbations of chronic bronchitis,acute rhinosinusitis, otitis media, upper respiratory tract infections (pharyngitis/tonsillitis), lower community-acquired respiratory tract infections (LRTIs), and skin and skin-structure infections (SSTI). Cefditoren might have a role in switching from parenteral to oral therapy in acute pyelonephritis and LRTIs. with a reduction of adverse effects and hospital costs. Eventually, due to its supposed binding to enterococcal penicillin binding proteins (PBPs) cefditoren, in combination with other beta-lactams, might have a role in partial oral enterococcal endocarditis treatment..
Topics: Humans; Staphylococcus aureus; Cephalosporins; Anti-Bacterial Agents; Monobactams; Respiratory Tract Infections
PubMed: 36853812
DOI: No ID Found -
Critical Care Medicine Sep 2023As causative pathogens are not usually identified at the time of initiating antibiotics in sepsis, carbapenems are commonly used as an initial treatment. To reduce... (Observational Study)
Observational Study
OBJECTIVES
As causative pathogens are not usually identified at the time of initiating antibiotics in sepsis, carbapenems are commonly used as an initial treatment. To reduce indiscriminate use of carbapenems, the efficacy of alternative empiric regimens, such as piperacillin-tazobactam and the fourth-generation cephalosporins, should be elucidated. This study aimed to evaluate survival effect associated with carbapenems as initial therapy for sepsis compared with these antibiotics.
DESIGN
Multicenter retrospective observational study.
SETTING
Tertiary hospitals in Japan.
PATIENTS
Adult patients diagnosed as having sepsis from 2006 to 2019.
INTERVENTIONS
Administration of carbapenems as initial antibiotic therapy.
MEASUREMENTS AND MAIN RESULTS
This study used data of adult patients with sepsis extracted from a large-scale database in Japan. Patients were divided into two groups as follows: patients receiving carbapenems and patients receiving noncarbapenem broad-spectrum beta-lactam antibiotics as initial treatment. In-hospital mortality was compared between the groups by a logistic regression model adjusted by an inverse probability treatment weighting using propensity scores. To evaluate heterogeneity of effects according to patient characteristics, we also fitted logistic models in several subgroups. Among 7,392 patients with sepsis, 3,547 patients received carbapenems, and 3,845 patients received noncarbapenem agents. The logistic model showed no significant association between carbapenem therapy and lower mortality (adjusted OR 0.88, p = 0.108). Subgroup analyses suggested that there were significant survival benefits associated with carbapenem therapy in patients with septic shock, in ICUs, or with mechanical ventilation ( p for effect modifications: < 0.001, 0.014, and 0.105, respectively).
CONCLUSIONS
Compared with the noncarbapenem broad-spectrum antibiotics, carbapenems as an initial therapy for sepsis were not associated with significantly lower mortality.
Topics: Adult; Humans; Anti-Bacterial Agents; Carbapenems; Monobactams; Piperacillin, Tazobactam Drug Combination; Retrospective Studies; Sepsis; Hospital Mortality; Treatment Outcome
PubMed: 37232855
DOI: 10.1097/CCM.0000000000005932 -
Medizinische Klinik, Intensivmedizin... Mar 2023Infections due to antibiotic-resistant bacteria are threatening modern healthcare, and antibacterial resistance has become one of the greatest threats to public health.... (Review)
Review
BACKGROUND
Infections due to antibiotic-resistant bacteria are threatening modern healthcare, and antibacterial resistance has become one of the greatest threats to public health. In Germany 54,500 patients become infected with antibiotic-resistant bacteria per year, causing about 2400 attributable deaths. Rising resistance in Gram-negative bacteria especially carbapenem-resistant pathogens is of particular concern due to the lack of effective and safe alternative treatment options.
OBJECTIVE
The results from trials and compassionate-use programs with the new antibiotic cefiderocol, which was approved by the European Medicines Agency (EMA) in April 2020 for the treatment of adults with infections caused by aerobic Gram-negative bacteria, are summarized.
RESULTS
The new β‑lactam antibiotic cefiderocol is the first siderophore cephalosporin indicated for the treatment of infections due to aerobic Gram-negative organisms in adults with limited treatment options. Its chemical structure and its unique mechanism of action confer enhanced stability against β‑lactamases including all classes of clinically relevant carbapenemases. In vitro data show high antibacterial activity against multidrug resistant Gram-negative bacteria, Enterobacterales and nonfermenters, including carbapenem-resistant strains. In clinical trials, cefiderocol showed superiority in complicated urinary tract infection in comparison to imipenem and non-inferiority versus meropenem in hospital-acquired/ventilator-associated pneumonia patients and severe infections caused by carbapenem-resistant pathogens.
CONCLUSION
Clinical trial data and case reports identified in the literature search show that cefiderocol is a promising treatment option for severe infections caused by drug-resistant Gram-negative bacteria, particularly carbapenem-resistant bacteria.
Topics: Adult; Humans; Cephalosporins; Anti-Bacterial Agents; Monobactams; Carbapenems; Cefiderocol
PubMed: 35913604
DOI: 10.1007/s00063-022-00925-5