RESUMO
ß-lactam antibiotics have been prescribed for most bacterial infections since their discovery. However, resistance to ß-lactams, mediated by ß-lactamase (Bla) enzymes such as extended spectrum ß-lactamases (ESBLs), has become widespread. Bla inhibitors can restore the efficacy of ß-lactams against resistant bacteria, an approach which preserves existing antibiotics despite declining industry investment. However, the effects of combination treatment on selection for ß-lactam resistance are not well understood. Bla production confers both private benefits for resistant cells and public benefits which faster-growing sensitive cells can also exploit. These benefits may be differentially impacted by Bla inhibitors, leading to non-intuitive selection dynamics. In this study, we demonstrate strain-to-strain variation in effective combination doses, with complex growth dynamics in mixed populations. Using modeling, we derive a criterion for the selection outcome of combination treatment, dependent on the burden and effective private benefit of Bla production. We then use engineered strains and natural isolates to show that strong private benefits of Bla are associated with increased selection for resistance. Finally, we demonstrate that this parameter can be coarsely estimated using high-throughput phenotyping of clonal populations. Our analysis shows that quantifying the phenotypic responses of bacteria to combination treatment can facilitate resistance-minimizing optimization of treatment.
Assuntos
Antibacterianos , beta-Lactamases , beta-Lactamases/metabolismo , beta-Lactamases/genética , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Inibidores de beta-Lactamases/farmacologia , Inibidores de beta-Lactamases/uso terapêutico , Resistência beta-Lactâmica/genética , Resistência beta-Lactâmica/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Quimioterapia Combinada , beta-Lactamas/farmacologia , beta-Lactamas/uso terapêutico , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Humanos , Seleção GenéticaRESUMO
SOURCE CITATION: Abdul-Aziz MH, Hammond NE, Brett SJ, et al. Prolonged vs intermittent infusions of ß-lactam antibiotics in adults with sepsis or septic shock: a systematic review and meta-analysis. JAMA. 12 June 2024. [Epub ahead of print.] 38864162.
Assuntos
Antibacterianos , Sepse , Choque Séptico , beta-Lactamas , Humanos , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Choque Séptico/tratamento farmacológico , Choque Séptico/mortalidade , beta-Lactamas/administração & dosagem , beta-Lactamas/uso terapêutico , Sepse/tratamento farmacológico , Sepse/mortalidade , Infusões Intravenosas , Esquema de Medicação , Antibióticos beta LactamRESUMO
SOURCE CITATION: Dulhunty JM, Brett SJ, De Waele JJ, et al; BLING III Study Investigators. Continuous vs intermittent ß-lactam antibiotic infusions in critically ill patients with sepsis: the BLING III randomized clinical trial. JAMA. 12 June 2024. [Epub ahead of print.] 38864155.
Assuntos
Antibacterianos , Sepse , beta-Lactamas , Humanos , Sepse/tratamento farmacológico , Sepse/mortalidade , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , beta-Lactamas/administração & dosagem , beta-Lactamas/uso terapêutico , Infusões Intravenosas , Estado Terminal/mortalidade , Esquema de Medicação , Pessoa de Meia-Idade , Masculino , Antibióticos beta LactamRESUMO
BACKGROUND: The optimal duration of therapy of aminoglycosides in combination regimens is expected to be different from that of monotherapy regimens, and shorter durations could help minimize toxicity without compromising efficacy. The aim of this review was to assess the evidence for the optimal duration of aminoglycosides in ß-lactam/aminoglycoside combinations used for the treatment of Gram-negative bacterial infections. MATERIALS AND METHODS: PubMed, Cochrane, Embase, Scopus, Web of Science, and CINHAL databases were searched. Covidence software was used for article screening and management. Studies were included if they clearly reported the duration of therapy of aminoglycosides in ß-lactam/aminoglycoside combinations used against Gram-negative bacteria. The protocol is registered with PROSPERO (CRD42023392709). RESULTS: A total of 45 ß-lactam/aminoglycoside combination courses from 32 articles were evaluated. The duration of therapy of aminoglycosides in combinations regimens ranged from 1 to 14 days, varying with the type of infection treated. In half (51.1%; (23/45) of the combinations, aminoglycosides were administered for a duration ranging from 6 to 9 days. In 26.7% (12/45) of the combinations, the duration of aminoglycoside therapy was ≤ 5 days. In the remaining 22.2% (10/45) of these combinations, the aminoglycosides were administered for a duration of ≥ 10 days. Aminoglycosides were administered for a longer duration of 7-14 days in 12 (75%) of the 16 combination courses that induced toxicity. CONCLUSIONS: Long duration of aminoglycoside use is associated with increased risk of toxicity. However, there is a lack of evidence on defining an optimal duration of aminoglycoside therapy in ß-lactam/aminoglycoside combination regimens that ensures clinical efficacy outcomes whilst minimizing toxicity outcomes.
Assuntos
Aminoglicosídeos , Antibacterianos , Quimioterapia Combinada , Infecções por Bactérias Gram-Negativas , beta-Lactamas , Aminoglicosídeos/uso terapêutico , Aminoglicosídeos/administração & dosagem , Humanos , beta-Lactamas/uso terapêutico , beta-Lactamas/administração & dosagem , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Antibacterianos/uso terapêutico , Antibacterianos/administração & dosagem , Bactérias Gram-Negativas/efeitos dos fármacosRESUMO
Clinical studies investigating the benefits of beta-lactam therapeutic drug monitoring (TDM) among critically ill patients are hindered by small patient groups, variability between studies, patient heterogeneity, and inadequate use of TDM. Accordingly, definitive conclusions regarding the efficacy of TDM remain elusive. To address these challenges, we propose an innovative approach that leverages data-driven methods to unveil the concealed connections between therapy effectiveness and patient data, collected through a randomized controlled trial (DRKS00011159; 10th October 2016). Our findings reveal that machine learning algorithms can successfully identify informative features that distinguish between healthy and sick states. These hold promise as potential markers for disease classification and severity stratification, as well as offering a continuous and data-driven "multidimensional" Sequential Organ Failure Assessment (SOFA) score. The positive impact of TDM on patient recovery rates is demonstrated by unraveling the intricate connections between therapy effectiveness and clinically relevant data via machine learning.
Assuntos
Monitoramento de Medicamentos , Aprendizado de Máquina , Sepse , Humanos , Sepse/tratamento farmacológico , Sepse/diagnóstico , Monitoramento de Medicamentos/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , beta-Lactamas/uso terapêutico , Antibacterianos/uso terapêutico , Algoritmos , Estado Terminal , Escores de Disfunção OrgânicaRESUMO
Beta-lactam antibiotics are widely used in the intensive care unit due to their favorable effectiveness and safety profiles. Beta-lactams given to patients with sepsis must be delivered as soon as possible after infection recognition (early), treat the suspected organism (appropriate), and be administered at a dose that eradicates the infection (adequate). Early and appropriate antibiotic delivery occurs in >90% of patients, but less than half of patients with sepsis achieve adequate antibiotic exposure. This project aimed to address this quality gap and improve beta-lactam adequacy using the Define, Measure, Analyze, Improve, and Control Lean Six Sigma quality improvement framework. A multidisciplinary steering committee was formed, which completed a stakeholder analysis to define the gap in practice. An Ishikawa cause and effect (Fishbone) diagram was used to identify the root causes and an impact/effort grid facilitated prioritization of interventions. An intervention that included bundled education with the use of therapeutic drug monitoring (TDM; i.e. drug-level testing) was projected to have the highest impact relative to the amount of effort and selected to address beta-lactam inadequacy in the critically ill. The education and TDM intervention were deployed through a Plan, Do, Study, Act cycle. In the 3 months after "go-live," 54 episodes of beta-lactam TDM occurred in 41 unique intensive care unit patients. The primary quality metric of beta-lactam adequacy was achieved in 94% of individuals after the intervention. Ninety-four percent of clinicians gauged the education provided as sufficient. The primary counterbalance of antimicrobial days of therapy, a core antimicrobial stewardship metric, was unchanged over time (favorable result; P = .73). Application of the Define, Measure, Analyze, Improve, and Control Lean Six Sigma quality improvement framework effectively improved beta-lactam adequacy in critically ill patients. The approach taken in this quality improvement project is widely generalizable to other drugs, drug classes, or settings to increase the adequacy of drug exposure.
Assuntos
Antibacterianos , Estado Terminal , Unidades de Terapia Intensiva , Melhoria de Qualidade , Gestão da Qualidade Total , beta-Lactamas , Humanos , Estado Terminal/terapia , Antibacterianos/uso terapêutico , Antibacterianos/administração & dosagem , beta-Lactamas/uso terapêutico , Sepse/tratamento farmacológico , Monitoramento de Medicamentos/métodosRESUMO
Antibiotic resistance has become a global threat as it is continuously growing due to the evolution of ß-lactamases diminishing the activity of classic ß-lactam (BL) antibiotics. Recent antibiotic discovery and development efforts have led to the availability of ß-lactamase inhibitors (BLIs) with activity against extended-spectrum ß-lactamases as well as Klebsiella pneumoniae carbapenemase (KPC)-producing carbapenem-resistant organisms (CRO). Nevertheless, there is still a lack of drugs that target metallo-ß-lactamases (MBL), which hydrolyze carbapenems efficiently, and oxacillinases (OXA) often present in carbapenem-resistant Acinetobacter baumannii. This review aims to provide a snapshot of microbiology, pharmacology, and clinical data for currently available BL/BLI treatment options as well as agents in late stage development for CRO harboring various ß-lactamases including MBL and OXA-enzymes.
Assuntos
Antibacterianos , Carbapenêmicos , Bactérias Gram-Negativas , Inibidores de beta-Lactamases , beta-Lactamas , Humanos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Inibidores de beta-Lactamases/farmacologia , Inibidores de beta-Lactamases/uso terapêutico , beta-Lactamas/farmacologia , beta-Lactamas/uso terapêutico , Carbapenêmicos/farmacologia , Carbapenêmicos/uso terapêutico , Bactérias Gram-Negativas/efeitos dos fármacos , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Negativas/microbiologia , Resistência beta-Lactâmica , beta-LactamasesRESUMO
Importance: Current evidence is conflicting for associations of extended-infusion ß-lactam (EI-BL) therapy with clinical outcomes. Objective: To investigate the association of EI-BL therapy with survival, adverse events, and emergence of antibiotic resistance in adults with gram-negative bloodstream infections (GN-BSI). Design, Setting, and Participants: This cohort study of consecutive adults with GN-BSI admitted to 24 United States hospitals between January 1, 2019, and December 31, 2019, receiving EI-BL were compared with adults with GN-BSI receiving the same agents as intermittent infusion ß-lactam (II-BL; ≤1-hour infusions). Statistical analysis was performed from January to October 2023. Exposures: EI-BL (ie, ≥3-hour infusion). Main Outcomes and Measures: EI-BL and II-BL groups underwent 1:3 nearest-neighbor propensity score matching (PSM) without replacement. Multivariable regression was applied to the PSM cohort to investigate outcomes, all censored at day 90. The primary outcome was mortality; secondary outcomes included antibiotic adverse events and emergence of resistance (≥4-fold increase in the minimum inhibitory concentration of the ß-lactam used to treat the index GN-BSI). Results: Among the 4861 patients included, 2547 (52.4%) were male; and the median (IQR) age was 67 (55-77) years. There were 352 patients in the EI-BL 1:3 PSM group, and 1056 patients in the II-BL 1:3 PSM group. Among 1408 PSM patients, 373 (26.5%) died by day 90. The odds of mortality were lower in the EI-BL group (adjusted odds ratio [aOR], 0.71 [95% CI, 0.52-0.97]). In a stratified analysis, a survival benefit was only identified in patients with severe illness or elevated minimum inhibitory concentrations (ie, in the intermediate range for the antibiotic administered). There were increased odds of catheter complications (aOR, 3.14 [95% CI, 1.66-5.96]) and antibiotic discontinuation because of adverse events (eg, acute kidney injury, cytopenias, seizures) in the EI-BL group (aOR, 3.66 [95% CI, 1.68-7.95]). Emergence of resistance was similar in the EI-BL and II-BL groups at 2.9% vs 7.2%, respectively (P = .35). Conclusions and Relevance: In this cohort study of patients with GN-BSI, EI-BL therapy was associated with reduced mortality for patients with severe illness or those infected with nonsusceptible organisms; potential advantages in other groups remain unclear and need to be balanced with potential adverse events. The subsequent emergence of resistance warrants investigation in a larger cohort.
Assuntos
Antibacterianos , Bacteriemia , Infecções por Bactérias Gram-Negativas , beta-Lactamas , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Negativas/mortalidade , Antibacterianos/uso terapêutico , Antibacterianos/administração & dosagem , beta-Lactamas/uso terapêutico , beta-Lactamas/administração & dosagem , Idoso , Bacteriemia/tratamento farmacológico , Bacteriemia/mortalidade , Infusões Intravenosas , Estudos de Coortes , Estados Unidos/epidemiologia , Adulto , Estudos RetrospectivosRESUMO
BACKGROUND: Novel beta-lactams show activity against many multidrug-resistant Gram-negative bacteria that cause severe lung infections. Understanding pharmacokinetic/pharmacodynamic characteristics of these agents may help optimise outcomes in the treatment of pneumonia. OBJECTIVES: To describe and appraise studies that report pulmonary pharmacokinetic and pharmacodynamic data of cefiderocol, ceftazidime/avibactam, ceftolozane/tazobactam, imipenem/cilastatin/relebactam and meropenem/vaborbactam. METHODS: MEDLINE (PubMed), Embase, Web of Science and Scopus libraries were used for the literature search. Pulmonary population pharmacokinetic and pharmacokinetic/pharmacodynamic studies on adult patients receiving cefiderocol, ceftazidime/avibactam, ceftolozane/tazobactam, imipenem/cilastatin/relebactam, and meropenem/vaborbactam published in peer-reviewed journals were included. Two independent authors screened, reviewed and extracted data from included articles. A reporting guideline for clinical pharmacokinetic studies (ClinPK statement) was used for bias assessment. Relevant outcomes were included, such as population pharmacokinetic parameters and probability of target attainment of dosing regimens. RESULTS: Twenty-four articles were included. There was heterogeneity in study methods and reporting of results, with diversity across studies in adhering to the ClinPK statement checklist. Ceftolozane/tazobactam was the most studied agent. Only two studies collected epithelial lining fluid samples from patients with pneumonia. All the other phase I studies enrolled healthy subjects. Significant population heterogeneity was evident among available population pharmacokinetic models. Probabilities of target attainment rates above 90% using current licensed dosing regiments were reported in most studies. CONCLUSIONS: Although lung pharmacokinetics was rarely described, this review observed high target attainment using plasma pharmacokinetic data for all novel beta-lactams. Future studies should describe lung pharmacokinetics in patient populations at risk of carbapenem-resistant pathogen infections.
Assuntos
Antibacterianos , Cefalosporinas , Combinação de Medicamentos , Bactérias Gram-Negativas , Inibidores de beta-Lactamases , beta-Lactamas , Humanos , Inibidores de beta-Lactamases/farmacocinética , Inibidores de beta-Lactamases/uso terapêutico , Inibidores de beta-Lactamases/farmacologia , Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Antibacterianos/farmacologia , beta-Lactamas/farmacocinética , beta-Lactamas/uso terapêutico , beta-Lactamas/farmacologia , Cefalosporinas/farmacocinética , Cefalosporinas/uso terapêutico , Cefalosporinas/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Tazobactam/farmacocinética , Tazobactam/uso terapêutico , Tazobactam/farmacologia , Pneumonia Bacteriana/tratamento farmacológico , Compostos Azabicíclicos/farmacocinética , Compostos Azabicíclicos/uso terapêutico , Compostos Azabicíclicos/farmacologia , Carbapenêmicos/farmacocinética , Carbapenêmicos/uso terapêutico , Carbapenêmicos/farmacologia , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Ceftazidima/farmacocinética , Ceftazidima/uso terapêutico , Cefiderocol , Meropeném/farmacocinética , Meropeném/uso terapêutico , Meropeném/farmacologia , Imipenem/farmacocinética , Imipenem/uso terapêutico , Farmacorresistência Bacteriana Múltipla , Testes de Sensibilidade Microbiana , Combinação Imipenem e Cilastatina/farmacocinética , Combinação Imipenem e Cilastatina/uso terapêutico , Ácidos Borônicos , Compostos Heterocíclicos com 1 AnelRESUMO
Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is a serious clinical challenge with high mortality rates. Antibiotic combination therapy is currently used in cases of persistent infection; however, the limited development of new antibiotics will likely increase the need for combination therapy, and better methods are needed for identifying effective combinations for treating persistent bacteremia. To identify pairwise combinations with the most consistent potential for benefit compared to monotherapy with a primary anti-MRSA agent, we conducted a systematic study with an in vitro high-throughput methodology. We tested daptomycin and vancomycin each in combination with gentamicin, rifampicin, cefazolin, and oxacillin, and ceftaroline with daptomycin, gentamicin, and rifampicin. Combining cefazolin with daptomycin lowered the daptomycin concentration required to reach 95% growth inhibition (IC95) for all isolates tested and lowered daptomycin IC95 below the sensitivity breakpoint for five out of six isolates that had daptomycin minimum inhibitory concentrations at or above the sensitivity breakpoint. Similarly, vancomycin IC95s were decreased when vancomycin was combined with cefazolin for 86.7% of the isolates tested. This was a higher percentage than was achieved by adding any other secondary antibiotic to vancomycin. Adding rifampicin to daptomycin or vancomycin did not always reduce IC95s and failed to produce synergistic interaction in any of the isolates tested; the addition of rifampicin to ceftaroline was frequently synergistic and always lowered the amount of ceftaroline required to reach the IC95. These analyses rationalize further in vivo evaluation of three drug pairs for MRSA bacteremia: daptomycin+cefazolin, vancomycin+cefazolin, and ceftaroline+rifampicin.IMPORTANCEBloodstream infections caused by methicillin-resistant Staphylococcus aureus (MRSA) have a high mortality rate despite the availability of vancomycin, daptomycin, and newer antibiotics including ceftaroline. With the slow output of the antibiotic pipeline and the serious clinical challenge posed by persistent MRSA infections, better strategies for utilizing combination therapy are becoming increasingly necessary. We demonstrated the value of a systematic high-throughput approach, adapted from prior work testing antibiotic combinations against tuberculosis and other mycobacteria, by using this approach to test antibiotic pairs against a panel of MRSA isolates with diverse patterns of antibiotic susceptibility. We identified three antibiotic pairs-daptomycin+cefazolin, vancomycin+cefazolin, and ceftaroline+rifampicin-where the addition of the second antibiotic improved the potency of the first antibiotic across all or most isolates tested. Our results indicate that these pairs warrant further evaluation in the clinical setting.
Assuntos
Antibacterianos , Bacteriemia , Daptomicina , Staphylococcus aureus Resistente à Meticilina , Testes de Sensibilidade Microbiana , Rifampina , Infecções Estafilocócicas , Vancomicina , beta-Lactamas , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Bacteriemia/tratamento farmacológico , Bacteriemia/microbiologia , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Humanos , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Daptomicina/farmacologia , Daptomicina/uso terapêutico , Vancomicina/farmacologia , beta-Lactamas/farmacologia , beta-Lactamas/uso terapêutico , Rifampina/farmacologia , Rifampina/uso terapêutico , Ceftarolina , Cefalosporinas/farmacologia , Cefalosporinas/uso terapêutico , Cefazolina/farmacologia , Cefazolina/uso terapêutico , Quimioterapia Combinada , Sinergismo Farmacológico , Oxacilina/farmacologia , Gentamicinas/farmacologia , Gentamicinas/uso terapêuticoRESUMO
BACKGROUND: Accurate prediction of the optimal dose for ß-lactam antibiotics in neonatal sepsis is challenging. We aimed to evaluate whether a reliable clinical decision support system (CDSS) based on machine learning (ML) can assist clinicians in making optimal dose selections. METHODS: Five ß-lactam antibiotics (amoxicillin, ceftazidime, cefotaxime, meropenem and latamoxef), commonly used to treat neonatal sepsis, were selected. The CDSS was constructed by incorporating the drug, patient, dosage, pharmacodynamic, and microbiological factors. The CatBoost ML algorithm was used to build the CDSS. Real-world studies were used to evaluate the CDSS performance. Virtual trials were used to compare the CDSS-optimized doses with guideline-recommended doses. FINDINGS: For a specific drug, by entering the patient characteristics and pharmacodynamic (PD) target (50%/70%/100% fraction of time that the free drug concentration is above the minimal inhibitory concentration [fT > MIC]), the CDSS can determine whether the planned dosing regimen will achieve the PD target and suggest an optimal dose. The prediction accuracy of all five drugs was >80.0% in the real-world validation. Compared with the PopPK model, the overall accuracy, precision, recall, and F1-Score improved by 10.7%, 22.1%, 64.2%, and 43.1%, respectively. Using the CDSS-optimized doses, the average probability of target concentration attainment increased by 58.2% compared to the guideline-recommended doses. INTERPRETATION: An ML-based CDSS was successfully constructed to assist clinicians in selecting optimal ß-lactam antibiotic doses. FUNDING: This work was supported by the National Natural Science Foundation of China; Distinguished Young and Middle-aged Scholar of Shandong University; National Key Research and Development Program of China.
Assuntos
Antibacterianos , Sistemas de Apoio a Decisões Clínicas , Aprendizado de Máquina , beta-Lactamas , Humanos , beta-Lactamas/administração & dosagem , beta-Lactamas/uso terapêutico , Recém-Nascido , Antibacterianos/uso terapêutico , Antibacterianos/administração & dosagem , Sepse Neonatal/tratamento farmacológico , Sepse Neonatal/diagnóstico , Testes de Sensibilidade Microbiana , AlgoritmosRESUMO
NaHCO3 responsiveness is a novel phenotype where some methicillin-resistant Staphylococcus aureus (MRSA) isolates exhibit significantly lower minimal inhibitory concentrations (MIC) to oxacillin and/or cefazolin in the presence of NaHCO3. NaHCO3 responsiveness correlated with treatment response to ß-lactams in an endocarditis animal model. We investigated whether treatment of NaHCO3-responsive strains with ß-lactams was associated with faster clearance of bacteremia. The CAMERA2 trial (Combination Antibiotics for Methicillin-Resistant Staphylococcus aureus) randomly assigned participants with MRSA bloodstream infections to standard therapy, or to standard therapy plus an anti-staphylococcal ß-lactam (combination therapy). For 117 CAMERA2 MRSA isolates, we determined by broth microdilution the MIC of cefazolin and oxacillin, with and without 44 mM of NaHCO3. Isolates exhibiting ≥4-fold decrease in the MIC to cefazolin or oxacillin in the presence of NaHCO3 were considered "NaHCO3-responsive" to that agent. We compared the rate of persistent bacteremia among participants who had infections caused by NaHCO3-responsive and non-responsive strains, and that were assigned to combination treatment with a ß-lactam. Thirty-one percent (36/117) and 25% (21/85) of MRSA isolates were NaHCO3-responsive to cefazolin and oxacillin, respectively. The NaHCO3-responsive phenotype was significantly associated with sequence type 93, SCCmec type IVa, and mecA alleles with substitutions in positions -7 and -38 in the regulatory region. Among participants treated with a ß-lactam, there was no association between the NaHCO3-responsive phenotype and persistent bacteremia (cefazolin, P = 0.82; oxacillin, P = 0.81). In patients from a randomized clinical trial with MRSA bloodstream infection, isolates with an in vitro ß-lactam-NaHCO3-responsive phenotype were associated with distinctive genetic signatures, but not with a shorter duration of bacteremia among those treated with a ß-lactam.
Assuntos
Antibacterianos , Cefazolina , Staphylococcus aureus Resistente à Meticilina , Testes de Sensibilidade Microbiana , Oxacilina , Infecções Estafilocócicas , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/genética , Humanos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Cefazolina/farmacologia , Cefazolina/uso terapêutico , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Oxacilina/farmacologia , Bacteriemia/tratamento farmacológico , Bacteriemia/microbiologia , Fenótipo , beta-Lactamas/farmacologia , beta-Lactamas/uso terapêutico , Masculino , Bicarbonato de Sódio/farmacologia , Feminino , Pessoa de Meia-IdadeRESUMO
Individuals with compromised lung function and immunity are susceptible to developing chronic Mycobacterium abscessus infection. Current treatment recommendations typically involve using one ß-lactam antibiotic in combination with non-ß-lactam antibiotics. However, a recent case study (B. Becken, K. M. Dousa, J. L. Johnson, S. M. Holland, and R. A. Bonomo, Antimicrob Agents Chemother 68:e00319-24, 2024, https://doi.org/10.1128/aac.00319-24) demonstrated successful treatment of chronic M. abscessus lung disease in a child using two ß-lactam antibiotics simultaneously. This commentary reviews the emerging evidence and outstanding questions regarding dual ß-lactam therapy for M. abscessus infections.
Assuntos
Antibacterianos , Pneumopatias , Infecções por Mycobacterium não Tuberculosas , Mycobacterium abscessus , beta-Lactamas , Mycobacterium abscessus/efeitos dos fármacos , Humanos , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Infecções por Mycobacterium não Tuberculosas/microbiologia , Antibacterianos/uso terapêutico , beta-Lactamas/uso terapêutico , Pneumopatias/tratamento farmacológico , Pneumopatias/microbiologia , Quimioterapia Combinada , CriançaRESUMO
BACKGROUND: Evidence regarding the best antibiotic regimen and the route of administration to treat acute focal bacterial nephritis (AFBN) is scarce. The aim of the present study was to compare the effectiveness of intravenous (IV) ß-lactam antibiotics versus oral quinolones. METHODS: This is a retrospective single centre study of patients diagnosed with AFBN between January 2017 and December 2018 in Hospital Universitari Vall d'Hebron, Barcelona (Spain). Patients were identified from the diagnostic codifications database. Patients treated with oral quinolones were compared with those treated with IV ß-lactam antibiotics. Therapeutic failure was defined as death, relapse, or evolution to abscess within the first 30 days. RESULTS: A total of 264 patients fulfilled the inclusion criteria. Of those, 103 patients (39%) received oral ciprofloxacin, and 70 (26.5%) IV ß-lactam. The most common isolated microorganism was Escherichia coli (149, 73.8%) followed by Klebsiella pneumoniae (26, 12.9%). Mean duration of treatment was 21.3 days (SD 7.9). There were no statistical differences regarding therapeutic failure between oral quinolones and IV ß-lactam treatment (6.6% vs. 8.7%, p = 0.6). Out of the 66 patients treated with intravenous antibiotics, 4 (6.1%) experienced an episode of phlebitis and 1 patient (1.5%) an episode of catheter-related bacteraemia. CONCLUSIONS: When susceptible, treatment of AFBN with oral quinolones is as effective as IV ß-lactam treatment with fewer adverse events.
Assuntos
Administração Intravenosa , Antibacterianos , Quinolonas , beta-Lactamas , Humanos , Estudos Retrospectivos , Masculino , Feminino , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Administração Oral , Pessoa de Meia-Idade , beta-Lactamas/administração & dosagem , beta-Lactamas/uso terapêutico , Quinolonas/administração & dosagem , Quinolonas/uso terapêutico , Idoso , Adulto , Espanha , Resultado do Tratamento , Doença Aguda , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/microbiologiaRESUMO
INTRODUCTION: Guideline-based therapy for Mycobacterium avium complex (MAC) pulmonary disease achieves sustained sputum conversion rates in only 43-53% of patients. Repurposing of ß-lactam antibiotics such as ertapenem could expedite design of more efficacious regimens, compared to developing new drugs. METHODS: We performed an ertapenem exposure-response study in the hollow fibre system model of intracellular MAC (HFS-MAC). We recapitulated human-like intrapulmonary concentration-time profiles of eight once-daily intravenous doses of ertapenem over 28 days and performed repetitive sampling for drug concentration-time profiles and MAC burden. The % of time concentration persisted above MIC (%TMIC) mediating either 50% or 80% of maximal effect (E50, EC80) were identified. The EC80 was used as target exposure in a 10 000 subject Monte Carlo experiments for ertapenem doses of 1G, 2G, or 4G administered once versus twice daily. RESULTS: The ertapenem MIC ranged from 0.5 to 2 mg/L on three occasions. Ertapenem achieved a half-life of 4.04 ± 0.80 h in the HFS-MAC and killed a maximum of 2.17 log10 CFU/mL below day 0. The EC50 was %TMIC of 75.9% (95% confidence interval: 68.43%-86.54%) and the EC80 was %TMIC of 100%. Target attainment probability was >90% for 1G twice daily up to an MIC of 2 mg/L, while for 2G twice daily the susceptibility MIC breakpoint was 4-8 mg/L. CONCLUSIONS: Ertapenem microbial kill below day 0 burden was better than guideline-based therapy drugs in the HFS-MAC in the past. Ertapenem is a promising drug for novel combination therapies for MAC lung disease.
Assuntos
Antibacterianos , Ertapenem , Testes de Sensibilidade Microbiana , Complexo Mycobacterium avium , Infecção por Mycobacterium avium-intracellulare , Ertapenem/uso terapêutico , Humanos , Antibacterianos/uso terapêutico , Infecção por Mycobacterium avium-intracellulare/tratamento farmacológico , Infecção por Mycobacterium avium-intracellulare/microbiologia , Complexo Mycobacterium avium/efeitos dos fármacos , Método de Monte Carlo , Pneumopatias/tratamento farmacológico , Pneumopatias/microbiologia , beta-Lactamas/uso terapêuticoRESUMO
Importance: ß-lactam (BL) allergies are the most common drug allergy worldwide, but most are reported in error. BL allergies are also well-established risk factors for adverse drug events and antibiotic-resistant infections during inpatient health care encounters, but the understanding of the long-term outcomes of patients with BL allergies remains limited. Objective: To evaluate the long-term clinical outcomes of patients with BL allergies. Design, Setting, and Participants: This longitudinal retrospective cohort study was conducted at a single regional health care system in western Pennsylvania. Electronic health records were analyzed for patients who had an index encounter with a diagnosis of sepsis, pneumonia, or urinary tract infection between 2007 and 2008. Patients were followed-up until death or the end of 2018. Data analysis was performed from January 2022 to January 2024. Exposure: The presence of any BL class antibiotic in the allergy section of a patient's electronic health record, evaluated at the earliest occurring observed health care encounter. Main Outcomes and Measures: The primary outcome was all-cause mortality, derived from the Social Security Death Index. Secondary outcomes were defined using laboratory and microbiology results and included infection with methicillin-resistant Staphylococcus aureus (MRSA), Clostridium difficile, or vancomycin-resistant Enterococcus (VRE) and severity and occurrence of acute kidney injury (AKI). Generalized estimating equations with a patient-level panel variable and time exposure offset were used to evaluate the odds of occurrence of each outcome between allergy groups. Results: A total of 20â¯092 patients (mean [SD] age, 62.9 [19.7] years; 12â¯231 female [60.9%]), of whom 4211 (21.0%) had BL documented allergy and 15â¯881 (79.0%) did not, met the inclusion criteria. A total of 3513 patients (17.5%) were Black, 15â¯358 (76.4%) were White, and 1221 (6.0%) were another race. Using generalized estimating equations, documented BL allergies were not significantly associated with the odds of mortality (odds ratio [OR], 1.02; 95% CI, 0.96-1.09). BL allergies were associated with increased odds of MRSA infection (OR, 1.44; 95% CI, 1.36-1.53), VRE infection (OR, 1.18; 95% CI, 1.05-1.32), and the pooled rate of the 3 evaluated antibiotic-resistant infections (OR, 1.33; 95% CI, 1.30-1.36) but were not associated with C difficile infection (OR, 1.04; 95% CI, 0.94-1.16), stage 2 and 3 AKI (OR, 1.02; 95% CI, 0.96-1.10), or stage 3 AKI (OR, 1.06; 95% CI, 0.98-1.14). Conclusions and Relevance: Documented BL allergies were not associated with the long-term odds of mortality but were associated with antibiotic-resistant infections. Health systems should emphasize accurate allergy documentation and reduce unnecessary BL avoidance.
Assuntos
Antibacterianos , Hipersensibilidade a Drogas , beta-Lactamas , Humanos , Hipersensibilidade a Drogas/epidemiologia , Feminino , Masculino , beta-Lactamas/efeitos adversos , beta-Lactamas/uso terapêutico , Estudos Retrospectivos , Pessoa de Meia-Idade , Idoso , Antibacterianos/efeitos adversos , Antibacterianos/uso terapêutico , Estudos Longitudinais , Pennsylvania/epidemiologia , Adulto , Infecções Urinárias/epidemiologia , Fatores de Risco , Registros Eletrônicos de Saúde/estatística & dados numéricosRESUMO
PURPOSE: We aimed to identify factors associated with achieving target BL plasma concentrations and describe real world data for therapeutic drug monitoring (TDM). METHODS: A retrospective single center study was conducted. We collected data from patients admitted to ICU with at least one BL TDM. We assessed the proportion of patients attaining the recommended plasma concentrations (i.e 100%fT > 4 to 8 MIC). Univariate and multivariate analyses was performed to identify the determinants of BL target attainment. RESULTS: 156 patients were included. At the first dosing, 34% achieved target BL plasma concentrations, 50% were overdosed, and 16% were underdosed. Median time for 1st TDM were 4 (SD = 2.9) days. Multivariate analysis revealed that CKD-EPI estimated glomerular filtration rate (OR = 1.02; CI [1.01; 1.03]; p < 0.0001) and total body weight (OR = 1.03; CI [1.01; 1.04]; p = 0.0048) were the main determinant of BL target attainment. Conversely, Continuous Renal Replacement Therapy (OR = 0.28; CI [0.09; 0.89]; p = 0.0318) and meropenem use (OR = 0.31; CI [0.14; 0.69]; p = 0.0041) were identified as risk factors for overdosing. No factor was associated with underdosing. CONCLUSION: Achieving target BL plasma concentrations remains challenging in ICUs. Identifying predictive factors of BL target attainment would favor implementing rapid dosing optimization strategies in both under and overdosing high risk patients.
Assuntos
Antibacterianos , Estado Terminal , Monitoramento de Medicamentos , Unidades de Terapia Intensiva , beta-Lactamas , Humanos , Estudos Retrospectivos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Antibacterianos/farmacocinética , Antibacterianos/administração & dosagem , Antibacterianos/sangue , beta-Lactamas/farmacocinética , beta-Lactamas/administração & dosagem , beta-Lactamas/uso terapêutico , Taxa de Filtração GlomerularRESUMO
SOURCE CITATION: López-Cortés LE, Delgado-Valverde M, Moreno-Mellado E, et al; SIMPLIFY study group. Efficacy and safety of a structured de-escalation from antipseudomonal ß-lactams in bloodstream infections due to Enterobacterales (SIMPLIFY): an open-label, multicentre, randomised trial. Lancet Infect Dis. 2024;24:375-385. 38215770.
Assuntos
Antibacterianos , Bacteriemia , Infecções por Enterobacteriaceae , beta-Lactamas , Humanos , Bacteriemia/tratamento farmacológico , Antibacterianos/uso terapêutico , Infecções por Enterobacteriaceae/tratamento farmacológico , beta-Lactamas/uso terapêutico , Enterobacteriaceae/efeitos dos fármacos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Esquema de MedicaçãoRESUMO
Treatment of Mycobacterium abscessus infection presents significant challenges, exacerbated by the emergence of macrolide-resistant strains that necessitate the use of multiple antimicrobials in combination and carry the potential for significant toxic effects. Select dual beta-lactam combinations, with or without beta-lactamase inhibitors, have been shown to be highly active in vitro. Herein, we describe a 6-year-old child with underlying mild bilateral lower lobe cylindrical bronchiectatic lung disease who developed pulmonary Mycobacterium abscessus infection and was treated with a multi-drug regimen including two ß-lactam antibiotics, achieving both early clinical and microbiological cure. This case highlights the potential benefit of dual ß-lactam therapy for the treatment of drug-resistant Mycobacterium abscessus infection.