Ceftazidima/avibactam frente a otros antimicrobianos para el tratamiento de bacteriemias por Enterobacterales productores de carbapenemasa KPC: datos de la vida real en un hospital universitario de Argentina

Introducción: Las bacteriemias por Enterobacterales productores de carbapenemasa KPC (EPC-KPC) presentan una mortalidad elevada y opciones terapéuticas limitadas. Objetivos: Describir y comparar la evolución de los pacientes con bacteriemia por EPC-KPC tratados con ceftazidima/avibactam (CA) frente a otros antimicrobianos (OA). Pacientes y Métodos: Estudio prospectivo y retrospectivo de casos y controles. Se incluyeron pacientes adultos con bacteriemia por EPC-KPC, con una proporción entre casos tratados con CA y controles tratados con OA. de 1:2. Se analizaron variables clínicas, epidemiológicas y de evolución. Resultados: Se incluyeron 48 pacientes (16 CA y 32 OA). Los casos se encontraban más frecuentemente neutropénicos (50 vs.16%, p = 0,012); asimismo, presentaron medianas de score de APACHE II más altas y de score de Pitt más bajas. El 65% de la cohorte total presentó un foco clínico y Klebsiellapneumoniae fue el microorganismo más frecuentemente aislado. Los casos recibieron una mayor proporción de tratamiento antimicrobiano empírico adecuado (81 vs. 53%, p = 0,05). La antibioterapia dirigida en casos y controles fue combinada en 38 y 91%, p = 0,009. Los casos presentaron menor mortalidad al día 7 y al día 30 relacionada a infección (0 vs. 22%, p = 0,04 y 0 vs. 34%, p = 0,008). Solo los controles desarrollaron shock, ingresaron a la unidad de cuidados intensivos y presentaron bacteriemia de brecha. Conclusión: CA mostró beneficio clínico frente a OA para el tratamiento de pacientes con bacteriemia por EPC-KPC.

Background: KPC-producing Enterobacterales bacteremia (KPCCPE) is associated with a high mortality rate and limited therapeutic options. Aim: To describe and compare the outcome of patients with KPC-CPE bacteremia treated with ceftazidime/avibactam (CA) versus other antibiotics (OA). Methods: Prospective and retrospective cases and control study performed in adult patients with KPC-CPE bacteremia, with a 1:2 ratio between cases treated with CA. and controls treated with OA. Clinical, epidemiological, and outcome variables were analyzed. Results: Forty-eight patients (16 CA and 32 OA) were included. Cases were more frequently neutropenic (50 vs. 16%, p = 0.012), presented higher median APACHE II score and lower Pitt score. Of the total cohort, 65% had a clinical source, and Klebsiella pneumoniae was the most frequently isolated microorganism. Cases received more adequate empirical antibiotic treatment (81 vs. 53%, p = 0.05). Targeted antibiotic therapy in cases and controls was combined in 38 and 91%, p = 0.009. Cases had a lower 7-day mortality and 30-day infection-related mortality (0 vs. 22%, p = 0.04 and 0 vs. 34%, p = 0.008). Only controls developed shock, were admitted to the intensive care unit, and had breakthrough bacteremia. Conclusion: CA. showed clinical benefit over OA in the treatment of patients with EPC-KPC bacteremia.

Uso de ceftazidima-avibactam en una recién nacida prematura con infección urinaria bacteriémica por Klebsiella pneumoniae productora de carbapenemasa

Los recién nacidos tienen un alto riesgo de morbimortalidad asociada a infecciones durante su estancia en unidades de cuidado intensivo neonatal, a lo que se asocia un aumento progresivo de infecciones por microorganismos multi-resistentes que requiere el uso de nuevos antimicrobianos. Presentamos el caso de una recién nacida de pretérmino de 36 semanas que cursó con una infección del tracto urinario bacteriémica por Klebsiella pneumoniae productora de carbapenemasa tratada de forma efectiva con 14 días de cefazi- dima-avibactam, sin efectos adversos observados. Según nuestro conocimiento, este es el primer caso reportado en nuestro país del uso de este antimicrobiano en población neonatal. Se necesita más información sobre la eficacia y seguridad de ceftazidima-avibactam en este grupo de pacientes.

Neonates are high risk patients regarding morbimortality secondary to infections during their neonatal intensive care unit stay, which is associated to a progressive increase in the report of multidrug resistant organism infections, that require the use of new antimicrobial. We report the case of a 36-week preterm with an urinary tract infection with bacteriemia caused by carbapenemase- producing Klebsiella pneumoniae treated effectively with 14 day of ceftazidime-avibactam, without observed adverse effects. To our knowledge, this is the first case report in our country of the use of this antibiotic in neonatal population. More information is needed regarding efficacy and safety of ceftazidime-avibactam in this group of patients.

Epidemiology and in vitro activity of ceftazidime-avibactam and comparator agents against multidrug-resistant isolates of Enterobacterales and Pseudomonas aeruginosa collected in Latin America as part of the ATLAS surveillance program in 2015‒2020

Abstract Introduction The incidence of antimicrobial resistance is increasing in many parts of the world. The focus of this report is to examine changes in antimicrobial resistance epidemiology among clinical isolates of Enterobacterales and Pseudomonas aeruginosa collected in six Latin American countries as part of the Antimicrobial Testing Leadership and Surveillance (ATLAS) program from 2015 to 2020, with a focus on the in vitro activity of ceftazidime-avibactam against Multidrug-Resistant (MDR) isolates. Methods Non-duplicate, clinical isolates of Enterobacterales (n= 15,215) and P. aeruginosa (n= 4,614) collected by 40 laboratories in Argentina, Brazil, Chile, Colombia, Mexico, and Venezuela, from 2015 to 2020, underwent centralized Clinical Lab Standards Institute (CLSI) broth microdilution susceptibility testing. Minimum Inhibitory Concentration (MIC) values were interpreted using 2022 CLSI breakpoints. An MDR phenotype was defined by resistance to ≥ 3 of seven sentinel agents. Results In total, 23.3% of Enterobacterales and 25.1% of P. aeruginosa isolates were MDR. Annual percent MDR values for Enterobacterales were stable from 2015 to 2018 (21.3% to 23.7% year) but markedly increased in 2019 (31.5%) and 2020 (32.4%). Annual percent MDR values for P. aeruginosa were stable from 2015 to 2020 (23.0% to 27.6% year). Isolates were divided into two 3-year time-periods, 2015‒2017 and 2018‒2020, for additional analyses. For Enterobacterales, 99.3% of all isolates and 97.1% of MDR isolates from 2015‒2017 were ceftazidime-avibactam-susceptible compared to 97.2% and 89.3% of isolates, respectively, from 2018‒2020. For P. aeruginosa, 86.6% of all isolates and 53.9% of MDR isolates from 2015‒2017 were ceftazidime-avibactam-susceptible compared to 85.3% and 45.3% of isolates, respectively, from 2018‒2020. Among individual countries, Enterobacterales and P. aeruginosa collected in Venezuela showed the greatest reductions in ceftazidime-avibactam susceptibility over time. Conclusion MDR Enterobacterales increased in Latin America from 22% in 2015 to 32% in 2020 while MDR P. aeruginosa remained constant at 25%. Ceftazidime-avibactam remains highly active against all clinical isolates of both Enterobacterales (97.2% susceptible, 2018‒2020) and P. aeruginosa (85.3%), and inhibited more MDR isolates (Enterobacterales, 89.3% susceptible, 2018‒2020; P. aeruginosa, 45.3%) than carbapenems, fluoroquinolones, and aminoglycosides.

Evaluation of in-vitro susceptibility of ß-lactam-resistant Gram-negative bacilli to ceftazidime-avibactam and ceftolozane-tazobactam from clinical samples of a general hospital in southern Brazil

ABSTRACT Background: The spread of carbapenemase- and extended-spectrum β-lactamase (ESBL)-producing gram-negative bacilli (GNB) represent a global public health threat that limits therapeutic options for hospitalized patients. This study aimed to evaluate the in-vitro susceptibility of β-lactam-resistant GNB to ceftazidime-avibactam (C/A) and ceftolozane-tazobactam (C/T), and investigate the molecular determinants of resistance. Methods: Overall, 101 clinical isolates of Enterobacterales and Pseudomonas aeruginosa collected from a general hospital in Brazil were analyzed. Susceptibility to the antimicrobial agents was evaluated using an automated method, and the minimum inhibitory concentrations (MIC50/90) of C/A and C/T were determined using Etest®. The β-lactamase-encoding genes were investigated using polymerase chain reaction. Results: High susceptibility to C/A and C/T was observed among ESBL-producing Enterobacterales (100% and 97.3% for CLSI and 83.8% for BRCAST, respectively) and carbapenem-resistant P. aeruginosa (92.3% and 87.2%, respectively). Carbapenemase-producing Klebsiella pneumoniae exhibited high resistance to C/T (80%- CLSI or 100%- BRCAST) but high susceptibility to C/A (93.4%). All carbapenem-resistant K. pneumoniae isolates were susceptible to C/A, whereas only one isolate was susceptible to C/T. Both antimicrobials were inactive against metallo-β-lactamase-producing K. pneumoniae isolates. Resistance genes were concomitantly identified in 44 (44.9%) isolates, with bla CTX-M and bla SHV being the most common. Conclusions: C/A and C/T were active against microorganisms with β-lactam-resistant phenotypes, except when resistance was mediated by metallo-β-lactamases. Most C/A- and C/T-resistant isolates concomitantly carried two or more β-lactamase-encoding genes (62.5% and 77.4%, respectively).

Mecanismos de resistencia bacteriana frente a ceftazidima avibactam. Revisión Sistemática / Mechanisms of bacterial resistance against ceftazidime avibactam. Systematic Review / Mecanismos de resistência bacteriana contra ceftazidima avibactam. Revisão sistemática

La resistencia a los antibióticos representa una problemática a nivel mundial determinada por la capacidad que poseen las bacterias para desarrollar mecanismos de resistencia que les permitan adaptarse y sobrevivir en el entorno en el que se desenvuelven. La combinación ceftazidima-avibactam (CAZ/AVI) desde su aprobación en 2015 por la Food and Drug Administration (FDA) ha demostrado ser muy eficiente frente a bacilos Gram negativos productores de carbapenemasas, pero al igual que otras estrategias frente a bacterias multirresistentes no está exenta del desarrollo de mecanismos de resistencia. Métodos. Se realizó una revisión sistemática de la literatura en las bases de datos Web of Science, PubMed y Scopus siguiendo la metodología PRISMA, se incluyeron 29 artículos en los que se reportó la resistencia a CAZ/AVI en aislados clínicos. Resultados. los mecanismos de resistencia más relevantes fueron las mutaciones en el gen blaKPC en la posición 179 (D179Y) en el bucle conservado omega estimulada por la exposición previa a CAZ/AVI, generando de esta forma nuevas variantes como blaKPC-31 y blaKPC-33. Conclusiones. la evidente presencia de mecanismos de resistencia a CAZ/AVI a pesar de ser una combinación de uso relativamente reciente hace un llamado al uso adecuado de esta combinación.

Antibiotic resistance represents a worldwide problem determined by the ability of batteries to develop resistance mechanisms that allow them to adapt and survive in the environment in which they operate. Since its approval in 2015 by the Food and Drug Administration (FDA), the ceftazidime-avibactam (CAZ/AVI) combination has proven to be very efficient against Gram-negative bacilli that produce carbapenemase, but like other strategies against multiresistant bacteria, it is not exempt from the development of resistance mechanisms. Methods. a systematic review of the literature was carried out in the Web of Science, PubMed and Scopus databases following the PRISMA methodology, including 29 articles in which resistance to CAZ/AVI was reported in clinical isolates. Results. The most relevant resistance mechanisms were mutations in the blaKPC gene at position 179 (D179Y) in the conserved omega loop, stimulated by previous exposure to CAZ/AVI, thus generating new variants such as blaKPC-31 and blaKPC-33. Conclusions. The evident presence of resistance mechanisms to CAZ/AVI, despite being a combination of relatively recent use, calls for the appropriate use of this combination.

A resistência aos antibióticos representa um problema mundial determinado pela capacidade das bactérias desenvolverem mecanismos de resistência que lhes permitem adaptar-se e sobreviver no ambiente em que operam. Desde sua aprovação em 2015 pela Food and Drug Administration (FDA), a combinação ceftazidima-avibactam (CAZ/AVI) tem se mostrado muito eficiente contra bacilos Gram-negativos produtores de carbapenemases, mas como outras estratégias contra bactérias multirresistentes, é não isentos do desenvolvimento de mecanismos de resistência. Métodos. Foi realizada uma revisão sistemática da literatura nas bases de dados Web of Science, PubMed e Scopus seguindo a metodologia PRISMA, incluindo 29 artigos nos quais foi relatada resistência ao CAZ/AVI em isolados clínicos. Resultados. Os mecanismos de resistência mais relevantes foram mutações no gene blaKPC na posição 179 (D179Y) na alça ômega conservada, estimuladas pela exposição prévia ao CAZ/AVI, gerando novas variantes como blaKPC-31 e blaKPC-31. 33. Conclusões. A evidente presença de mecanismos de resistência ao CAZ/AVI, apesar de ser uma combinação de uso relativamente recente, exige o uso adequado dessa combinação.

Susceptibility testing for aztreonam plus ceftazidime/avibactam combination: A general guidance for clinical microbiology laboratories in India

Metallo beta-lactamases-producing Gram-negative infection is often challenging and there is no defined treatment option. In recent years, the combination of aztreonam with ceftazidime-avibactam has gained much clinical attention mainly for MBL-producing Enterobacterales, while MBL-producing P. aeruginosa and A. baumannii are likely to be resistant. A consensus susceptibility testing method for this triple combination has yet to be recommended. Various methods such as broth disk elution, disk stacking, gradient strip stacking, and strip crossing have been proposed for testing this combination. Among them, broth disk elution and strip based testing methods showed good correlation with the broth micro-dilution method.

Treatment for abdominal infection caused by metallo- β-lactamase-producing Klebsiella pneumoniae in an infant after liver transplantation ：a case report and literature review / 中国药房

OBJECTIVE To investigate the treatment plan for az treonam-resistant metallo- β-lactamase（MBL）-producing Enterobacteriaceae infection in pediatric solid organ transplant recipients. METHODS The clinical data of aztreonam-resistant MBL-producing Klebsiella pneumoniae caused intra-abdominal infection of an infant after liver transplantation were retrospectively analyzed. Abdominal infection occurred after operation. The pathogenic bacterium was MBL-producing K. pneumoniae . The drug sensitivity results showed that the infant was resistant to aztreonam. Based on the results of sensitivity test ，polymyxin B combined with tigecycline were selected as initial regimen. The treatment effect was poor ，with recurrent disease and shock spots. The clinical pharmacist assisted the clinician to formulate treatment regimen of ceftazidime avibactam 0.5 g，q8 h combined with aztreonam 0.18 g，q6 h. Relevant domestic and foreign literature were reviewed ，and the treatment plan of MBL-producing Enterobacteriaceae infection after solid organ transplantation was summarized. RESULTS & CONCLUSIONS The infant was finally cured and discharged with ceftazidime avibatan combined and aztreonam. Several foreign literature reported that ceftazidime avibactam combined with aztreonam could effectively treat the infection caused by aztreonam-resistant MBL-producing Enterobacteriaceae infection in patients with organ transplantation. It is expected to be an effective treatment for aztreonam-resistant MBL-producing Enterobacteriaceae infection in pediatric solid organ transplant recipients.

In vitro activity of ceftazidime-avibactam against Gram-negative strains in patients with complicated urinary tract infection and complicated intra-abdominal infection in Colombia 2014-2018

ABSTRACT Ceftazidime/avibactam (CAZ/AVI) has excellent in vitro activity against enterobacterales and Pseudomonas aeruginosa. The study aimed to analyze the in vitro antimicrobial activity of CAZ/AVI and other antibiotics against isolates of enterobacterales and P. aeruginosa from patients with complicated urinary tract infection (cUTI) and complicated intra-abdominal infection (cIAI) in Colombian hospitals between 2014 and 2018, using the Antimicrobial Testing Leadership and Surveillance (ATLAS) database. Enterobacterales and P. aeruginosa samples were obtained from patients with cUTI and cIAI. Susceptibility was determined using The Clinical and Laboratory Standards Institute (CLSI) breakpoints. Meropenem-non-susceptible isolates were screened for extended-spectrum b-lactamase (ESBL) production. Isolates that were positive for ESBL activity were examined by Multiplex Polymerase Chain Reaction (Multiplex PCR) to detect genotypic resistance. A total of 565 Enterobacterales and 95 P. aeruginosa from patients with cUTI and 345 Enterobacterales and 65 P. aeruginosa from patients with cIAI were isolated. In vitro activity showed susceptibility to CAZ/AVI greater than 99% for Enterobacterales and in lower percentages for P. aeruginosa in cUTI (78.46%) and cIAI (83.33%). CAZ/AVI showed good in vitro activity against multidrug-resistant (MDR) Enterobacterales and P. aeruginosa in patients with cUTI and cIAI.

Effect of donor-derived infection on clinical prognosis of kidney transplant recipients / 器官移植

Objective To evaluate the effect of donor-derived infection (DDI) on clinical prognosis of kidney transplant recipients. Methods Clinical data of 82 donors from donation after citizen's death and 148 kidney transplant recipients were retrospectively analyzed. According to the culture results of the lavage fluid of donor kidney, all recipients were divided into the lavage fluid culture of donor kidney positive group (positive group, n=92) and lavage fluid culture of donor kidney negative group (negative group, n=56). All recipients were assigned into the DDI group (n=19) and non-DDI group (n=129) according to whether they developed DDI or not. The distribution and composition ratio of positive strains in the lavage fluid of donor kidney were analyzed. The incidence of postoperative infection and other complications was assessed in the recipients. Perioperative conditions of the recipients were statistically compared between the DDI and non-DDI groups. The treatment efficacy and clinical prognosis of DDI recipients were evaluated. Results Among 148 recipients, 92 obtained positive culture results in the lavage fluid of donor kidney. A total of 131 pathogenic strains were isolated, including 41.2% (54/131) of Gram-positive cocci, 48.9% (64/131) of Gram-negative bacilli and 9.9%(13/131) of fungi. Among 148 recipients, 52 cases were infected. And 45% (41/92) and 20% (11/56) of the recipients were infected in the positive and negative group, respectively. Statistical significance was noted between two groups (P=0.002). Surgical site was the most common infection site in 52 infected recipients, followed by the urinary system. Nineteen recipients developed DDI with an incidence rate of 12.8% and fatality of 16%. Compared with the non-DDI recipients, DDI recipients had significantly higher graft loss rate and fatality, and longer postoperative hospital stay (all P < 0.05). Eight cases presented with carbapenem-resistant Klebsiella pneumoniae (CRKP) infection, after treatment with tigecycline and/or polymyxin and carbapenems, 3 cases died, and 3 underwent kidney graft resection. In the other 8 recipients with CRKP infection, 2 cases were treated with ceftazidime-avibactam (CAZ-AVI) alone, 3 treated with CAZ-AVI combined with carbapenems, and 3 initially treated with tigecycline combined with carbapenems followed by CAZ-AVI for salvage treatment. After corresponding treatment, the recipients achieved long-term survival. Conclusions DDI may lead to severe complications, while early specific antibacterial treatment plays a positive role.

The efficacy and safety of ceftazidime/avibactam therapy on carbapenem-resistant Enterobacteriaceae infections: a Meta-analysis / 药学实践杂志

Objective To systematically evaluate the efficacy and safety of ceftazidime/avibactam(CAZ/AVI) in the treatment of carbapenem-resistant Enterobacteriaceae(CRE) or carbapenem-resistance Klebsiella pneumonia (CRKP), and to provide evidence-cased reference for clinic therapy. Methods A comprehensive literature search from PubMed, Embase, the Cochrane Library, CBM, CNKI and VIP database was conducted for the CAZ/AVI therapy on CRE/CRKP infections published before May.2020. Two reviewers independently screened literatures according to the inclusion and exclusion criteria, extracted data, and assessed the methodological quality of the included studies. The results were analyzed by RevMan 5.3 statistical software. Results Five studies in English involving 392 patients were included for the analysis. In terms of effectiveness, the results showed CAZ/AVI group significantly increased the clinical cure rate[OR=3.57, 95% CI (2.03, 6.26), P<0.00001] compared with the control group. Also CAZ/AVI group significantly decreased the 28/30 day all-cause mortality [OR=0.27, 95% CI (0.14, 0.50), P<0.0001]. There were no significant difference between the two groups in the clinical remission rate [OR=1.92, 95% CI (0.93, 3.97), P=0.08] and the infection recurrence rate [OR=0.44, 95% CI (0.11, 1.85), P=0.26]. In terms of safety, the incidence of adverse events in CAZ/AVI group were lower than those in control group [OR=0.29, 95% CI (0.10, 0.80), P=0.02]. There was no significant difference between two groups in the incidence of serious adverse events[OR=0.33, 95% CI (0.09, 1.19), P=0.09]. Conclusion The current evidence shows that CAZ/AVI therapy has advantage in survival rate for the treatment of CRE/CRKP infections without increase of SAEs. Limited by the quality and quantity of the included studies, the above conclusions need to be verified with more high-quality RCTs.

Research progress on carbapenem-resistant Klebsiella pneumoniae infection in organ transplantation / 器官移植

Klebsiella pneumoniae (KP) is a common conditional pathogen, and also one of the common pathogens causing infection in immunocompromised patients, with its infection rate increasing year by year. Carbapenem antibiotics are effective drugs to control KP infection. But with the widespread use of carbapenem antibiotics, carbapenemresistant Klebsiella pneumoniae (CRKP) appears and increases year by year. Organ transplant recipients are at high risk of CRKP infection due to the suppressed immune system. Once drug-resistant bacteria infection occurs, it is often difficult to control and the survival rate of transplant organs is reduced, which brings great challenges to clinical treatment. In this article, the current status and treatment progress of CRKP infection in organ transplantation are summarized.

Will ceftazidime/avibactam plus aztreonam be effective for NDM and OXA-48-Like producing organisms: Lessons learnt from In vitro study

Introduction: Carbapenem resistance (CR) in Klebsiella pneumoniae is mainly mediated by bla NDM and bla OXA-48 carbapenemases. Newer Food and Drug Administration-approved antimicrobial ceftazidime/avibactam (C/A) has a potent activity against bla OXA-48-like producers. However, its activity is limited in organisms co-producing bla NDM and bla OXA-48-like. Addition of aztreonam (ATM) to C/A potentially expands the spectrum of coverage for carbapenemase co-producers. With this, we aimed to determine the synergistic activity of combination of C/A plus ATM against bla NDM, bla OXA-48-like and co-producers of bla NDM + bla OXA-48-like producing CR Klebsiella pneumoniae (CRKp). Materials and Methods: A total of 12 isolates of CRKp-harbouring genes encoding bla NDM and bla OXA-48-like were tested. Minimum inhibitory concentrations (MICs) were determined for several antimicrobial agents, including C/A (0.5�?g/ml) by broth microdilution method. Checkerboard assay was performed for the combination of C/A plus ATM at varying concentrations. Fold differences in the MIC of C/A with and without addition of ATM were determined to infer synergistic effects. Results: MIC of C/A and ATM ranged from 0.5 to >8 ?g/ml and 64 to 2048 ?g/ml, respectively. Two isolates were susceptible to C/A with MIC of 0.5 and 1 ?g/ml, while others were resistant with MIC of >8 ?g/ml. Synergistic effects of >8-fold MIC difference in C/A MIC were noted with addition of ATM at 4 ?g/ml. This was observed for all CRKp with profiles of bla NDM, bla OXA-48-like and co-producers of bla NDM + bla OXA-48-like genes, which was a promising effect. Notably, all five of the colistin-resistant CRKp were inhibited with >8-fold MIC difference in the combination of C/A plus ATM at 4 ?g/ml. Conclusion: With the increasing burden of CRKp, the use of C/A with ATM combination seems to be very promising, especially for bla NDM, bla OXA-48-like and co-producers of bla NDM + bla OXA-48like carbapenemases.