Study protocol for ADAPT-TDM: A beta-lactam antibiotic Dose AdaPtation feasibility randomised controlled Trial using Therapeutic Drug Monitoring.

INTRODUCTION: Critically ill patients are at risk of suboptimal beta-lactam antibiotic (beta-lactam) exposure due to the impact of altered physiology on pharmacokinetics. Suboptimal concentrations can lead to treatment failure or toxicity. Therapeutic drug monitoring (TDM) involves adjusting doses based on measured plasma concentrations and individualising dosing to improve the likelihood of improving exposure. Despite its potential benefits, its adoption has been slow, and data on implementation, dose adaptation and safety are sparse. The aim of this trial is to assess the feasibility and fidelity of implementing beta-lactam TDM-guided dosing in the intensive care unit setting. METHODS AND ANALYSIS: A beta-lactam antibiotic Dose AdaPtation feasibility randomised controlled Trial using Therapeutic Drug Monitoring (ADAPT-TDM) is a single-centre, unblinded, feasibility randomised controlled trial aiming to enroll up to 60 critically ill adult participants (≥18 years). TDM and dose adjustment will be performed daily in the intervention group; the standard of care group will undergo plasma sampling, but no dose adjustment. The main outcomes include: (1) feasibility of recruitment, defined as the number of participants who are recruited from a pool of eligible participants, and (2) fidelity of TDM, defined as the degree to which TDM as a test is delivered as intended, from accurate sample collection, sample processing to result availability. Secondary outcomes include target attainment, uptake of TDM-guided dosing and incidence of neurotoxicity, hepatotoxicity and nephrotoxicity. ETHICS AND DISSEMINATION: This study has been approved by the Alfred Hospital human research ethics committee, Office of Ethics and Research Governance (reference: Project No. 565/22; date of approval: 22/11/2022). Prospective consent will be obtained and the study will be conducted in accordance with the Declaration of Helsinki. The finalised manuscript, including aggregate data, will be submitted for publication in a peer reviewed journal. ADAPT-TDM will determine whether beta-lactam TDM-guided dose adaptation is reproducible and feasible and provide important information required to implement this intervention in a phase III trial. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry, ACTRN12623000032651.

Population pharmacokinetic meta-analysis of five beta-lactams antibiotics to support dosing regimens in dogs for surgical antimicrobial prophylaxis.

The Pharmacokinetic/Pharmacodynamic (PK/PD) relationship of antimicrobial drugs (AMD) for surgical prophylaxis has been poorly studied, hampering evidence-based decision making around AMD dosing and timing. Our objective is to use PK/PD principles to inform (1) the timing of administration and (2) the interval for re-administration of AMD used peri-operatively in dogs. Raw plasma concentrations of cefazolin, cefuroxime, cefalexin, amoxicillin and ampicillin were retrieved from original intravenous studies performed in dogs. E. coli and methicillin-susceptible staphylococci were identified as possible intraoperative contaminants and their epidemiological cut-offs (ECOFF) were retrieved from the EUCAST database. Individual PK data were refitted with non-linear mixed effect models (Phoenix®). We performed Monte Carlo simulation to compute i) the 95th percentile of time of peak concentration in the peripheral compartment (informing timing between administration and first incision) and ii) the duration for which at least 90% of dogs maintain a free plasma concentration above ECOFF (informing timing of re-administration: 1.5-4 h). Cefazolin (22-25 mg/kg), cefuroxime (20 mg/kg), cefalexin (15 mg/kg) and amoxicillin (16.7 mg/kg) reached peak peripheral concentrations within 30 min, but ampicillin (20 mg/kg) required 82 min, respectively. For methicillin-susceptible staphylococci, cefazolin and cefuroxime require re-administration every 2 h, whereas cefalexin and both amoxicillin and ampicillin can be readministered every 3 and 4 h, respectively. For E. coli, only cefazolin provided adequate perioperative coverage with 2-hourly administration, where cefuroxime and cefalexin failed uniformly. Alternatively, ampicillin and amoxicillin (critically ill dogs) may cover E. coli contaminations, but only if readministered every 1.5 h. These PK-derived conclusions provide a rationale for perioperative AMD administration timing.

Determinants of beta-lactam PK/PD target attainment in critically ill patients: A single center retrospective study.

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.

Assessment of the practical impact of adjusting beta-lactam dosages based on therapeutic drug monitoring in critically ill adult patients: a systematic review and meta-analysis of randomized clinical trials and observational studies.

An estimated 70% of critically ill patients receive antibiotics, most frequently beta-lactams. The pharmacokinetic properties of these substances in this patient population are poorly predictable. Therapeutic drug monitoring (TDM) is helpful in making personalized decisions in this field, but its overall impact as a clinical decision-supporting tool is debated. We aimed to evaluate the clinical implications of adjusting beta-lactam dosages based on TDM in the critically ill population by performing a systematic review and meta-analysis of available investigations. Randomized controlled trials and observational studies were retrieved by searching three major databases. The intervention group received TDM-guided beta-lactam treatment, that is, at least one dose reconsideration based on the result of the measurement of drug concentrations, while TDM-unadjusted dosing was employed in the comparison group. The outcomes were evaluated using forest plots with random-effects modeling and subgroup analysis. Eight eligible studies were identified, including 1044 patients in total. TDM-guided beta-lactam treatment was associated with improved clinical cure from infection [odds ratio (OR): 2.22 (95% confidence interval (CI): 1.78-2.76)] and microbiological eradication [OR: 1.72 (CI: 1.05-2.80)], as well as a lower probability of treatment failure [OR: 0.47 (CI: 0.36-0.62)], but the heterogeneity of studies was remarkably high, especially in terms of mortality (70%). The risk of bias was moderate. While the TDM-guided administration of beta-lactams to critically ill patients has a favorable impact, standardized study designs and larger sample sizes are required for developing evidence-based protocols in this field.

Impact of attaining aggressive vs. conservative PK/PD target on the clinical efficacy of beta-lactams for the treatment of Gram-negative infections in the critically ill patients: a systematic review and meta-analysis.

BACKGROUND: To perform a systematic review with meta-analysis with the dual intent of assessing the impact of attaining aggressive vs. conservative beta-lactams PK/PD target on the clinical efficacy for treating Gram-negative infections in critical patients, and of identifying predictive factors of failure in attaining aggressive PK/PD targets. METHODS: Two authors independently searched PubMed-MEDLINE and Scopus database from inception to 23rd December 2023, to retrieve studies comparing the impact of attaining aggressive vs. conservative PK/PD targets on clinical efficacy of beta-lactams. Independent predictive factors of failure in attaining aggressive PK/PD targets were also assessed. Aggressive PK/PD target was considered a100%fT>4xMIC, and clinical cure rate was selected as primary outcome. Meta-analysis was performed by pooling odds ratios (ORs) extrapolated from studies providing adjustment for confounders using a random-effects model with inverse variance method. RESULTS: A total of 20,364 articles were screened, and 21 observational studies were included in the meta-analysis (N = 4833; 2193 aggressive vs. 2640 conservative PK/PD target). Attaining aggressive PK/PD target was significantly associated with higher clinical cure rate (OR 1.69; 95% CI 1.15-2.49) and lower risk of beta-lactam resistance development (OR 0.06; 95% CI 0.01-0.29). Male gender, body mass index > 30 kg/m2, augmented renal clearance and MIC above the clinical breakpoint emerged as significant independent predictors of failure in attaining aggressive PK/PD targets, whereas prolonged/continuous infusion administration of beta-lactams resulted as protective factor. The risk of bias was moderate in 19 studies and severe in the other 2. CONCLUSIONS: Attaining aggressive beta-lactams PK/PD targets provided significant clinical benefits in critical patients. Our analysis could be useful to stratify patients at high-risk of failure in attaining aggressive PK/PD targets.

What are the optimal pharmacokinetic/pharmacodynamic targets for ß-lactamase inhibitors? A systematic review.

BACKGROUND: Pharmacokinetic/pharmacodynamic (PK/PD) indices are widely used for the selection of optimum antibiotic doses. For ß-lactam antibiotics, fT>MIC, best relates antibiotic exposure to efficacy and is widely used to guide the dosing of ß-lactam/ß-lactamase inhibitor (BLI) combinations, often without considering any PK/PD exposure requirements for BLIs. OBJECTIVES: This systematic review aimed to describe the PK/PD exposure requirements of BLIs for optimal microbiological efficacy when used in combination with ß-lactam antibiotics. METHODS: Literature was searched online through PubMed, Embase, Web of Science, Scopus and Cochrane Library databases up to 5 June 2023. Studies that report the PK/PD index and threshold concentration of BLIs approved for clinical use were included. Narrative data synthesis was carried out to assimilate the available evidence. RESULTS: Twenty-three studies were included. The PK/PD index that described the efficacy of BLIs was fT>CT for tazobactam, avibactam and clavulanic acid and fAUC0-24/MIC for relebactam and vaborbactam. The optimal magnitude of the PK/PD index is variable for each BLI based on the companion ß-lactam antibiotics, type of bacteria and ß-lactamase enzyme gene transcription levels. CONCLUSIONS: The PK/PD index that describes the efficacy of BLIs and the exposure measure required for their efficacy is variable among inhibitors; as a result, it is difficult to make clear inference on what the optimum index is. Further PK/PD profiling of BLI, using preclinical infection models that simulate the anticipated mode(s) of clinical use, is warranted to streamline the exposure targets for use in the optimization of dosing regimens.

Cefditoreno: una realidad para el tratamiento de las infecciones comunitarias / Cefditoren: a reality for the treatment of community infections

Cefditoreno, una cefalosporina de tercera generación, es el betalactámico oral con mayor actividad sobre los principales patógenos que causan las infecciones respiratorias adquiridas en la comunidad (incluidos los fenotipos resistentes como Streptococcus pneumoniae resistente a penicilina y Haemophilus influenzae resistente a ampicilina), y similar a la de cefotaxima. La experiencia obtenida en ensayos clínicos y estudios posteriores (eficacia y seguridad) acreditan el uso de cefditoreno en las infecciones leves y moderadas más habituales de la comunidad como las respiratorias y las urinarias, sobre todo en zonas donde son prevalentes los fenotipos resistentes a los antibióticos orales más utilizados (AU)

Cefditoren, a third-generation cephalosporin, is the oral b-lactam more active against the main community-acquired respiratory tract pathogens (including resistance phenotypes such as penicillin-resistant Streptococcus pneumoniae and ampicillin-resistant Haemophilus influenzae), similar to cefotaxime. Data obtained from clinical trials and later evidence on efficacy and safety, support that cefditoren is an suitable option for the treatment of mild-to moderate community respiratory and urinary tract infections, particularly in regions where non-susceptible phenotipes to common oral antibiotics are prevalent (AU)

Interacciones farmacológicas relacionadas con la administración de antibióticos betalactámicos / Drug interactions related to the administration of beta-lactam antibiotics

Los antibióticos betalactámicos son los que más se usan en el tratamientoy profilaxis de las infecciones odontogénicas. Con frecuenciaes necesario prescribir un segundo antibiótico que incremente el efectodel primero. Debido a ello se hizo una revisión de los antibióticos y otros medicamentos que administrados simultáneamente o en forma secuencial con betalactámicos producen efectos deseados (sinergismo, potenciación) o indeseados (antagonismo) o provocan efectos adversos en el organismo.

Beta-lactams are the most commonly used antibiotics in the treatmentand prophylaxis of odontogenic infections. It is often necessary toprescribe a second antibiotic to increase the eff ect of the fi rst. For thisreason, we performed a review of antibiotics and other medicationswhich, when administered simultaneously or sequentially with betalactams,produce desirable (synergism, potentiation) or undesirable(antagonism) eff ects or provoke adverse eff ects in the organism.

Pharmacokinetic/pharmacodynamic target attainment of intravenous β-lactam regimens against Gram-negative bacteria isolated in a Brazilian teaching hospital

ABSTRACTINTRODUCTION: Monte Carlo simulations have been used for selecting optimal antibiotic regimens for treatment of bacterial infections. The aim of this study was to assess the pharmacokinetic and pharmacodynamic target attainment of intravenous β-lactam regimens commonly used to treat bloodstream infections (BSIs) caused by Gram-negative rod-shaped organisms in a Brazilian teaching hospital.METHODS: In total, 5,000 patients were included in the Monte Carlo simulations of distinct antimicrobial regimens to estimate the likelihood of achieving free drug concentrations above the minimum inhibitory concentration (MIC; fT > MIC) for the requisite periods to clear distinct target organisms. Microbiological data were obtained from blood culture isolates harvested in our hospital from 2008 to 2010.RESULTS: In total, 614 bacterial isolates, including Escherichia coli, Enterobacterspp., Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa, were analyzed Piperacillin/tazobactam failed to achieve a cumulative fraction of response (CFR) > 90% for any of the isolates. While standard dosing (short infusion) of β-lactams achieved target attainment for BSIs caused by E. coliand Enterobacterspp., pharmacodynamic target attainment against K. pneumoniaeisolates was only achieved with ceftazidime and meropenem (prolonged infusion). Lastly, only prolonged infusion of high-dose meropenem approached an ideal CFR against P. aeruginosa; however, no antimicrobial regimen achieved an ideal CFR against A. baumannii.CONCLUSIONS:These data reinforce the use of prolonged infusions of high-dose β-lactam antimicrobials as a reasonable strategy for the treatment of BSIs caused by multidrug resistant Gram-negative bacteria in Brazil.

Betalactamasas de espectro extendido en las infecciones del tracto urinario causadas por enterobacterias: aproximación a su conocimiento y pautas de actuación / Extended-spectrum beta-lactamases in urinary tract infections caused by Enterobacteria: Understanding and guidelines for action

Contexto: Las betalactamasas son enzimas bacterianas que protegen a los microorganismos de los efectos letales de los antibióticos β-lactámicos. Su producción es el mecanismo más importante de resistencia a estos antibióticos, especialmente en bacterias gramnegativas. Objetivo: Revisar la magnitud del problema de las betalactamasas de espectro extendido (BLEE) en el ámbito urológico y presentar las pautas de actuación fundamentales al respecto, los principales factores de riesgo y las estrategias de prevención. Adquisición de evidencia: Se lleva a cabo una estrategia de búsqueda estructurada tipo paciente, problema, intervención, comparación y resultado en PubMed-Medline identificando los estudios más relevantes relacionados con el manejo de pacientes con infección urinaria por microorganismos productores de BLEE. Se presenta también análisis de la casuística de nuestro centro en esta misma problemática. íntesis de evidencia: Las BLEE se encuentran en enterobacterias, fundamentalmente Klebsiella sp. y Escherichia coli y se caracterizan por tener capacidad hidrolítica frente a los antibióticos betalactámicos, lo que implica resistencia frente a penicilinas, cefalosporinas y aztreonam. También se asocian a resistencia a otros antibióticos. Existe alto riesgo de infección o colonización por productores de BLEE en pacientes con estancia hospitalaria prolongada o que han precisado dispositivos invasivos. El uso previo de antibióticos y la estancia en residencia de cuidados son también elementos de riesgo. Los programas de prevención deben centrarse en evitar la infección nosocomial. Resulta fundamental implantar una política restrictiva en el uso de antibióticos. La terapia de elección en infecciones graves se centra en carbapenémicos, aunque debe evitarse su uso indiscriminado. En la infección de tracto urinario bajo no complicada fosfomicina y nitrofurantoína son las mejores alternativas terapéuticas. Conclusión: Las cepas productoras de BLEE constituyen un verdadero problema de salud a nivel mundial. Las estrategias de prevención deben centrarse en la infección nosocomial, pero no debe olvidarse que cada vez es más frecuente la aparición de estos patógenos en infecciones comunitarias. Las decisiones terapéuticas deben basarse en el conocimiento de la distribución local de los microorganismos y sus patrones de resistencia

Context: Beta-lactamases are bacterial enzymes that protect microorganisms from the lethal effects of β-lactam antibiotics. The production of beta-lactamases is the most important mechanism of resistance to these antibiotics, especially in Gram-negative bacteria. Objective: Review the magnitude of the problem of extended-spectrum beta-lactamases (ESBL) in the urological setting and present the fundamental action guidelines on the issue, the main risk factors and the prevention strategies. Acquisition of evidence: A structured search strategy for patient, problem, intervention, comparison and result was conducted in the PubMed-Medline database to identify the most relevant studies related to the management of patients with urinary tract infection by ESBL-producing microorganisms. We also present a caseload analysis of our center on this issue. Summary of the evidence: ESBL are found in Enterobacteria, mainly Klebsiella sp. and Escherichia coli and are characterized by their hydrolytic ability compared with beta-lactam antibiotics, which entails resistance to penicillin, cephalosporin and aztreonam. They are also associated with resistance to other antibiotics. There is a high risk of infection and colonization by ESBL producers in patients with prolonged hospital stays or who required invasive devices. The prior use of antibiotics and stays in residential care are also risk factors. Prevention programs should focus on preventing nosocomial infection. It is essential that a restrictive policy on the use of antibiotics be implemented. The therapy of choice for severe infections is focused on carbapenems, although their indiscriminate use should be avoided. In uncomplicated lower urinary tract infections, fosfomycin and nitrofurantoin are the best treatment alternatives. Conclusion: ESBL-producing strains constitute a true global health problem. Prevention strategies should focus on nosocomial infection. We should not forget, however, that the appearance of these pathogens in community-acquired infections is increasingly frequent. Therapeutic decisions should be based on an understanding of the local distribution of microorganisms and their resistance patterns

Pharmacodynamic profiling of commonly prescribed antimicrobial drugs against Escherichia coli isolates from urinary tract

Since antimicrobial resistance among uropathogens against current first line agents has affected the management of severe urinary tract infection, we determined the likelihood that antibiotic regimens achieve bactericidal pharmacodynamic exposures using Monte Carlo simulation for five antimicrobials (ciprofloxacin, ceftriaxone, piperacillin/tazobactam, ertapenem, and meropenem) commonly prescribed as initial empirical treatment of inpatients with severe community acquired urinary tract infections. Minimum inhibitory concentration determination by Etest was performed for 205 Brazilian community urinary tract infection Escherichia coli strains from 2008 to 2012 and 74 E. coli bloodstream strains recovered from a surveillance study. Pharmacodynamic exposure was modeled via a 5000 subject Monte Carlo simulation. All isolates were susceptible to ertapenem and meropenem. Piperacillin/tazobactam, ceftriaxone and ciprofloxacin showed 100%, 97.5% and 83.3% susceptibility among outpatient isolates and 98.6%, 75.7% and 64.3% among inpatient isolates, respectively. Against outpatient isolates, all drugs except ciprofloxacin (82.7% in aggressive and 77.6% in conservative scenarios) achieved high cumulative fraction of response: car-bapenems and piperacillin/tazobactam cumulative fraction of responses were close to 100%, and ceftriaxone cumulative fraction of response was 97.5%. Similar results were observed against inpatients isolates for carbapenems (100%) and piperacillin/tazobactam (98.4%), whereas ceftriaxone achieved only 76.9% bactericidal cumulative fraction of response and ciprofloxacin 61.9% (aggressive scenario) and 56.7% (conservative scenario) respectively. Based on this model, standard doses of beta-lactams were predicted to deliver sufficient pharmacodynamic exposure for outpatients. However, ceftriaxone should be avoided for inpatients and ciprofloxacin empirical prescription should be avoided in both inpatients and outpatients with complicated urinary tract infection.

Importancia de los controles de calidad para la detección de la resistencia a antibióticos beta-lactámicos en enterobacterias / Importance of quality control for the detection of beta-lactam antibiotic resistance in Enterobacteriaceae

Los beta-lactámicos son los antimicrobianos más utilizados para el tratamiento de las infecciones producidas por enterobacterias, y el principal mecanismo de resistencia frente a ellos es la producción de beta-lactamasas. Las beta-lactamasas de mayor relevancia clínica, debido a su perfil de sustrato y a sus repercusiones epidemiológicas, son las de espectro extendido, las de clase C y las carbapenemasas. La detección fenotípica de estas beta-lactamasas puede ser complicada y se basa, generalmente, en la utilización de inhibidores específicos y en la demostración de la pérdida de actividad frente a beta-lactámicos indicadores. A pesar de que diferentes comités internacionales no consideran necesaria la determinación del mecanismo de resistencia ni la interpretación del antibiograma, son varias las voces críticas que estiman imprescindible esta detección y alertan de la conveniencia de interpretar el antibiograma mientras no se disponga de más datos sobre la eficacia clínica de los beta-lactámicos en estos casos.Por estas dificultades metodológicas y los constantes cambios de criterios de interpretación, consideramos imprescindibles las labores de docencia en este campo. En este sentido, los controles de calidad externos son de gran relevancia para la continua actualización en esta área. Cualquiera de estos programas debe ir siempre acompañado de una revisión de los resultados, de la metodología y de las causas de los posibles errores, para poder realizar una actividad docente completa. En el presente trabajo se repasan y contextualizan todos los aspectos relacionados con la detección e interpretación de estas beta-lactamasas (AU)

The beta-lactam antimicrobial agents are frequently used to treat infections caused by Enterobacteriaceae. The main mechanism of resistance to these antibiotics is the production of certain enzymes, collectively named beta-lactamases. Due to their substrate profile and their epidemiological implications, the most clinically important beta-lactamases are extended-spectrum beta-lactamases, class C beta-lactamases and carbapenemases. Phenotypic detection of these enzymes may be complicated and is based on the use of specific inhibitors of each beta-lactamase and on the loss of activity on some beta-lactam indicators. Various international committees postulate that it is no longer necessary to interpret the susceptibility results or determine the mechanism of resistance. Several critics disagree, however, and consider that susceptibility results should be interpreted until more data are available on the clinical efficacy of treatment with beta-lactams.Given these methodological difficulties and constant changes in the interpretation criteria, we consider that training and external quality controls are essential to keep updated in this field. For learning purposes, these external quality controls should always be accompanied by a review of the results and methodology used, and the analysis of errors. In this paper we review and contextualize all the aspects related to the detection and interpretation of these beta-lactamases (AU)

Guía de tratamiento antimicrobiano de la infección por Staphylococcus aureus / No disponible

No disponible

Resistance of Bacteroides isolates recovered among clinical samples from a major Costa Rican hospital between 2000 and 2008 to ß-lactams, clindamycin, metronidazole, and chloramphenicol

Objetivo. Determinar la sensibilidad a varios ß-lactámicos, cloranfenicol, clindamicina y metronidazol de 100 aislamientos de Bacteroides spp. obtenidos en uno de los principales hospitales de Costa Rica entre 2000 y 2008. Métodos. Se utilizó el sistema ATB ANA® para determinar la sensibilidad a la amoxicilina, amoxicilina con ácido clavulánico, piperacilina, piperacilina con tazobactam, ticarcilina, ticarcilina con ácido clavulánico, cefoxitina, cefotetan, imipenem, cloranfenicol, clindamicina y metronidazol. Debido a la utilización en Costa Rica de clindamicina y metronidazol como tratamientos de elección para infecciones anaerobias, se determinó la concentración mínima inhibitoria (CMI) de ambas drogas con el método de microdilución en caldo. Las cepas ATCC 25285 y ATCC 29741 se utilizaron como referencia. Resultados. De acuerdo con el sistema ATB ANA®, 93 aislamientos fueron resistentes al menos a un antibiótico. La resistencia a los b-lactámicos fue frecuente, mientras que la resistencia a b-lactámicos con inhibidores de b-lactamasa fue escasa. Todas las cepas se inhibieron con imipenem y cloranfenicol. Con el método de microdilución en caldo, la resistencia a clindamicina fue del 20%, con CMI de 64 mg/La 256 mg/L; todas las cepas fueron sensibles a metronidazol. Conclusiones. La alta CMI de clindamicina de la mayoría de las cepas resistentes sugiere la presencia de mecanismos de resistencia adquiridos en los aislamientos, por lo que se requieren estudios de vigilancia epidemiológica para determinar su eficacia. La baja resistencia observadadel metronidazol destaca su valor como una droga de primera línea. Por otra parte, imipenem podría usarse para tratar infecciones que no responden bien a metronidazol o clindamicina(AU)

Objective. To assess the susceptibility of 100 isolates of Bacteroides spp. recovered in a major Costa Rican hospital between 2000 and 2008 to several ß-lactams, chloramphenicol, clindamycin and metronidazole. Methods. Susceptibility to amoxicillin, amoxicillin with clavulanic acid, piperacillin, piperacillin with tazobactam, ticarcillin, ticarcillin with clavulanic acid, cefoxitin, cefotetan, imipenem, chloramphenicol, clindamycin, and metronidazole was determined with the ATB ANA® system. In addition, minimum inhibitory concentrations (MIC) of clindamycin and metronidazole were determined with the broth microdilution method because these drugs are the treatment of choice for anaerobic infections in Costa Rica. Reference strains ATCC® 25285 and ATCC® 29741 were employed as indicated. Results. According to the ATB ANA® system, 93 isolates were resistant to at least one antibiotic. Resistance to b-lactams was common. By contrast, resistance to b-lactams supplemented with b-lactamase inhibitors was rare. All of the strains were inhibited by imipenem and chloramphenicol. By a broth microdilución test, resistance to clindamycin was 20%, with MIC ranging from 64 mg/L to 256 mg/L; all of the strains were susceptible to metronidazole. Conclusions. The high MIC for clindamycin obtained for the majority of the resistant strains is highly suggestive of the presence of mechanisms of acquired resistance among the isolates, therefore surveillance studies are required to determine its efficacy. The low resistance to metronidazole observed underlines its value as a first-line drug. On the other hand, imipenem could be used to treat infections that do not respond well to metronidazole or clindamycin(AU)

Enterococcus: resistencias fenotípicas y genotípicas y epidemiología en España / Enterococcus: phenotype and genotype resistence and epidemiology in Spain

Los enterococos son importantes patógenos nosocomiales debido a la dificultad de tratamiento condicionada por su multirresistencia intrínseca y a la adquisición de nuevos genes de resistencia. La resistencia adquirida a beta-lactámicos se debe a la hiperproducción o a alteraciones en la PBP5. La producción de betalactamasa es anecdótica. La resistencia de alto nivel a aminoglucósidos (RAN) se debe a la producción de enzimas inactivantes de estos antibióticos y anula el efecto sinérgico con agentes activos en la pared celular. La enzima más frecuente es la AAC(6’)-APH(2”), que inactiva a todos los aminoglucósidos más frecuentemente utilizados en la práctica clínica. La resistencia adquirida a glucopéptidos se debe a la adquisición de operones de resistencia denominados vanA, vanB, vanD, vanE, vanG, VanL, vanM y vanN. La resistencia a linezolid se debe a mutaciones ribosómicas o a la adquisición del gen cfr. Algunas cepas presentan sensibilidad disminuida a la daptomicina. En España, la resistencia de los enterococos a los beta-lactámicos y la RAN a aminoglucósidos es elevada, y Enterococcus faecalis es casi uniformemente sensible a la ampicilina. La resistencia de los enterococos a los glucopéptidos es baja, con la excepción de algunos brotes, y los nuevos antimicrobianos (linezolid, daptomicina, tigeciclina) son casi uniformemente activos frente a estos microorganismos. La gran diseminación de los complejos clonales de alto riesgo como el CC2 y CC9 (E. faecalis) y el CC17 (E. faecium) hace necesario realizar estudios para vigilar la diseminación de genes de resistencia a antimicrobianos y para detectar estos CC de alto riesgo y predecir tendencias futuras en la adquisición de genes de resistencia (AU)

Enterococci are major nosocomial pathogens due to their intrinsic resistance to many antimicrobials as well as to their ability to acquire new mechanisms of resistance. Acquired resistance to beta-lactams is due to PBP5 overproduction or alterations in this protein. Beta-lactamase production is anecdotal. High-level resistance (HLR) to aminoglycosides is due to the production of aminoglycoside-modifying enzymes that delete synergistic killing in association with cell wall-active agents. The most frequent enzyme is AAC(6’)- APH(2”), which inactivates all the aminoglycosides most frequently used in clinical practice. Acquired resistance to glycopeptides is due to the acquisition of gene clusters called vanA, vanB, vanD, vanE, vanG, vanL, vanM and vanN. Linezolid resistance is due to ribosomal mutations or to the acquisition of the cfr gene. Some isolates present diminished susceptibility to daptomycin. In Spain, both enterococcal resistance to beta-lactams and HLR to aminoglycosides are high. E. faecalis is almost uniformly susceptible to ampicillin. Enterococcal resistance to glycopeptides is low, with the exception of occasional outbreaks. The new antimicrobials (linezolid, daptomycin, tigecycline) are almost uniformly active against these microorganisms. Because of the wide dissemination of the high-risk clonal complexes CC2 and CC9 (E. faecalis), and CC17 (E. faecium), surveillance studies are required to detect antimicrobial resistance genes as well as to identify high-risk clonal complexes in order to predict future trends in the acquisition of resistance genes (AU)

Detección fenotípica de mecanismos de resistencia en microorganismos gramnegativos / Detection of resistance phenotypes in gram-negative bacteria

Detecting resistance in gram-negative microorganisms has a strong clinical and epidemiological impact, but there is still a great deal of debate about the most sensitive phenotypic method and whether in vitro susceptibility results should be interpreted. The present work reviews the phenotypes and mechanisms of resistance to beta-lactams, quinolones and aminoglycosides in gram-negative bacilli and also revises the different phenotypic methods used for their detection. A clinical interpretation of in vitro susceptibility results is also discussed. Extended-spectrum and inhibitor resistant beta-lactamases, AmpC type beta-lactamases and carbapenemases are thoroughly reviewed. As regards quinolones, the resistance mediated both by plasmids and by mutations in the DNA gyrase and the topoisomerase IV genes is also reviewed. This report includes resistance patterns to aminoglycosides caused by modifying enzymes. Phenotypic detection of beta-lactam resistance in Neisseria spp. and Haemophilus influenzae is also reviewed in a separate section (AU)

La detección de los mecanismos de resistencia en los microorgansimos gramnegativos tiene una granrepercusión clínica y epidemiológica, existiendo aún hoy en día una cierta discusión sobre cuál es lamejor técnica fenotípica para este fin, así como si se deben o no interpretar los resultados in vitro desensibilidad. Se describen los fenotipos y mecanismos de resistencia a antibióticos betalactámicos, quinolonasy aminoglucósidos en bacilos gramnegativos, así como las diferentes herramientas fenotipicasdisponibles para su detección e interpretación clínica. También se incluyen las betalactamasas de espectroextendido, las resistentes a los inhibidores, las de tipo AmpC y las carbapenemasas; las resistenciasa quinolonas por mutaciones en los genes de la DNA girasa y la topoisomesasa IV o las mediadas porplásmidos; y los patrones de resistencia a aminoglucósidos debidos a la expresión de enzimas modificadoras.En un apartado específico se discute la detección fenotípica de la resistencia a los antibióticosbetalactámicos en Neisseria spp. y Haemophilus influenzae (AU)

Lectura interpretada del antibiograma de enterobacterias / Interpretive reading of enterobacteria antibiograms

El patrón de resistencia observado en el antibiograma de un microorganismo debe ser la suma del patrón de resistencia natural característico de la especie más el de las resistencias adquiridas. El principal mecanismo de resistencia a los betalactámicos y aminoglucósidos en enterobacterias es el enzimático, donde cada enzima reconoce uno/os determinado/os betalactámicos o aminoglucósidos, respectivamente. Ello, se traduce en un patrón de resistencia concreto que permite deducir la/las enzimas implicadas. Sin embargo, la resistencia enzimática no es el único mecanismo y, frecuentemente, el patrón observado es multifactorial. La resistencia a las quinolonas se debe mayoritariamente a mutaciones cromosómicas puntuales y secuenciales, que pueden seleccionarse por tratamientos con fluoroquinolonas inicialmente activas. En los últimos años, sin embargo, ciertos genes plasmídicos que codifican enzimas modificadoras de las quinolonas o protectores de la diana, se han visto implicados en la resistencia de bajo nivel a este grupo de antimicrobianos (AU)

The resistance pattern observed in the antibiogram of an isolate should be the sum of its natural resistance pattern, characteristic of the species, plus the acquired resistances. In Enterobacteriaceae, the production of inactivating enzymes is the main mechanism of resistance to beta-lactams and aminoglycosides. Each one of these enzymes recognizes one or more specific beta-lactams or aminoglycosides as substrate. This substrate specificity implies a specific resistance pattern from which we can deduce the enzymes present in the isolate. However, enzymatic-mediated resistance is not the only mechanism implicated and resistance is frequently multifactorial. Resistance to quinolones is mainly due to precise, sequential chromosomal mutations that can be selected by fluoroquinolone treatments. Recently, certain plasmid-mediated genes which code enzymes that modify quinolones or that are target protectors have been implicated in the low level resistance to quinolones (AU)

Encuesta multicéntrica nacional sobre el manejo de la infección en pacientes alérgicos a betalactámicos / Multicenter national survey on infection management in patients with penicillin allergy

Introducción. Los antibióticos betalactámicos son los másampliamente usados por su eficacia, espectro y seguridad. Suuso se encuentra limitado por la resistencia bacteriana y porlas reacciones adversas, fundamentalmente hipersensibilidad.La correcta valoración de una posible alergia a betalactámicos(ABLA) requiere medios especializados no siempre disponiblesen la práctica clínica. Pretendemos conocer la opiniónde los clínicos españoles en cuanto a la frecuencia y métodosde evaluación de los pacientes con ABLA así como las preferenciasen el uso de antimicrobianos alternativos a betalactámicospara el manejo de cuadros infecciosos habituales.Métodos. Estudio descriptivo transversal multicéntricopromovido por el Grupo de Trabajo en Enfermedades Infecciosas(GTEI) de la Sociedad Española de Medicina Interna(SEMI) basado en la realización de una encuesta de 10 preguntasde opinión a médicos especialistas que trabajan encentros médicos españoles.Resultados. Un total de 311 médicos respondieron a laencuesta (92,2 % médicos especialistas en medicina interna)repartidos por todo el territorio español. Una media del10,7% de los pacientes atendidos se declara con ABLA aunquesólo una media del 10,8% de los mismos aporta documentaciónal respecto. Los pacientes son remitidos paraestudio alergológico en una media del 33,6 %. Los tratamientosde desensibilización se realizan en un 4,3% de casos.La preferencia por el uso de antibióticos alternativos abetalactámicos varía ampliamente según el cuadro infecciosoy el origen comunitario o nosocomial e incluye quinolonas,macrólidos, glucopéptidos, lincosamidas, oxazolidinonasy tigeciclina (AU)

Introduction. Beta-lactam antibiotics are widely prescribedto treat many infections because of efficacy,spectrum and safety. Their use is limited in patients withresistant microbial agents and in those with a history ofpenicillin allergy (HPA) because of cross-reactivity risk.Accurate clinical assessment of possible HPA requiresspecialized resources not always available in clinicalpractice. We intended to get to know the opinion ofSpanish physicians about frequency and methodsof evaluation of the patients with HPA as well as thepreferences in the use of antimicrobial alternatives forcommon infectious diseases in patients with HPA.Methods. Multicentric cross-sectional descriptivestudy ran by the Infectious Diseases Study Group of theSpanish Society for Internal Medicine based on the accomplishmentof a survey of 10 questions of opinion tospecialist doctors who work in Spanish medical centers.Results. A total of 311 doctors responded to the survey(92.2% Internal Medicine specialists) distributed by allthe Spanish territory. An average of 10.7% of patientsself-reported having HPA although only an average of10.8 % of them gave documentation on the matter. Patientswere sent for specific allergy tests in an average of33.6 %. Desensitization treatments were performed in4.3 % of cases. The preferences for alternative antibiotictherapy to beta-lactan widely varied according to the infectiouspicture and the communitarian or nosocomialorigin, and they included quinolones, macrolides, glycopeptides,lincosamides, oxazolidinones and tigecycline (AU)