Utilización de antibióticos restringidos en la práctica clínica: ceftolozano/tazobactam, ceftazidima/avibactam, ceftarolina y dalbavancina / Use of restricted antibiotics in clinical practice: ceftolozane/tazobactam, ceftazidime/avibactam, ceftaroline and dalbavancin

Objetivo: Evaluar la utilización en la práctica clínica de cuatro antibióticos de amplio espectro o innovadores: ceftolozano/tazobactam, ceftazidima/avibactam, ceftarolina y dalbavancina. Métodos: Estudio retrospectivo en que se han recogido datos de los pacientes que han recibido dichos antibióticos entre julio de 2018 y junio de 2019 en un hospital terciario. Se recogen las condiciones de uso y los resultados en efectividad a los 30 días para dalbavancina, y para el resto de antimicrobianos a los 3-5 días del inicio, a los 14 y a los 30 días para determinar mortalidad. Resultados: Se recogieron datos de 51 pacientes, con una mediana de edad de 63 años. La infección más comúnmente tratada fue neumonía (41,2%). Tres pacientes (5,9%) recibieron la terapia en estudio como primera línea y 43 (84,3%) recibieron antibióticos concomitantes. En el 66,7% de las infecciones se había aislado previamente un microorganismo sensible. En el 19,6% de los casos el cultivo fue negativo. En el grupo dalbavancina, el 75% de los pacientes se curaron a los 30 días. En el resto de antimicrobianos, el tratamiento resultó efectivo a los 3-5 días en el 65,1%. El 51,2% se curaron a los 14 días y un 30,2% fallecieron a los 30 días. Conclusiones: Los resultados de efectividad resultan comparables a estudios publicados con diseños similares. Se detecta la importancia de fomentar un uso adecuado de los antibióticos, como tratamientos dirigidos o empíricos en casos de riesgo de resistencias, priorizando su desescalada. Es esencial la implantación de equipos multidisciplinares PROA. (AU)

Objective: To evaluate the use in clinical practice of four recently marketed antibiotics: ceftolozane/tazobactam, ceftazidime/avibactam, ceftaroline, and dalbavancin. Methods: Retrospective study in which data have been collected from patients who have received these antibiotics between July 2018 and June 2019, in a third-level hospital. The conditions of use and the results in clinical efficacy measured in three periods have been studied: 3-5 days after the start of treatment, 14 days and 30 days to determine mortality. Results: Data were collected from a total of 51 patients, with a median age of 63 years. The most commonly treated infection was pneumonia (41.2%). Three patients (5.9%) received study therapy as the first line of treatment and 43 (84.3%) received concomitant antibiotics. In 66.7% of the infections, a sensitive microorganism to the antibiotic under study had been previously isolated. In 19.6% of the cases, the culture was negative. In the dalbavancin group, 75% of the pacients cured at day 30. In the other groups, the treatment was effective at 3-5 days in 65.1% of the cases. 51.2% experienced clinical cure at 14 days and 30.2% died at 30 days. Conclusions: The effectiveness results are comparable to published studies with similar designs. The importance of promoting an adequate use of antibiotics is detected, as directed or empirical treatments in cases of risk of resistance, prioritizing their de-escalation. The implementation of multidisciplinary PROA teams is essential. (AU)

Contemporary diversity of ß-lactamases among Enterobacteriaceae in the nine U.S. census regions and ceftazidime-avibactam activity tested against isolates producing the most prevalent ß-lactamase groups.

Escherichia coli (328 isolates), Klebsiella pneumoniae (296), Klebsiella oxytoca (44), and Proteus mirabilis (33) isolates collected during 2012 from the nine U.S. census regions and displaying extended-spectrum-ß-lactamase (ESBL) phenotypes were evaluated for the presence of ß-lactamase genes, and antimicrobial susceptibility profiles were analyzed. The highest ESBL rates were noted for K. pneumoniae (16.0%, versus 4.8 to 11.9% for the other species) and in the Mid-Atlantic and West South Central census regions. CTX-M group 1 (including CTX-M-15) was detected in 303 strains and was widespread throughout the United States but was more prevalent in the West South Central, Mid-Atlantic, and East North Central regions. KPC producers (118 strains [112 K. pneumoniae strains]) were detected in all regions and were most frequent in the Mid-Atlantic region (58 strains). Thirteen KPC producers also carried blaCTX-M. SHV genes encoding ESBL activity were detected among 176 isolates. Other ß-lactamase genes observed were CTX-M group 9 (72 isolates), FOX (10), TEM ESBL (9), DHA (7), CTX-M group 2 (3), NDM-1 (2 [Colorado]), and CTX-M groups 8 and 25 (1). Additionally, 62.9% of isolates carried ≥2 ß-lactamase genes. KPC producers were highly resistant to multiple agents, but ceftazidime-avibactam (MIC50/90, 0.5/2 µg/ml) and tigecycline (MIC50/90, 0.5/1 µg/ml) were the most active agents tested. Overall, meropenem (MIC50, ≤0.06 µg/ml), ceftazidime-avibactam (MIC50, 0.12 to 0.5 µg/ml), and tigecycline (MIC50, 0.12 to 2 µg/ml) were the most active antimicrobials when tested against this collection. NDM-1 producers were resistant to all ß-lactams tested. The diversity and increasing prevalence of ß-lactamase-producing Enterobacteriaceae have been documented, and ceftazidime-avibactam was very active against the vast majority of ß-lactamase-producing strains isolated from U.S. hospitals.

Desenvolvimento de metodologia qualitativa para identificação de ceftazidima / Qualitative methods for the identification of ceftazidime

A partir deste estudo, métodos para análise qualitativa foram desenvolvidos a fim de identificar ceftazidima em matéria-prima e em formulações farmacêuticas. Esses métodos incluíram testes físico-químicos baseados em propriedades químicas por reações clássicas de coloração e testes instrumentais, tais como cromatografia em camada delgada, calorimetria e espectroscopia no ultravioleta. Os resultados foram obtidos diretamente através de identificação visual pela coloração desenvolvida e pela análise dos espectros obtidos nos testes instrumentais. Esses métodos mostraram-se reprodutíveis e rápidos para identificar ceftazidima na presença de outros antibióticos ?-lactâmicos, podendo ser usados rotineiramente em análises de controle de qualidade

In this study, qualitative analytical methods were developed for the identification of ceftazidime in raw material and in pharmaceutical formulations. These methods included physicochemical tests based on chemical properties, performed by classical colorimetric reactions, and instrumental tests, such as thin-layer chromatography, calorimetry and ultraviolet spectroscopy. Results were obtained directly, through the visual identification of the drug by the color developed, and by analyzing the spectra obtained. These methods proved to be reproducible and fast means of identifying ceftazidime in the presence of other beta-lactam antibiotics and may be used for routine quality control tests.

Cefditoren versus ceftazidime in inducer-substrate combinations for the evaluation of AmpC production in a disc approximation test

Objetivo: Evaluar el cefditoren en combinaciones inductor-substrato para la detección de inducción de AmpC.Métodos: 100 aislados clínicos (25 P. aeruginosa, 25 E.cloacae, 14 M. morganii, 13 S. marcescens, 12 C. freundii,7 P. rettgeri, and 4 E. aerogenes) se ensayaron por el métodode disco Kirby-Bauer utilizando discos de cefditoren yceftazidima como substratos y de cefditoren e imipenemcomo inductores.Resultados: Ninguna cepa mostró inducción de AmpCcon la combinación cefditoren-ceftazidima como inductorsubstrato.La combinación de imipenem-cefditoren comoinductor-substrato no fue adecuada para evaluar las cepasde P. aeruginosa ya que no hubo halo de inhibición alrededordel disco de cefditoren. En las enterobacterias que sepudieron evaluar (por presentar halo de inhibición alrededordel substrato), se detectó AmpC inducible en 48 de 63(76.2%) con cefditoren, y en 33 de 68 (48.5%) de los aisladoscon ceftazidima como substrato. Se detectó un númerosignificantivamente (p= 0.013) mayor de productores deAmpC con cefditoren que con ceftazidima (76.2% vs.48.5%), debido a las diferencias encontradas en E. cloacae(72.8% vs. 21.7%; p= 0.0009) y S. marcescens (100% vs.54.5%; p= 0.03). Las reducciones medias del diámetro alrededorde los discos del substrato fueron mayores para cefditoren(4.17 mm) que para ceftazidima (3.79 mm), alcanzandosignificación estadística (p<0.05) en proteáceasindol-positivo: M. morganii (5.32 mm vs. 3.92 mm) y P.rettgeri (3.47 mm vs. 2.64 mm).Conclusión: Cefditoren no presentó capacidad de inducción, y utilizado como substrato (con imipenem comoinductor) ofreció una tasa de detección de AmpC inducibleen enterobacterias superior de la de la combinación imipenem-ceftazidima, principalmente en Enterobacter spp. ySerratia spp., con mayores reducciones del diámetro enproteáceas indol-positivo(AU)

Objective: To evaluate cefditoren in inducer-substratecombinations to screen for AmpC induction.Methods: 100 clinical isolates (25 P. aeruginosa, 25 E.cloacae, 14 M. morganii, 13 S. marcescens, 12 C. freundii, 7 P.rettgeri, and 4 E. aerogenes) were tested by the Kirby-Bauerdisc approximation method using cefditoren and ceftazidimediscs as substrates, and cefditoren and imipenem discs asinducers.Results: None of the strains showed induction of AmpCwith cefditoren-ceftazidime as inducer-substrate combination.Imipenem-cefditoren as inducer-substrate combination wasnot useful for evaluating strains of P. aeruginosa since noinhibition zones surrounding the cefditoren disc were found.Among evaluable enterobacteria (those showing substrateinhibition zone), inducible Amp C was detected in 48 out of 63(76.2%) with cefditoren, and in 33 out of 68 (48.5%) isolateswith ceftazidime as substrate. Significantly (p= 0.013) highernumber of AmpC producers were detected with cefditorenversus ceftazidime (76.2% vs. 48.5%), due to the differencesfound for E. cloacae (72.8% vs. 21.7%; p= 0.0009) and S.marcescens (100% vs. 54.5%; p= 0.03). Higher meanreductions of diameters around substrate discs were found forcefditoren (4.17 mm) vs. ceftazidime (3.79 mm), reachingstatistical significance (p<0.05) for indol-positive proteae: M.morganii (5.32 mm vs. 3.92 mm) and P. rettgeri (3.47 mm vs.2.64 mm).Conclusion: Cefditoren showed no induction capability,and when used as substrate (with imipenem as inducer) itoffered detection rates of AmpC inducible enterobacteriahigher than the imipenem-ceftazidime combination, mainly forEnterobacter spp. and Serratia spp., with higher diameterreductions for indol-positive proteae(AU)

[Pseudomonas stutzeri osteitis: A case study]. / Ostéite à Pseudomonas stutzeri à propos d'un cas.

We report a case of osteitis in a 46-year-old patient, caused by Pseudomonas stutzeri following an open fracture of the left femur. The patient was treated with 1g ceftazidime every 8 hours for two weeks combined with 160 mg/day of amikacin for 10 days. A second-line ofloxacin oral treatment at 400 mg/day was then given during 4 weeks. Surgical treatment consisted in debridement of the fracture region. Sterilization of the fracture region led to an osteosynthesis by blade plate and bone graft. The result was favorable.

Unilateral submandibular suppurative sialadenitis in a premature infant.

UNLABELLED: Isolated submandibular suppurative sialadenitis is extremely rare in newborn infants and is associated with prematurity and prolonged gavage feeding. This report describes a premature infant who developed a life-threatening airway obstruction due to suppurative submandibular sialadenitis. The diagnosis was made on clinical grounds and confirmed by ultrasonography. Staphylococcus aureus was grown from the pus expressed from the Wharton's duct orifice. Upper airway obstruction and respiratory failure were managed with intubation and mechanical ventilation, and the sialadenitis resolved quickly and completely with flucloxacillin treatment. Possible causes of sialadenitis include dehydration, decreased saliva flow and stasis during gavage feeding, duct obstruction by stones and direct bacterial inoculation. Ultrasonography is the diagnostic imaging of choice to exclude congenital tumours, lymphadenitis, congenital malformations of the Wharton's duct or the gland itself, and subcutaneous fat necrosis. CONCLUSION: Early diagnosis and antibiotic treatment of suppurative submandibular sialadenitis may prevent complications such as abscess formation, septicaemia and respiratory failure.

Structures of ceftazidime and its transition-state analogue in complex with AmpC beta-lactamase: implications for resistance mutations and inhibitor design.

Third-generation cephalosporins are widely used beta-lactam antibiotics that resist hydrolysis by beta-lactamases. Recently, mutant beta-lactamases that rapidly inactivate these drugs have emerged. To investigate why third-generation cephalosporins are relatively stable to wild-type class C beta-lactamases and how mutant enzymes might overcome this, the structures of the class C beta-lactamase AmpC in complex with the third-generation cephalosporin ceftazidime and with a transition-state analogue of ceftazidime were determined by X-ray crystallography to 2.0 and 2.3 A resolution, respectively. Comparison of the acyl-enzyme structures of ceftazidime and loracarbef, a beta-lactam substrate, reveals that the conformation of ceftazidime in the active site differs from that of substrates. Comparison of the structures of the acyl-enzyme intermediate and the transition-state analogue suggests that ceftazidime blocks formation of the tetrahedral transition state, explaining why it is an inhibitor of AmpC. Ceftazidime cannot adopt a conformation competent for catalysis due to steric clashes that would occur with conserved residues Val211 and Tyr221. The X-ray crystal structure of the mutant beta-lactamase GC1, which has improved activity against third-generation cephalosporins, suggests that a tandem tripeptide insertion in the Omega loop, which contains Val211, has caused a shift of this residue and also of Tyr221 that would allow ceftazidime and other third-generation cephalosporins to adopt a more catalytically competent conformation. These structural differences may explain the extended spectrum activity of GC1 against this class of cephalosporins. In addition, the complexed structure of the transition-state analogue inhibitor (K(i) 20 nM) with AmpC reveals potential opportunities for further inhibitor design.

Stability of reconstituted solutions of ceftazidime for injections: an HPLC and CE approach.

The stability of aqueous reconstituted ceftazidime injection vials containing ceftazidime pentahydrate blended with anhydrous sodium carbonate was investigated in different storage conditions (4 degrees C and 10 degrees C for 7 days in a refrigerator, 20 and 30 degrees C for 24 h) with validated HPLC and (micellar) CE methods. Stability indicating data were obtained for ceftazidime and two degradation products: pyridine and the delta2-ceftazidime isomer. Other degradation products were also identified (the complementarity of the two used experimental procedures was useful in such exercise) and characterized by their UV spectra and retention times. Stability data (7 days at 4 degrees C in a refrigerator and 18 h at room temperature) resulted in agreements with the manufacturers prescription and point out the need of a strict temperature control of the refrigerator's compartment used to store the reconstituted solution.

Analysis of ceftazidime and related compounds by micellar electrokinetic chromatography.

A micellar electrokinetic chromatographic method for the separation and quantification of ceftazidime, its delta2-isomer and pyridine (two ceftazidime related impurities) was developed and validated. Optimised conditions were obtained using an electrolyte system consisting of 25 mM sodium tetraborate, at pH 9.2, and 75 mM sodium dodecylsulphate. A limit of detection of 0.2 microg ml(-1) and a limit of quantitation of 0.6 microg ml(-1) were estimated for pyridine and delta2-isomer: this means that levels of < 0.1% of pyridine and delta2-isomer in ceftazidime can be determined. Calibration curves for all analytes were linear over the studied ranges with correlation coefficients >0.999. Good reproducibility for migration times and corrected peak areas were achieved (RSD % 0.3 and 1.0, respectively). The results demonstrate that the method is reproducible, accurate and appropriate for ceftazidime assay in pharmaceutical samples.

In vitro activities of ICI 194008 and ICI 193428, two new cephem antimicrobial agents.

The in vitro activities of two new cephem antibiotics, ICI 193428 and ICI 194008, were compared with those of cefpirome, cefotaxime, ceftazidime, and piperacillin. Essentially all strains of the family Enterobacteriaceae were inhibited by both study drugs at concentrations of less than or equal to 4 micrograms/ml. Both new cephems were comparable to ceftazidime against Pseudomonas aeruginosa (MIC for 90% of strains, 8 micrograms/ml) and were the most active agents tested against Pseudomonas maltophilia (MIC for 90% of strains, 16 micrograms/ml).

Susceptibility of Pseudomonas aeruginosa to beta-lactam antibiotics.

Since the discovery of carbenicillin in 1970, several groups of beta-lactam agents with remarkable activity against P. aeruginosa are actually available among penicillins such as ticarcillin, azlocillin, piperacillin, apalcillin and among cephalosporins: cefoperazone, cefsulodin as well as new structures including monobactams (aztreonam) and carbapenems with imipenem. An attempt to establish hierarchy in terms of weight for weight activity, particularly against susceptible isolates is made. The most active antimicrobial agents are: imipenem, apalcillin, ceftazidime, cefsulodin, piperacillin and azlocillin. The bactericidal activity is reported for virtually all of them but more accurate techniques such as time-killing curves are needed to make comparisons, because some discrepancies were reported. Nevertheless, among several factors affecting their inhibitory and bactericidal activities, some of them appeared predominant: inoculum effect and beta-lactamases. The different behavior of beta-lactam antibiotics may be in relation with other mechanisms such as impermeability. A few surveys on the resistance mechanism indicated that impermeability can be prevalent, instead beta-lactamases. But in any case, the enzyme distribution showed carbenicillinases (PSE-1, PSE-4) and OXA were observed with a high prevalence among ticarcillin-resistant isolates and more recently cephalosporinases. These drugs acted synergistically with all of the aminoglycosides in vitro against P. aeruginosa isolates and also in animal models of infection. If the synergism appeared to play a major role in the therapy of P. aeruginosa infections, these new beta-lactam antibiotics offer the possibility of other approaches to combination therapy.