Synergistic antimicrobial combination of third-generation cephalosporins and polymyxin B against carbapenem-polymyxin-resistant Klebsiella pneumoniae: an in vitro and in vivo analysis.

Antibiotic combination therapy is a promising approach to address the urgent need for novel treatment options for infections caused by carbapenem-polymyxin-resistant Klebsiella pneumoniae (CPR-Kp). The present study aimed to investigate the synergistic potential of four cephalosporins in combination with polymyxin B (PMB). A checkerboard assay was performed to evaluate the synergistic effects of cephalexin (CLX), cefixime, cefotaxime (CTX), and cefmenoxime (CMX) in combination with PMB. Subsequently, experiments evaluating the use of CTX or CMX in combination with PMB (CTX-PMB or CMX-PMB, respectively), including growth curve and SynergyFinder analysis, antibiofilm activity assays, cell membrane integrity assays, and scanning electron microscopy, were performed. Safety assessments were also conducted, including hemolysis and toxicity evaluations, using Caenorhabditis elegans. Furthermore, an in vivo model in C. elegans was adopted to assess the treatment efficacy against CPR-Kp infections. CTX-PMB and CMX-PMB exhibited low fractional inhibitory concentration indexes ranging from 0.19 to 0.50 and from 0.25 to 1.5, respectively, and zero interaction potency scores of 37.484 and 15.076, respectively. The two combinations significantly reduced growth and biofilm formation in CPR-Kp. Neither CTX-PMB nor CMX-PMB compromised bacterial cell integrity. Safety assessments revealed a low hemolysis percentage and high survival rates in the C. elegans toxicity evaluations. The in vivo model revealed that the CTX-PMB and CMX-PMB treatments improved the survival rates of C. elegans. The synergistic effects of the CTX-PMB and CMX-PMB combinations, both in vitro and in vivo, indicate that these antibiotic pairings could represent effective therapeutic options for infections caused by CPR-Kp.

Mioclonías positivas y negativas en paciente con enfermedad renal crónica / Positive and negative myoclonus in a patient with end stage renal disease

Introducción: Las mioclonías son contracciones musculares paroxísticas de corta duración o pérdida abrupta del tono muscular, denominadas mioclonías positivas y negativas, respectivamente. Se presenta un caso clínico de mioclonías positivas y negativas generalizadas y se pretende describir los múltiples mecanismos fisiopatológicos y etiologías que lo desencadenan. Presentación del caso: Hombre de 35 años, con diabetes mellitus tipo 1 complicada con enfermedad renal diabética en hemodiálisis, desarrolló una bacteriemia asociada a catéter por Staphylococcus aureus y presentó mioclonías positivas y negativas. Se identificaron como posibles desencadenantes la uremia, la infección y los fármacos con potencial promioclónico; el hallazgo incidental de una lesión isquémica en núcleo caudado no explicaba la semiología encontrada en el paciente. Se hizo el control y retiro de todos los factores promioclónicos enunciados, junto a manejo farmacológico con levetiracetam, y con ello se logró el control de los síntomas. Discusión: Los pacientes con enfermedad renal crónica son susceptibles a la acumulación de productos tóxicos de tipo guanidinas, que tienen potencial para producir mioclonías. Además, las infecciones, el uso de fármacos con potencial promioclónico y lesiones estructurales como las isquemias corticales son etiologías que deben considerarse en el diagnóstico diferencial. El mayor impacto en los síntomas se observa con el control del factor desencadenante, y, en caso de persistir, la terapia farmacológica proporciona buenos resultados. Conclusión: Las mioclonías son trastornos del movimiento relativamente comunes en la enfermedad renal crónica. La identificación del desencadenante es crucial para su manejo junto al uso de fármacos con actividad antimioclónica.

Introduction: Myoclonus are paroxysmal muscle contractions of short duration or abrupt loss of muscle tone, called positive and negative myoclonus respectively. A clinical case of generalized positive and negative myoclonus is presented and the aim is to describe the multiple pathophysiological mechanisms and etiologies that trigger it. Case presentation: A 35-year-old man with type 1 diabetes mellitus complicated by diabetic kidney disease on hemodialysis developed catheter-associated bacteremia due to Staphylococcus aureus and presented positive and negative myoclonus. Uremia, infection, and drugs with pro-myoclonic potential were identified as possible triggers; The incidental finding of an ischemic lesion in the caudate nucleus did not explain the semiology found in the patient. The control and removal of all the pro-myoclonic factors mentioned was carried out, along with pharmacological management with levetiracetam, thus achieving control of the symptoms. Discussion: Patients with chronic kidney disease are susceptible to the accumulation of guanidine-type toxic products, which have the potential to produce myoclonus. Furthermore, infections, the use of drugs with pro-myoclonic potential and structural lesions such as cortical ischemia are etiologies that should be considered in the differential diagnosis. The greatest impact on symptoms is observed with the control of the triggering factor and if it persists, pharmacological therapy provides good results. Conclusion: Myoclonus are relatively common movement disorders in chronic kidney disease. Identification of the trigger is crucial for its management along with the use of drugs with anti-myoclonic activity.

QSAR analysis of five generations of cephalosporins to establish the structural basis of activity against methicillin-resistant and methicillin-sensitive Staphylococcus aureus.

Solving the worldwide problem of growing bacterial drug resistance will require a short-run and medium-term strategy. Structure-activity relationship (SAR) and quantitative SAR (QSAR) analyses have recently been utilized to reveal the molecular basis of the antibacterial activity and antibacterial spectrum of penicillins, the use of which is no longer solely empirical. Likewise, a more rational drug design can be achieved with cephalosporins, the largest group of ß-lactam antibiotics. The current contribution aimed to establish the molecular and physicochemical basis of the antibacterial activity of five generations of cephalosporins on methicillin-sensitive (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA). With SAR and QSAR analyses, the molecular portions that provide essential and additional antibacterial activity were identified. The substitutions with greater volume and polarity on the R2 side chain of the cephem nucleus increase potency on MSSA. The best effect is produced by substitutions with polar nitrogen atoms at the alpha-carbon (Cα). Substitutions with greater volume and polarity on the R1 side chain further enhance antibacterial activity. In contrast, the effect against MRSA seems to be independent of any substitution on R2 or at the Cα, while depending on the accessory portions with greater volume and polarity on R1.

Dermatosis por IgA lineal de la infancia inducida por cefalosporina

Introducción: La dermatosis por IgA lineal es un trastorno ampollar raro, que afecta sobre todo a niños menores de 5 años y se caracteriza por depósitos de IgA en la membrana basal dermoepidérmica. Se presenta con ampollas tensas que suelen localizarse en la zona peribucal y perineal. Objetivo: Describir una dermatosis por IgA lineal en la infancia inducida por cefalosporinas. Presentación de caso: Niño de 2 años de edad, fototipo III, que presentó una erupción vesículo-ampollar después de tratamiento con cefalosporinas por una infección en la piel. Por su presentación clínica característica y los hallazgos en la histopatología e inmunofluorescencia directa se diagnostica como dermatosis IgA lineal. Conclusiones: La dermatosis por IgA lineal es una enfermedad rara. Se conoce que en los últimos 20 años se han diagnosticado solo 4 casos en Cuba, por lo que es importante tener este hecho presente en el momento de plantear posibles causas de dermatosis ampollosas, para su intervención precoz. Es importante tener en cuenta que se puede manifestar por la exposición a fármacos como ocurrió en este caso.

Introduction: Linear IgA dermatosis is a rare blistering disorder, which mainly affects children under 5 years of age and is characterized by IgA deposits in the dermoepidermal basement membrane. It presents with tense blisters that are usually located in the perioral and perineal area. Objective: To describe linear IgA dermatosis in childhood induced by cephalosporins. Case Presentation: 2-year-old boy, phototype III, who developed a vesicle-blister rash after treatment with cephalosporins for a skin infection. Due to its characteristic clinical presentation and findings in histopathology and direct immunofluorescence it is diagnosed as linear IgA dermatosis. Conclusions: Linear IgA dermatosis is a rare disease. It is known that in the last 20 years only 4 cases have been diagnosed in Cuba, so it is important to have this fact present at the time of raising possible causes of bullous dermatoses, for early intervention. It is important to note that it can be manifested by exposure to drugs as happened in this case.

Potential Application of Cephalosporins Carried in Organic or Inorganic Nanosystems against Gram-Negative Pathogens.

Cephalosporins are ß-lactam antibiotics, classified into five generations and extensively used in clinical practice against infections caused by Gram-negative pathogens, including Enterobacteriaceae and P. aeruginosa. Commercially, conventional pharmaceutical forms require high doses to ensure clinical efficacy. Additionally, ß-lactam resistance mechanisms, such as the production of enzymes (called extended-spectrum ß-lactamases) and the low plasma half-life of these antibiotics, have been challenging in clinical therapy based on the use of cephalosporins. In this context, its incorporation into nanoparticles, whether organic or inorganic, is an alternative to temporally and spatially control the drug release and improve its pharmacokinetic and pharmacodynamic limitations. Considering this, the present review unites the cephalosporins encapsulated into organic and inorganic nanoparticles against resistant and nonresistant enterobacteria. We divide cephalosporin generation into subtopics in which we discuss all molecules approved by regulatory agencies. In addition, changes in the side chains at positions R1 and R2 of the central structure of cephalosporins for all semisynthetic derivatives developed were discussed and presented, as the changes in these groups are related to modifications in pharmacological and pharmacokinetic properties, respectively. Ultimately, we exhibit the advances and differences in the release profile and in vitro activity of cephalosporins incorporated in different nanoparticles.

Uso ambulatorio de cefalosporinas en una población colombiana: estudio de prescripción-indicación / Outpatient cephalosporin use in a Colombian population: prescription-indication study

INTRODUCCIÓN: El uso indebido de cefalosporinas puede provocar resistencia de las bacterias. OBJETIVO: Determinar el perfil de prescripción e indicación de cefalosporinas en un grupo de pacientes afiliados al Sistema de Salud de Colombia. MÉTODOS: Estudio transversal. A partir de una base de datos poblacional se obtuvo una muestra aleatoria de pacientes atendidos en consulta ambulatoria para identificar las indicaciones de cefalosporinas en registros clínicos. Se evaluaron variables farmacológicas relacionadas con formulación no indicada según guías de práctica clínica. RESULTADOS: En 381 pacientes, con edad media 41,2 ± 15,4 años, el 61,4% (n = 234) eran mujeres. Cefalexina fue la más utilizada (n=318; 83,5%), con duración media del tratamiento de 7,3 ± 3,2 días, seguida de cefradina (n = 43, 11,3%) y ceftriaxona (n = 20, 5,2%). Se prescribieron para infecciones de piel y tejidos blandos (n = 177; 46,4%, de las cuales 47,5% eran purulentas), del tracto urinario (n = 70; 18,4%), de vías respiratorias superiores (n = 57; 15,0%), e infecciones de transmisión sexual (n = 21; 5,5%). Estaban indicadas en 169 pacientes (44,4%), pero sólo 103 (60,9%) tenían prescripciones que cumplían las recomendaciones de dosificación. CONCLUSIONES: Más de la mitad de pacientes prescritos con cefalosporinas en un contexto ambulatorio tenían prescripciones consideradas no indicadas, en particular por su uso en infecciones de piel y tejidos blandos purulentas.

BACKGROUND: Misuse of cephalosporins can lead to bacterial resistance. Aim: To determine the prescription profile and indication of cephalosporins in the patients affiliated to the Colombian Health System. METHODS: Cross-sectional study. From a population database, a random sample of patients treated in an outpatient consultation was obtained, to identify the indications of the prescribed cephalosporins in their clinical record. Pharmacological variables, and those related to non-indicated formulations were evaluated according to the clinical practice guidelines. RESULTS: In 381 patients, the mean age was 41.2 ± 15.4 years, and 61.4% (n = 234) were women. Cefalexin was the most widely used (n=318; 83.5%), with a mean duration of treatment of 7.3 ± 3.2 days; followed by cefradine (n = 43; 11.3%), and ceftriaxone (n = 20; 5.2%). The most common uses were for skin and soft tissue infections (n = 177; 46.4% of which 47.5% were purulent), urinary tract infections (n = 70; 18.4%), upper respiratory airway infections (n = 57; 15.0%) and sexually transmitted diseases (n = 21; 5.5%). The use was considered indicated in 169 patients (44.4%), but only 103 (60.9%) had prescriptions that met the dosage recommendations from the clinical practice guidelines. CONCLUSIONS: More than half of the patients prescribed with cephalosporins in the outpatient setting had prescriptions considered not indicated, particularly for their use in purulent skin and soft tissue infections.

Reatividade cruzada entre betalactâmicos: uma abordagem prática / Cross-reactivity among beta-lactams: a practical approach

Os betalactâmicos são a classe de drogas que mais causam reações de hipersensibilidade envolvendo um mecanismo imunológico específico, e são os principais desencadeantes entre os antimicrobianos. São representados pelas penicilinas, cefalosporinas, carbapenêmicos, monobactâmicos e inibidores da betalactamase. A estrutura química básica destes fármacos consiste na presença dos seguintes componentes: anel betalactâmico, anel adjacente e cadeias laterais, sendo todos potenciais epítopos. Os anticorpos da classe IgE e linfócitos T estão frequentemente envolvidos no reconhecimento desses epítopos. A reatividade cruzada depende da estabilidade dos produtos intermediários (determinantes antigênicos) derivados da degradação dos anéis betalactâmicos, anéis adicionais e da semelhança estrutural das cadeias laterais entre as drogas. Classicamente acreditava-se num grande potencial de reatividade cruzada dentro de cada classe e até entre as classes, mas estudos da última década mostraram que indivíduos alérgicos à penicilina (com testes cutâneos positivos) reagiam às cefalosporinas em aproximadamente 3% dos casos, aos carbapenêmicos em cerca de 1%, e praticamente não reagiam aos monobactâmicos. Essa reatividade ou tolerância parece estar vinculada ao grau de similaridade entre as cadeias laterais desses antibióticos. Nesta revisão, ressaltamos a importância da investigação sistematizada na confirmação ou exclusão de alergia aos betalactâmicos, descrevemos a prevalência da reatividade cruzada entre estes fármacos e sugerimos um algoritmo de abordagem desses pacientes baseados em sua estrutura química e nos dados publicados na literatura.

Beta-lactams are the drugs most commonly involved in hypersensitivity reactions mediated by a specific immune mechanism and are the main triggers among antibiotics. They include penicillins, cephalosporins, carbapenems, monobactams and beta-lactam inhibitors. The basic chemical structure of these drugs consist on the presence of the following components: betalactam ring, an adjacent ring and side chains, all of which are potential epitopes. IgE antibodies and T lymphocytes are often involved in recognizing those epitopes. Cross-reactivity depends on the stability of intermediate products (antigenic determinants) derived from the degradation of the beta-lactam ring, on the adjacent rings, and on the structural similarity of the side chains between drugs. Classically, it was believed that there was a great potential for cross-reactivity within each class and even between classes, but studies from the last decade showed that individuals allergic to penicillin (with positive skin tests) reacted to cephalosporins in approximately 3% of cases, to carbapenems in about 1%, and rarely reacted to monobactams. This reactivity or tolerance seems to be linked to the degree of similarity between the side chains of these antibiotics. In this review, we emphasize the importance of systematic investigation to confirm or exclude allergy to beta-lactams, we describe the prevalence of crossreactivity between these drugs and we suggest an algorithm for approaching these patients based on their chemical structure and on data published in the literature.

Restricción programada de cefalosporinas de tercera generación en contexto de un brote de bacilos gramnegativos productores de beta-lactamasas tipo AmpC en unidades críticas: una experiencia de la vida real / Third-generation cephalosporins programmed restriction in the context of an outbreak of AmpC beta-lactamase-producing gram-negative bacilli in critical units: a real-life experience

INTRODUCCIÓN: La restricción programada (RP) de antimicrobianos puede disminuir selectivamente la tasa de infecciones por determinados microorganismos. En este sentido, los bacilos gramnegativos productores de beta-lactamasas AmpC (BGN-blaAmpC) son seleccionados por el sobreuso de cefalosporinas de tercera generación (C3G). Estas bacterias, también adquieren genes y co-producen otras beta-lactamasas, como las de Nueva Delhi (BGN-blaNDM). OBJETIVOS: Disminuir la tasa de aislamiento de BGN-blaAmpC y BGN-blaNDM en cultivos de pacientes de la UCI luego de una RP de C3G en el marco de un brote nosocomial por estos microrganismos. MATERIALES Y MÉTODOS: Estudio cuasi-experimental, previo (P1= 12 meses) y posterior (P2= 12 meses) a una RP de C3G en un hospital de adultos, donde, en el contexto de brote mencionado, se aplicaron medidas de control de infecciones generales. El uso de antimicrobianos se expresó como "porcentaje de los días de tratamiento (%DDT)"/100 camas ocupadas al día (100-COD). Se compararon las tasas de aislamiento de BGN-blaAmpC y BGN-blaNDM en hemocultivos (HC), mini-lavados bronquio-alveolares (mB) y urocultivos (UC) en la UCI. RESULTADOS: En P2 el consumo de C3G fue 2,5% DDT/100-COD. Hubo un descenso en los aislamientos de BGN-blaAmpC en HC (RR 0,48 [0,2-0,9] p < 0,02) y mB (RR 0,52 [0,3-0,9] p < 0,02), así como también de BGN-blaNDM en HC (RR 8,1 [1,6-39,4] p < 0,00). Conclusiones: La RP de C3G se asoció con la reducción de los BGN-blaAmpC y BGN-blaNDM en HC, así como de los BGN-blaAmpC mB.

BACKGROUND: Programmed restriction (PR) of antimicrobials can selectively decrease the rate of infections by certain microorganisms. In this sense, AmpC beta-lactamase-producing gram-negative bacilli (GNB-blaAmpC) are selected for the overuse of third generation cephalosporins (3GC). These bacteria also acquire genes and co-produce other β-lactamases, such as New Delhi ones (GNB-blaNDM). AIM: To decrease the isolation rate of GNB- blaAmpC and GNB- blaNDM in cultures from ICU patients after a PR of 3GC. METHODS: Quasi-experimental study, before (P1= 12 months) and after (P2= 12 months) a PR of 3GC in an adults' hospital. The use of antibiotics was expressed as "percentage days of treatment (%DOT)" /100 beds occupied per day (100-BOD). The rates of GNB-blaAmpC and GNB-blaNDM were compared in blood cultures (BC), mini-bronchio alveolar lavages (mB) and urine cultures (UC) in the ICU. RESULTS: In P2, 3GC consumption was 2.5% DOT/100-COD. There was a decrease in GNB-blaAmpC from BC (RR 0.48 [0.2-0.9] p < 0.02) and mB (RR 0.52 [0.3-0.9] p < 0.02), as well as of GNB-blaNDM from BC (RR 8.1 [1.6-39.4] p < 0.00). Conclusions: PR of 3GC was linked to the reduction of GNB-blaAmpC and GNB-blaNDM in BC, as well as GNB-blaAmpC in mB from ICU patients.

Molecular epidemiology of cefotaxime-resistant but ceftazidime-susceptible Enterobacterales and evaluation of the in vitro bactericidal activity of ceftazidime and cefepime.

Extended-spectrum ß-lactamases' (ESBLs) production is the main resistance mechanism to third-generation cephalosporins (TGCs) in gram-negative bacilli. In Argentina, there is a high prevalence of cefotaximase-type ESBLs (CTX-M). For this reason, dissociated resistance phenotype (DRP) displaying a profile of resistance to cefotaxime (CTX) and susceptibility to ceftazidime (CAZ) might be detected. The aims of this study were to determine the prevalence of DRP in Enterobacterales clinical isolates, to characterize the mechanisms responsible for this phenotype and to evaluate the in vitro behaviour against different antibiotics. Sixty Enterobacterales resistant to any TGC were studied, and among them, 25% displayed a DRP. The ß-lactamases associated with DRP were 5/11 CTX-M-2, 4/11 CTX-M-14, 1/11 CTX-M-15 and 1/11 CMY-2 in E. coli, 2/3 CTX-M-2 and 1/3 CMY-2 in P. mirabilis and 1/1 CTX-M-14 in K. pneumoniae. Furthermore, CTX-M-2 and CTX-M-14 were related with DRP in both wild-type isolates and the corresponding transconjugants. Time-kill experiments showed CAZ bactericidal activity on CTX-M-2-and CTX-M-14-producing strains and bacterial regrowth in those CMY-2 producers. An opposite behaviour was evident when cefepime (FEP) was used. However, CAZ and gentamicin combination showed a synergistic effect against the CMY-2 producers. We concluded that Enterobacterales with DRP responded differently to CAZ or FEP depending on the type of ß-lactamase they possess, suggesting that these cephalosporins could be a therapeutic option. Therefore, the characterization of the involved resistance mechanism might contribute to define the appropriate antibiotic treatment.

Pharmacokinetics and Pharmacodynamics of Cefepime in Adults with Hematological Malignancies and Febrile Neutropenia after Chemotherapy.

Patients with chemotherapy-induced febrile neutropenia (CIFN) may have changes in the pharmacokinetics (PK) compared to patients without malignancies or neutropenia. Those changes in antibiotic PK could lead to negative outcomes for patients if the therapy is not adequately adjusted to this. In this, open-label, non-randomized, prospective, observational, and descriptive study, a PK model of cefepime was developed for patients with hematological neoplasms and post-chemotherapy febrile neutropenia. This study was conducted at a cancer referral center, and study participants were receiving 2 g IV doses of cefepime every 8 h as 30-min infusions. Cefepime PK was well described by a two compartment model with a clearance dependent on a serum creatinine level. Using Monte Carlo simulations, it was shown that continuous infusions of 6g q24h could have a good achievement of PK/PD targets for MIC levels below the resistance cut-off point of Enterobacteriaceae. According to the simulations, it is unnecessary to increase the daily dose of cefepime (above 6 g daily) to increase the probability of target attainment (PTA). Cumulative fraction of response (CFR) using interment dosing was suboptimal for empirical therapy regimens against K. pneumoniae and P. aeruginosa, and continuous infusions could be used in this setting to maximize exposure. Patients with high serum creatinine levels were more likely to achieve predefined PK/PD targets than patients with low levels.

Laboratory-based surveillance of Shigella spp. from human clinical cases in Colombia, 1997-2018 / Vigilancia por el laboratorio de Shigella spp. aislada de casos clínicos humanos en Colombia, 1997-2018

INTRODUCTION: Shigellosis is endemic in low-and middle-income countries, causing approximately 125 million episodes of diarrhea and leading to approximately 160 .000 deaths annually one-third of which is associated with children. OBJECTIVE: To describe the characteristics and antimicrobial resistance profiles of Shigella species recovered in Colombia from 1997 to 2018. MATERIALS AND METHODS: We received isolates from laboratories in 29 Colombian departments. We serotyped with specific antiserum and determined antimicrobial resistance and minimal inhibitory concentrations for ten antibiotics with Kirby-Bauer tests following the Clinical and Laboratory Standards Institute recommendations. RESULTS: We analyzed 5,251 isolates of Shigella spp., most of them obtained from stools (96.4%); 2,511 (47.8%) were from children under five years of age. The two most common species were S. sonnei (55.1%) and S. flexneri (41.7%). The highest resistance rate was that of tetracycline (88.1%) followed by trimethoprim-sulfamethoxazole (79.3%) and ampicillin (65.5%); 50.8% of isolates were resistant to chloramphenicol, 43.6% to amoxicillin/clavulanic acid, and less than 1% to cefotaxime, ceftazidime, gentamicin, and ciprofloxacin. In S. sonnei, the most common resistance profile corresponded to trimethoprim-sulfamethoxazole (92%) whereas in S. flexneri the most common antibiotic profiles were multidrug resistance. CONCLUSIONS: In Colombia, children under five years are affected by all Shigella species. These findings should guide funders and public health officials to make evidence based decisions for protection and prevention measures. The antimicrobial resistance characteristics found in this study underline the importance of combating the dissemination of the most frequently isolated species, S. sonnei and S. flexneri.

Introducción. La shigelosis es endémica en los países de ingresos bajos y medios y ocasiona aproximadamente 125 millones de episodios de diarrea y 160.000 muertes al año, un tercio de los cuales se presenta en niños. Objetivo. Describir las características y los perfiles de resistencia antimicrobiana en aislamientos de Shigella spp. recuperados en Colombia entre 1997 y 2018. Materiales y métodos. Los aislamientos provenían de laboratorios en 29 departamentos de Colombia. La serotipificación se hizo con antisueros específicos de Shigella spp. y, la determinación de los perfiles de resistencia y la concentración inhibitoria mínima de diez antibióticos, por Kirby-Bauer. Resultados. Se estudiaron 5.251 aislamientos de Shigella spp. obtenidos de materia fecal (96,4 %); el 47,8 % de ellos correspondía a niños menores de cinco años. Las especies más frecuentes fueron S. sonnei (55,1 %) y S. flexneri (41,7 %). Se presentó resistencia a tetraciclina (88,1 %), trimetoprim-sulfametoxasol (79,3 %), ampicilina (65,5 %), cloranfenicol (50,8 %) y amoxicilina-acido clavulánico (43,6 %). La resistencia no superó el 1 % contra cefotaxime, ceftazidima, gentamicina y ciprofloxacina. Para S. sonnei, el perfil de resistencia más frecuente correspondió a trimetoprim-sulfametoxasol, en contraste con S. flexneri, cuyos perfiles fueron todos multirresistentes. Conclusiones. Los niños menores de cinco años se vieron afectados por todas las especies de Shigella spp., aspecto que los legisladores en salud pública deben considerar a la hora de tomar decisiones en torno a las medidas de prevención y protección frente a esta enfermedad. Las características de resistencia antimicrobiana de los aislamientos de Shigella spp. en Colombia ponen de manifiesto la importancia de combatir la diseminación de las dos especies más frecuentes en casos clínicos, S. sonnei y S. flexneri.

Laboratory-based surveillance of Shigella spp. from human clinical cases in Colombia, 1997-2018 / Vigilancia por el laboratorio de Shigella spp. aislada de casos clínicos humanos en Colombia, 1997-2018

Abstract | Introduction: Shigellosis is endemic in low-and middle-income countries, causing approximately 125 million episodes of diarrhea and leading to approximately 160.000 deaths annually one-third of which is associated with children. Objective: To describe the characteristics and antimicrobial resistance profiles of Shigella species recovered in Colombia from 1997 to 2018. Materials and methods: We received isolates from laboratories in 29 Colombian departments. We serotyped with specific antiserum and determined antimicrobial resistance and minimal inhibitory concentrations for ten antibiotics with Kirby-Bauer tests following the Clinical and Laboratory Standards Institute recommendations. Results: We analyzed 5,251 isolates of Shigella spp., most of them obtained from stools (96.4%); 2,511 (47.8%) were from children under five years of age. The two most common species were S. sonnei (55.1%) and S. fbxneri (41.7%). The highest resistance rate was that of tetracycline (88.1%) followed by trimethoprim-sulfamethoxazole (79.3%) and ampicillin (65.5%); 50.8% of isolates were resistant to chloramphenicol, 43.6% to amoxicillin/clavulanic acid, and less than 1% to cefotaxime, ceftazidime, gentamicin, and ciprofloxacin. In S. sonnei, the most common resistance profile corresponded to trimethoprim-sulfamethoxazole (92%) whereas in S. fbxneri the most common antibiotic profiles were multidrug resistance. Conclusions. In Colombia, children under five years are affected by all Shigella species. These findings should guide funders and public health officials to make evidence-based decisions for protection and prevention measures. The antimicrobial resistance characteristics found in this study underline the importance of combating the dissemination of the most frequently isolated species, S. sonnei and S. ftexneri.

Resumen | Introducción. La shigelosis es endémica en los países de ingresos bajos y medios y ocasiona aproximadamente 125 millones de episodios de diarrea y 160.000 muertes al año, un tercio de los cuales se presenta en niños. Objetivo. Describir las características y los perfiles de resistencia antimicrobiana en aislamientos de Shigella spp. recuperados en Colombia entre 1997 y 2018. Materiales y métodos. Los aislamientos provenían de laboratorios en 29 departamentos de Colombia. La serotipificación se hizo con antisueros específicos de Shigella spp. y, la determinación de los perfiles de resistencia y la concentración inhibitoria mínima de diez antibióticos, por Kirby-Bauer. Resultados. Se estudiaron 5.251 aislamientos de Shigella spp. obtenidos de materia fecal (96,4 %); el 47,8 % de ellos correspondía a niños menores de cinco años. Las especies más frecuentes fueron S. sonnei (55,1 %) y S. ftexneri (41,7 %). Se presentó resistencia a tetraciclina (88,1 %), trimetoprim-sulfametoxasol (79,3 %), ampicilina (65,5 %), cloranfenicol (50,8 %) y amoxicilina-acido clavulánico (43,6 %). La resistencia no superó el 1 % contra cefotaxime, ceftazidima, gentamicina y ciprofloxacina. Para S. sonnei, el perfil de resistencia más frecuente correspondió a trimetoprim-sulfametoxasol, en contraste con S. ftexneri, cuyos perfiles fueron todos multirresistentes. Conclusiones. Los niños menores de cinco años se vieron afectados por todas las especies de Shigella spp., aspecto que los legisladores en salud pública deben considerar a la hora de tomar decisiones en torno a las medidas de prevención y protección frente a esta enfermedad. Las características de resistencia antimicrobiana de los aislamientos de Shigella spp. en Colombia ponen de manifiesto la importancia de combatir la diseminación de las dos especies más frecuentes en casos clínicos, S. sonnei y S. ftexneri.

Genetic Features of Extended-Spectrum ß-Lactamase-Producing Escherichia coli from Poultry in Mayabeque Province, Cuba.

A total of 434 poultry cloacal samples were collected from seven different farms in different years (2013-2015) in the Cuban province of Mayabeque and analyzed for the presence of third-generation cephalosporin-resistant Escherichia coli (3GC-R-Ec). Sixty-two 3GC-R-Ec isolates were recovered in total from the farms, with detection rates of 2.9% in 2013, 10.3% in 2014, and 28.7% in 2015. Characterization of 32 3GC-R-Ec isolates revealed the presence of the extended-spectrum ß-lactamase (ESBL) genes blaCTX-M-1 (n = 27), blaCTX-M-15 (n = 4), and blaCTX-M-1 together with blaLAP-2 (n = 1). The isolates also contained different proportions of genes conferring decreased susceptibility to sulfonamides (sul1, sul2, sul3), trimethoprim (dfrA1, dfrA7, dfrA12, dfrA14, dfrA17), tetracyclines (tet(A), tet(B)), aminoglycosides (aac(6')-Ib-cr, strA, strB), chloramphenicol (cmlA1, floR), macrolides (mph(A), mph(D)), and quinolones (qnrS, qnrB, aac(6')-Ib-cr) as well as mutations in the fluoroquinolone-resistance determining regions of GyrA (S83L, D87N, D87Y) and ParC (S80I, E84G). The isolates belonged to 23 different sequence types and to phylogroups A (n = 25), B1 (n = 5), and D (n = 2), and they contained plasmid-associated incompatibility groups FII, X1, HI1, HI2, N, FIA, and FIB. These findings reveal a genetically diverse population of multiresistant ESBL-producing E. coli in poultry farms in Cuba, which suggests multiple sources of contamination and the acquisition of antibiotic resistance genes.

Cerium-modified iron oxides applied as catalysts in the heterogeneous Fenton system for degradation of cephalexin.

The effect of incorporation of different amounts of cerium on iron oxides and different heat treatment temperatures was evaluated for the degradation of cephalexin (CEX) using heterogeneous Fenton and photo-Fenton processes. The materials were characterized using X-ray diffraction (XRD), scanning electron microscopy (SEM), specific area (BET), and zeta potential (ZP). The conversion of magnetite to maghemite was observed when a 140 °C thermal treatment was applied. The insertion of cerium resulted in a loss of the uniform spherical shape of the particles. The material containing the lowest amount of cerium (0.5% w/w) presented an increase in the specific area from 91.2 to 171.6 m2 g-1 relative to the pure iron oxide, while with 2% (w/w) a decrease to 99.2 m2 g-1 was observed for the materials treated at 70 °C. The same behavior was observed for materials treated at 140 °C, however, with smaller areas. At pH 6.0, a low catalytic activity was observed contrasting to the high consumption of H2O2, suggesting its catalytic decomposition into water and oxygen. This was confirmed by the very low production of HO• in the degradation system. On the other hand, the high production of HO• was observed at pH 3.5, which was chosen as a working pH. The material treated at 140 °C and containing 1% Ce (w/w) was the highlight, promoting degradation of 0.052 mg of CEX per m2 area of the catalyst after 150 min using 1.0 mmol L-1 of H2O2. The CEX intermediates identified indicated hydroxylation as the major route of degradation.

Actividad antimicrobiana de ceftolozano-tazobactam y ceftazidima-avibactam contra bacilos gramnegativos clínicamente relevantes aislados en México / Ceftolozane/tazobactam and ceftazidime/avibactam antimicrobial activity against clinically relevant gram-negative bacilli isolated in Mexico

Resumen Introducción: Existe poca información acerca de la efectividad de las combinaciones ceftolozano/tazobactam y ceftazidima/avibactam en cepas clínicamente relevantes aisladas en México. Objetivo: Determinar el perfil antimicrobiano de ambos antibióticos en nuestra comunidad. Método: El presente estudio de investigación fue prospectivo, descriptivo y transversal. Se incluyeron cepas clínicamente relevantes aisladas a partir de cultivos de cepa pura durante el periodo de agosto de 2018 a enero de 2019 en Mexicali, Baja California, México. Resultados: Se analizaron 74 cepas de enterobacterias y 19 cepas de Pseudomonas aeruginosa; el porcentaje de sensibilidad de ceftazidima/avibactam fue de 100 % contra enterobacterias y de 72.7 % contra Pseudomonas aeruginosa; el porcentaje de sensibilidad de ceftolozano/tazobactam fue de 90.5 % para enterobacterias y de 72.7 % para Pseudomonas aeruginosa. Conclusiones: Las combinaciones ceftolozano/tazobactam y ceftazidima/avibactam ofrecen buena sensibilidad antimicrobiana in vitro, tanto contra enterobacterias productoras de betalactamasas de espectro extendido como contra Pseudomonas aeruginosa. Se requieren más datos para valorar la respuesta clínica en pacientes que reciben esas combinaciones de antibióticos.

Abstract Introduction: There is limited information on the effectiveness of ceftolozane/tazobactam and ceftazidime/avibactam combinations on clinically relevant strains isolated in Mexico. Objective: To determine the antimicrobial profile of both antibiotic combinations in our community. Method: The present research study was prospective, descriptive and cross-sectional. Clinically relevant strains isolated from pure-strain cultures were included during the period from August 2018 to January 2019 in Mexicali, Baja California, Mexico. Results: 74 enterobacteriaceae and 19 Pseudomonas aeruginosa strains were analyzed; the percentage of sensitivity of ceftazidime/avibactam was 100 % for enterobacteriaceae and 72.7 % for Pseudomonas aeruginosa; the percentage of sensitivity of ceftolozane/tazobactam for enterobacteriaceae was 90.5 % and 72.7 % for Pseudomonas aeruginosa. Conclusions: The ceftolozane/tazobactam and ceftazidime/avibactam combinations offer good antimicrobial sensitivity in vitro, both for ESBL-producing enterobacteriaceae and Pseudomonas aeruginosa. More data are required to assess clinical response in patients receiving these antibiotic combinations.

Comparative Kinetic Analysis of OXA-438 with Related OXA-48-Type Carbapenem-Hydrolyzing Class D ß-Lactamases.

Novel variants of OXA-48-type enzymes with the ability to hydrolyze oxyimino-cephalosporins and carbapenems are increasingly reported. Since its first report in 2011, OXA-163 is now extensively spread throughout Argentina, and several variants like OXA-247 have emerged. Here, we characterized a new blaOXA-48-like variant, OXA-438, and we performed a comparative kinetic analysis with the local variants OXA-247 and OXA-163 and the internationally disseminated OXA-48. blaOXA-163, blaOXA-247, and blaOXA-438 were located in a 70 kb IncN2 conjugative plasmid. OXA-438 presented mutations in the vicinity of conserved KTG (214-216), with a 2-aa deletion (R220-I221) and a D224E shift (as in OXA-163) compared to OXA-48. Despite Kpn163 (OXA-163), Kpn247 (OXA-247) and Eco438 (OXA-438) were resistant to meropenem and ertapenem, and the transconjugants (TC) remained susceptible (however, the carbapenems minimum inhibitory concentrations were ≥3 times 2-fold dilutions higher than the acceptor strain). TC163 and Eco48 were resistant to oxyimino-cephalosporins, unlike TC247 and TC438. kcat/Km values for cefotaxime in OXA-163 were slightly higher than the rest of the variants that were accompanied by a lower Km for carbapenems. For OXA-163, OXA-247, and OXA-438, the addition of NaHCO3 improved kcat values for both cefotaxime and ceftazidime; carbapenems kcat/Km values were higher than for oxyimino-cephalosporins. Mutations occurring near the conserved KTG in OXA-247 and OXA-438 are probably responsible for the improved carbapenems hydrolysis and decreased inactivation of oxyimino-cephalosporins compared to OXA-163. Dichroism results suggest that deletions at the ß5-ß6 loop seem to impact the structural stability of OXA-48 variants. Finally, additional mechanisms are probably involved in the resistance pattern observed in the clinical isolates.

Patterns of Antibiotic Prescription in Colombia: Are There Differences between Capital Cities and Municipalities?

The use of antibiotics is the most important modifiable risk factor for the development of microorganism resistance. A cross-sectional study of outpatients receiving antibiotic prescriptions registered in a population database in Colombia was conducted. The characteristics of the consumption in capital cities and small municipalities was studied and the AWaRe classification was used. AWaRe classifies antibiotics into three stewardship groups: Access, Watch and Reserve, to emphasize the importance of their optimal use and potential harms of antimicrobial resistance. A total of 182,397 patients were prescribed an antibiotic; the most common were penicillins (38.6%), cephalosporins (30.2%) and fluoroquinolones (10.9%). 'Access' antibiotics (86.4%) were the most frequently prescribed, followed by 'Watch' antibiotics (17.0%). Being 18 or older, being male, living in a municipality, having one or more comorbidities and urinary, respiratory or gastrointestinal disorders increased the probability of receiving 'Watch' or 'Reserve' antibiotics. Penicillin and urinary antiseptic prescriptions predominated in cities, while cephalosporin and fluoroquinolone prescriptions predominated in municipalities. This analysis showed that the goal set by the WHO Access of mainly using Access antibiotics is being met, although the high use of Watch antibiotics in municipalities should be carefully studied to determine if it is necessary to design specific campaigns to improve antibiotics use.

Adjuvant intraperitoneal ceftriaxone in the treatment of septic peritonitis in horses.

BACKGROUND: Intraperitoneal administration of ceftriaxone maintains therapeutic abdominal concentrations for 24 hours in healthy horses. Therefore, it is a possible treatment for septic peritonitis. The aim of this study was to evaluate the efficacy of ceftriaxone as an adjuvant treatment in horses with septic peritonitis. METHODS: Twenty-six horses with clinical signs, sonography and/or laboratory findings of septic peritonitis were included. Peritoneal fluid was collected for microbiological culture and in vitro microbial sensitivity profile assessment. Daily intraperitoneal administration of ceftriaxone (25 mg/kg) was initiated with supportive and systemic antimicrobial treatment. The animals were divided into three groups: group 1-gastrointestinal tract injuries and abdominal surgery (excluding perforations/ruptures); group 2-not related to changes in the gastrointestinal tract; group 3-secondary to intestinal rupture and/or faeces contamination. RESULTS: The mean success rate of the treatment was 77 per cent (20/26 animals), with success rates of 84.6 per cent in group 1; 87.5 per cent, group 2; and 40 per cent, group 3. CONCLUSIONS: This is the first study to report adjuvant intraperitoneal treatment ceftriaxone for septic peritonitis in horses and indicates that this treatment can successfully treat septic peritonitis in horses.

Effect of food on the pharmacokinetics of oral cefuroxime axetil in dogs.

Cefuroxime axetil pharmacokinetic profile was investigated in 12 Beagle dogs after single intravenous and oral administration of tablets or suspension at a dose of 20 mg/kg, under both fasting and fed conditions. A three-period, three-treatment crossover study (IV, PO under fasting and fed condition) was applied. Blood samples were withdrawn at predetermined times over a 12-hr period. Cefuroxime plasma concentrations were determined by HPLC. Data were analyzed by compartmental analysis. No statistically significant differences were observed between formulations and feeding conditions on PK parameters. Independently of the feeding condition, absorption of cefuroxime axetil after tablet administration was low and erratic. The drug has been quantified in plasma in 3 out of 6 and 5 out of 6 dogs in the fasted and fed groups. For this formulation, the bioavailability (F), peak plasma concentration (Cmax ), and area under the concentration-time curve (AUC) of cefuroxime axetil were significantly enhanced (p < .05) by the concomitant ingestion of food (32.97 ± 13.47-14.08 ± 7.79%, 6.30 ± 2.62-2.74 ± 0.66 µg/ml, and 15.75 ± 3.98-7.82 ± 2.76 µg.hr/ml for F, Cmax, and AUC in fed and fasted dogs, respectively), while for cefuroxime axetil suspension, feeding conditions affected only the rate of absorption, as reflected by the significantly shorter absorption half-life (T½(a) ) and time to peak concentration (Tmax ) (0.55 ± 0.27-1.15 ± 0.19 hr and 1.21 ± 0.22-1.70 ± 0.30 for T½(a) and Tmax in fed and fasted dogs, respectively). For cefuroxime axetil tablets, T > MIC (≤1 µg/ml) was <2 hr in fasted and ≈4 hr in fed animals, and for cefuroxime axetil suspension, T > MIC (≤1 µg/ml) was ≈5 hr and for T >MIC (≤4 µg/ml) was ≈2.5 hr for fasted and fed dogs, respectively. Cefuroxime axetil as a suspension formulation seems to be a better option than tablets. However, its short permanence in plasma could reduce its clinical usefulness in dogs.

Classical and New Pharmaceutical Uses of Bacterial Penicillin G Acylase.

BACKGROUND: ß-lactam antibiotics are the most used worldwide for the treatment of bacterial infections. The consumption of these classes of drugs is high, and it is increasing around the world. To date, the best way to produce them is using penicillin G Acylase (PGA) as a biocatalyst. OBJECTIVE: This manuscript offers an overview of the most recent advances in the current tools to improve the activity of the PGA and its pharmaceutical application. RESULTS: Several microorganisms produce PGA, but some bacterial strains represent the primary source of this enzyme. The activity of bacterial PGA depends on its adequate expression and carbon or nitrogen source, as well as a specific pH or temperature depending on the nature of the PGA. Additionally, the PGA activity can be enhanced by immobilizing it to a solid support to recycle it for a prolonged time. Likewise, PGAs more stable and with higher activity are obtained from bacterial hosts genetically modified. CONCLUSION: PGA is used to produce b-lactam antibiotics. However, this enzyme has pharmaceutical potential to be used to obtain critical molecules for the synthesis of anti-tumor, antiplatelet, antiemetic, antidepressive, anti-retroviral, antioxidant, and antimutagenic drugs.