Activity of imipenem/relebactam against Enterobacterales and Pseudomonas aeruginosa in Spain. SMART 2016-2020.

OBJECTIVE: To determine susceptibility to the novel ß-lactam/ß-lactamase inhibitor combination imipenem/relebactam in clinical isolates recovered from intra-abdominal (IAI), urinary (UTI), respiratory (RTI) and bloodstream (BSI) infections in the SMART (Study for Monitoring Antimicrobial Resistance Trends) study in SPAIN during 2016 - 2020. METHODS: Broth microdilution MICs for imipenem/relebactam and comparators were determined by a central laboratory against isolates of Enterobacterales and Pseudomonas aeruginosa. MICs were interpreted using EUCAST-2021 breakpoints. RESULTS: In total, 5,210 Enterobacterales and 1,418 P. aeruginosa clinical isolates were analyzed. Imipenem/relebactam inhibited 98.8% of Enterobacterales. Distinguishing by source of infection susceptibility was 99.1% in BSI, 99.2% in IAI, 97.9% in RTI, and 99.2% in UTI. Of intensive care unit isolates (ICU) 97.4% were susceptible and of non-ICU isolates 99.2% were susceptible. In Enterobacterales, activity against Class A, Class B and Class D carbapenemases was 96.2%, 15.4% and 73.2%, respectively. In P. aeruginosa, imipenem/relebactam was active in 92.2% of isolates. By source of infection it was 94.8% in BSI, 92.9% in IAI, 91.7% in RTI, and 93.1% in UTI. An 88.7% of ICU isolates and 93.6% of non-ICU isolates were susceptible to imipenem/relebactam. Imipenem/relebactam remained active against P. aeruginosa ceftazidime-resistant (76.3%), cefepime-resistant (73.6%), imipenem-resistant (71.5%) and piperacillin-resistant (78.7%) isolates. Of all multidrug-resistant or difficult-to-treat resistance P. aeruginosa isolates, 75.1% and 46.2%, respectively, were susceptible to imipenem/relebactam. CONCLUSIONS: Imipenem/relebactam showed high rates of susceptibility in Enterobacterales and P. aeruginosa isolates from different sources of infection as well as depending on patients' location (ICU or non-ICU scenarios).

Clinical management of cUTI, cIAI, and HABP/VABP attributable to carbapenem-resistant Gram-negative infections in Spain.

OBJECTIVE: Carbapenem-resistant Gram-negative (CRGN) infections are a major public health problem in Spain, often implicated in complicated, healthcare-associated infections that require the use of potentially toxic antibacterial agents of last resort. The objective of this study was to assess the clinical management of complicated infections caused by CRGN bacteria in Spanish hospitals. METHODS: The study included: 1) a survey assessing the GN infection and antibacterial susceptibility profile in five participating Spanish hospitals and 2) a non-interventional, retrospective single cohort chart review of 100 patients with complicated urinary tract infection (cUTI), complicated intra-abdominal infection (cIAI), or hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia (HABP/VABP) attributable to CRGN pathogens. RESULTS: In the participating hospitals CRGN prevalence was 9.3% amongst complicated infections. In the retrospective cohort, 92% of infections were healthcare-associated, and Klebsiella pneumoniae and Pseudomonas aeruginosa were the most common pathogens. OXA was the most frequently detected carbapenemase type (71.4%). We found that carbapenems were frequently used to treat cUTI, cIAI, HABP/VABP caused by CRGN pathogens. Carbapenem use, particularly in combination with other agents, persisted after confirmation of carbapenem resistance. Clinical cure was 66.0%, mortality during hospitalization 35.0%, mortality at the time of chart review 62.0%, and 6-months-post-discharge readmission 47.7%. CONCLUSIONS: Our results reflect the high burden and unmet needs associated with the management of complicated infections attributable to CRGN pathogens in Spain and highlight the urgent need for enhanced clinical management of these difficult-to-treat infections.

Antimicrobial activity of ceftolozane-tazobactam against Enterobacterales and Pseudomonas aeruginosa recovered during the Study for Monitoring Antimicrobial Resistance Trends (SMART) program in Spain (2016-2018).

OBJECTIVE: To analyse the susceptibility to ceftolozane-tazobactam and comparators in Enterobacterales and Pseudomonas aeruginosa isolates recovered from intraabdominal (IAI), urinary (UTI), respiratory (RTI) and bloodstream infection (BSI) in the SMART (Study for Monitoring Antimicrobial Resistance Trends) study. METHODS: The susceptibility of 5,351 isolates collected in 11 Spanish hospitals (2016-2018) were analysed (EUCAST-2020 criteria) by broth microdilution and were phenotypically studied for the presence of extended-spectrum beta-lactamases (ESBL). Ceftolozane-tazobactam and/or carbapenem resistant isolates were genetically characterized for ESBL and carbapenemases. RESULTS: Escherichia coli was the most frequent pathogen (49.3% IAI, 54.9% UTI, 16.7% RTI and 50% BSI), followed by Klebsiella pneumoniae (11.9%, 19.1%, 13.1% and 15.4%, respectively). P. aeruginosa was isolated in 9.3%, 5.6%, 32% and 9%, respectively. The frequency of isolates with ESBLs (2016-2017) was: 30.5% K. pneumoniae, 8.6% E. coli, 2.3% Klebsiella oxytoca and 0.7% Proteus mirabilis. Ceftolozane-tazobactam was very active against non-ESBL-(99.3% susceptible) and ESBL-(95.2%) producing E. coli being less active against K. pneumoniae (98% and 43.1%, respectively) isolates. CTX-M-15 was the most prevalent ESBL in E. coli (27.5%) and K. pneumoniae (51.9%) frequently associated with OXA-48-like carbapenemase. Overall, 93% of P. aeruginosa isolates were susceptible to ceftolozane-tazobactam, preserving this activity (>75%) in isolates resistant to other beta-lactams except in those resistant to meropenen or ceftazidime-avibactam. GES-5, PER-1, VIM-1/2 were the most prevalent enzymes in isolates resistant to ceftolozane-tazobactam. CONCLUSIONS: Ceftolozane-tazobactam showed high activity rates against isolates recovered in the SMART study although it was affected in K. pneumoniae and P. aeruginosa isolates with ESBL and/or carbapenemases.

Monitoring the antimicrobial susceptibility of Gram-negative organisms involved in intraabdominal and urinary tract infections recovered during the SMART study (Spain, 2016 and 2017).

OBJECTIVE: Continuous antimicrobial resistance surveillance is recommended by Public Health authorities. We up-dated data from the SMART (Study for Monitoring Antimicrobial Resistance Trends) surveillance study in Spain. METHODS: The antimicrobial susceptibility data and extended-spectrum beta-lactamase (ESBL) production in isolates recovered from intra-abdominal (IAI) (n=1,429) and urinary tract (UTI) (n=937) infections during the 2016- 2017 SMART study in 10 Spanish hospitals were analysed. RESULTS: Escherichia coli was the most frequently microorganism isolated (48.3% and 53.7%) followed by Klebsiella spp. (11.5% and 21.9%) in IAIs and UTIs, respectively. Figures for Pseudomonas aeruginosa were 9.0% and 6.1%, being more frequently recovered from patients with nosocomial infections. Overall, 9.9% (IAI) and 14.0% (UTI) of E. coli, Klebsiella spp. and Proteus mirabilis isolates were ESBL-producers, being Klebsiella pneumoniae (34.5%) from UTI of nosocomial origin the most frequent. ESBL-producers were higher in patients >60 years in both IAIs and UTIs. As in previous years, amikacin (96.3%-100% susceptibility), ertapenem (84.2%-100%) and imipenem (70.3%- 100%) were the most active antimicrobials tested among Enterobacterales species. The activity of amoxicillin-clavulanic, piperacillin-tazobactam, and ciprofloxacin susceptibility was lower, particularly among ESBL-producers. Ertapenem susceptibility (88.9%-100%) was retained in ESBL-E. coli isolates that were resistant to these antimicrobials but decreased (28.6%-100%) in similar isolates of K. pneumoniae. CONCLUSIONS: Continuous antimicrobial resistance surveillance from the SMART study reveals overall maintenance of ESBL-producers in Spain, although with higher presence in isolates from UTIs than from IAIs. Moreover, ertapenem activity was high in E. coli irrespective of ESBL production but decreased in K. pneumoniae, particularly among ESBL-producers.

Use of liposomal amphotericin B in critically ill patients: a retrospective, multicenter, clinical study.

The clinical use of liposomal amphotericin B in 179 patients admitted to 30 medical-surgical intensive Care Units (ICUs) treated with this agent in 2006 was analyzed. Invasive fungal infections were proven, probable and possible in 44%, 16%, and 25% of cases, respectively. Fungi isolated were Candida albicans (38%), non-albicans Candida spp. (15%) and Aspergillus spp. (7%). The mean duration of treatment was 15 days (mean dose 3.7 mg/kg/day). The drug was used as rescue treatment after fluconazole or caspofungin in 47% of patients and as first line in 52% with a satisfactory clinical response in 54% of cases (72.6% with proven infection). Microbiological eradication was achieved in 68% of cases. Adverse events occurred in 51 patients but were severe in only 4. The use of liposomal amphotericin B both as first line and rescue treatment and mainly for proven invasive fungal infection was associated with a high rate of satisfactory clinical response.

[Susceptibility of 36 Helicobacter pylori clinical isolates to four first-line antibiotics and virulence factors]. / Sensibilidad de 36 aislamientos de Helicobacter pylori a cuatro antibióticos de primera línea y características de virulencia.

Helicobacter pylori possess various virulence factors, including cagA and vacA genes, that are associated with more aggressive symptoms such as bleed-ing ulcer and gastric cancer. Although there are different treatment regimens, there is still a failure rate of up to 20% due to antibiotic resistance, among other causes. In our country resistance to metronidazole and clarithromycin is increasing, especially in children, although they are still susceptible to amoxicillin and tetracycline. In order to determine the susceptibility pattern to these antibiotics 36 H. pylori clinical isolates were studied. MIC was determined by agar diffusion and agar dilution, and vacA and cagA genes were detected by conventional PCR. All isolates were susceptible to amoxicillin and tetracycline. Resistance to metronidazole by diffusion or dilution tests was 35.7% and 36.1%, respectively, and to clarithromycin, 21.4% and 22.3%, respectively. There was one strain that showed intermediate resistance to clarithromycin (MIC 0.38 mg/l), using agar diffusion, and that was included among the resistant strains. Three discrepancies were observed between the diffusion and dilution methods. The vacA s1 allele was detected in 17.2% of the strains, and vacA s2 in 82.8%; 51.7% of the total were cagA+. In conclusion, all strains tested in our study were susceptible to amoxicillin and tetracycline, allowing them to be considered as first-line antibiotics, while clarithromycin and metronidazole maintain a slight increase in their resistance level. The cagA+ strains were detected in expected quantities, while the s1 allele of the vacA gene was detected in lower quantities.

Sensibilidad de 36 aislamientos de Helicobacter pylori a cuatro antibióticos de primera línea y características de virulencia / Susceptibility of 36 Helicobacter pylori clinical isolates

Helicobacter pylori posee diversos factores de patogenicidad, entre los que se encuentran los genes vacA y cagA, que se han asociado a síntomas más graves. Las diferentes pautas de tratamiento tienen fallos de erradicación de hasta el 20% debido, entre otras causas, al desarrollo de resistencia a los antibióticos. En nuestro medio está aumentando la resistencia de H. pylori al metronidazol y la claritromicina, especialmente en los niños, aunque mantiene su sensibilidad a la amoxicilina y la tetraciclina. Para conocer el patrón de sensibilidad a estos antibióticos se estudiaron 36 aislamientos clínicos de H. pylori. Se determinó la CMI por difusión y dilución en agar, y la detección de los genes vacA y cagA se realizó por PCR convencional. Todas las cepas fueron sensibles a la amoxicilina y la tetraciclina. La resistencia al metronidazol por difusión y por dilución fue del 35,7% y el 36,1%, y a la claritromicina del 21,4% y el 22,3%, respectivamente. Hubo una cepa con resistencia intermedia a la claritromicina (CMI de 0,38 mg/l) por el método de difusión en agar, que se incluyó entre las cepas resistentes. Se observaron tres discrepancias entre los dos métodos de sensibilidad. El alelo s1 del gen vacA se detectó en el 17,2% de las cepas y el alelo s2 en el 82,8%. El 51,7% de ellas presentaban el gen cagA. Por lo tanto, todas las cepas probadas fueron sensibles a la amoxicilina y la tetraciclina, pudiendo considerar a estos antibióticos como de primera línea, mientras se mantiene un ligero aumento en los valores de resistencia a claritromicina y metronidazol. El gen cagA se presentó en los porcentajes esperados, mientras que el alelo s1 del gen vacA fue detectado en una proporción menor

Helicobacter pylori possess various virulence factors, including cagA and vacA genes, that are associated with more aggressive symptoms such as bleeding ulcer and gastric cancer. Although there are different treatment regimens, there is still a failure rate of up to 20% due to antibiotic resistance, among other causes. In our country resistance to metronidazole and clarithromycin is increasing, especially in children, although they are still susceptible to amoxicillin and tetracycline. In order to determine the susceptibility pattern to these antibiotics 36 H. pylori clinical isolates were studied. MIC was determined by agar diffusion and agar dilution, and vacA and cagA genes were detected by conventional PCR. All isolates were susceptible to amoxicillin and tetracycline. Resistance to metronidazole by diffusion or dilution tests was 35.7% and 36.1%, respectively, and to clarithromycin, 21.4% and 22.3%, respectively. There was one strain that showed intermediate resistance to clarithromycin (MIC 0.38 mg/l), using agar diffusion, and that was included among the resistant strains. Three discrepancies were observed between the diffusion and dilution methods. The vacA s1 allele was detected in 17.2% of the strains, and vacA s2 in 82.8%; 51.7% of the total were cagA+. In conclusion, all strains tested in our study were susceptible to amoxicillin and tetracycline, allowing them to be considered as first-line antibiotics, while clarithromycin and metronidazole maintain a slight increase in their resistance level. The cagA+ strains were detected in expected quantities, while the s1 allele of the vacA gene was detected in lower quantities

Actividad in vitro de la furazolidona y la nitrofurantoína en aislamientos clínicos de Helicobacter pylori y estudio de la tasa de mutación / In vitro activity of furazolidone and nitrofurantoin in Helicobacter pylori clinical isolates and study of mutation rate

Claritromicina, amoxicilina, tetracilina y metronidazol son los antimicrobianos más utilizados en las infecciones por Helicobacter pylori. La resistenciaa la tetraciclina y a la amoxicilina es poco frecuente, pero la resistencia a la claritromicina y al metronidazol depende de la poblaciónestudiada y es un importante marcador de fallo terapéutico. El objetivo de este estudio era determinar la actividad in vitro de furazolidonay nitrofurantoína en 164 aislamientos clínicos de H. pylori mediante dilución en agar, y determinar la tasa de mutación espontánea enocho cepas. La resistencia al metronidazol fue del 23,77% (IC95%: 18,96-29,14) y a la claritromicina del 16,78% (IC95%: 12,64-21,62);además, un 1,4% (IC95%: 0,38-3,54) mostraron resistencia intermedia a la claritromicina. Todas las cepas fueron sensibles a la amoxicilina ya la tetraciclina. El porcentaje de resistencia a la furazolidona y la nitrofurantoína fue del 1,82% (IC95%: 0,37-5,25) y el 0,6% (IC95%: 0-3,35),respectivamente. Las tres cepas resistentes a la furazolidona fueron sensibles a la nitrofurantoína (CMI = 4 mg/l para furazolidona y 2 mg/l paranitrofurantoína), y la única cepa resistente a la nitrofurantoína fue sensible a la furazolidona (CMI = 4 mg/l para nitrofurantoína y 1 mg/l parafurazolidona). Estas cuatro cepas eran resistentes al metronidazol (CMI = 16 mg/l). No se detectó mutación espontánea que confiriera resistenciaa furazolidona ni a nitrofurantoína en las ocho cepas de H. pylori estudiadas; sin embargo, sí se detectaron mutantes resistentes ametronidazol en las ocho cepas, con una tasa de mutación de 7,4 × 10-10 a 9,4 × 10-10. La furazolidona y la nitrofurantoína mostraron una excelenteactividad in vitro, lo que puede ratificar la utilidad de la furazolidona como antimicrobiano de segunda línea cuando ha fallado el tratamiento,o como tratamiento de primera línea en poblaciones con pocos recursos económicos

Clarithromycin, amoxicillin, tetracycline and metronidazole are the most frequently used antimicrobials for Helicobacter pylori infection treatment.While tetracycline and amoxicillin resistance are rare, clarithromycin and metronidazole resistance vary in different populations andare considered factors for treatment failure. The aim of this study was to determine the in vitro activity of furazolidone and nitrofurantoinin 164 H. pylori clinical isolates by agar dilution and to determine the spontaneous mutation rate. Metronidazole and clarithromycin resistancewere 23.77% (CI95%: 18.96-29.14) and 16.78% (CI95%: 12.64-21.62), respectively; moreover, 1.4% (CI95%: 0.38-3.54) were intermediateto clarithromycin. All the isolates were susceptible to amoxicillin and tetracycline. Furazolidone and nitrofurantoin resistancerates were 1.82% (CI95%: 0.37-5.25) and 0.6% (CI95%: 0-3.35), respectively. The three furazolidone-resistant strains were nitrofurantoinesusceptible(MIC 4 mg/l for furazolidone and 2 mg/l for nitrofurantoin) and the nitrofurantoin-resistant strains were furazolidone-susceptible(MIC 4 mg/l for nitrofurantoin and 1 mg/l for furazolidone). These four strains were metronidazole-resistant (MIC 16 mg/l). Furazolidoneor nitrofurantoin spontaneous mutants were not detected in the eight H. pylori strains tested. However, mutants with resistance to metronidazolewere found with all the strains with a mutation rate of 7.4 × 10-10 to 9.4 × 10-10. Furazolidone and nitrofurantoin showed an excellentin vitro activity against the H. pylori clinical isolates included herein, supporting the usefulness of furazolidone as second-line antimicrobialafter treatment failure or as first-line therapy in populations with low economical resources

Clinical use and tolerability of voriconazole in the treatment of fungal infections in critically ill patients.

The clinical use and tolerability of voriconazole in daily practice for the treatment of fungal infection in critically ill patients was assessed in an open-label, non-comparative, observational study. All patients admitted to medical-surgical Intensive Care Units (ICUs) of 21 hospitals in Spain between February 2003 and January 2004, who were treated with voriconazole because of known or suspected fungal infection, were included. A total of 130 patients received voriconazole (6.2 cases per ICU). Fungal infections were classified as proven in 50 patients (38.5%) and probable in 38 (29.2%). The etiology was established in 103 patients, with Candida albicans and Aspergillus fumigatus as the most common pathogens. In 98 (75.4%) patients, voriconazole was initially administered intravenously. Fifty-three patients (40.8%) were treated with other antifungal agents prior to the use of voriconazole. In 21 patients (16.2%), voriconazole was administered in combination with other antifungal drugs. Clinical responses were cure and improvement in 65 (50%) patients, failure in 26 (20%), and undetermined in 39 (30%). The crude ICU mortality was 49.2%. According to multivariate analysis, ICU mortality was significantly associated with pneumonia (OR = 3.30, 95% CI 1.07-10.18) and infection caused by Aspergillus spp. (OR = 3.70, 95% Cl 1.12-12.28), whereas eradication of the causative microorganisms was inversely associated (OR = 0.13, 95% CI 0.05-0.34). Adverse events were recorded in 65 patients, probably or possibly related to the study drug in 21. In conclusion, in critically ill patients admitted to the ICU, the use of voriconazole was affective in 50% of cases. The drug was well tolerated and discontinuation of voriconazole treatment due to adverse events was not necessary.

[In vitro activity of furazolidone and nitrofurantoin in Helicobacter pylori clinical isolates and study of mutation rate]. / Actividad in vitro de la furazolidona y la nitrofurantoína en aislamientos clínicos de Helicobacter pylori y estudio de la tasa de mutación.

Clarithromycin, amoxicillin, tetracycline and metronidazole are the most frequently used antimicrobials for Helicobacter pylori infection treatment. While tetracycline and amoxicillin resistance are rare, clarithromycin and metronidazole resistance vary in different populations and are considered factors for treatment failure. The aim of this study was to determine the in vitro activity of furazolidone and nitrofurantoin in 164 H. pylori clinical isolates by agar dilution and to determine the spontaneous mutation rate. Metronidazole and clarithromycin resistance were 23.77% (CI95%: 18.96-29.14) and 16.78% (CI95%: 12.64-21.62), respectively; moreover, 1.4% (CI95%: 0.38-3.54) were intermediate to clarithromycin. All the isolates were susceptible to amoxicillin and tetracycline. Furazolidone and nitrofurantoin resistance rates were 1.82% (CI95%: 0.37-5.25) and 0.6% (CI95%: 0-3.35), respectively. The three furazolidone-resistant strains were nitrofurantoine-susceptible (MIC 4 mg/l for furazolidone and 2 mg/l for nitrofurantoin) and the nitrofurantoin-resistant strains were furazolidone-susceptible (MIC 4 mg/l for nitrofurantoin and 1 mg/l for furazolidone). These four strains were metronidazole-resistant (MIC 16 mg/l). Furazolidone or nitrofurantoin spontaneous mutants were not detected in the eight H. pylori strains tested. However, mutants with resistance to metronidazole were found with all the strains with a mutation rate of 7.4 x 10(-10) to 9.4 x 10(-10). Furazolidone and nitrofurantoin showed an excellent in vitro activity against the H. pylori clinical isolates included herein, supporting the usefulness of furazolidone as second-line antimicrobial after treatment failure or as first-line therapy in populations with low economical resources.