A retrospective study of antibiotic resistance patterns of bacterial pathogens isolated from patients in two Lebanese hospitals for two consecutive years (2018 and 2019)

Background: Misuse of antibiotics is the leading factor promoting emergence of bacterial resistance, a situation that has become a serious public health challenge. Among the leading bacteria that have developed resistance to antibiotics are Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa, which have caused infections in patients, resulting in considerable mortality. The objective of this retrospective study was to assess antibiotic resistance rates of bacterial pathogens isolated from clinical specimens in two Lebanese hospitals between the years 2018 and 2019. Methodology: Bacteria isolated from routine clinical specimens collected from hospitalized patients in two hospitals, Haroun and Bekaa, in Lebanon for 2018 and 2019, were analyzed. Bacteria isolation and identification were carried out at the laboratory of each hospital using conventional microbiological methods. Antimicrobial susceptibility testings (AST) of each bacterial isolate to antibiotics were performed by the disc diffusion test and interpreted using EUCAST, CLSI or WHO/AST guidelines. Comparisons of the mean resistance rates of each isolate to individual antibiotics by year of isolation were done using the Z-test and p< 0.05 was considered statistically significant. Results: There were a total of 1698 bacteria isolates recovered from hospitalized patients in the two hospitals for 2018 and 2019, of which 87.5% were Gram-negative and 12.5% were Gram-positive bacteria. The most frequent among the Gram-negative isolates was E. coli (66.1%) followed by P. aeruginosa (13.3%), K. pneumoniae (7.7%), Proteus mirabilis (6.7%) and Enterobacter spp (6.3%), while coagulase positive staphylococci CoPS (68.4%) and E. faecalis (31.6%) were the two Gram positive isolates. Of the Gram-negative isolates over the two-year period, 72.2% of E. coli and 76.3% of K. pneumoniae were resistant to ceftazidime, 93% of P. mirabilis to colistin, and 98% of Enterobacter to cefoxitin, but low resistance rates were demonstrated by E. coli to imipenem (1%), K. pneumoniae to tigecycline and amikacin (0.9%), P. mirabilis to imipinem (2%), and Enterobacter to amikacin, ertapenem and tigecycline (3%). Resistance of P. aeruginosa varied between 2% to colistin and 24% to levofloxacin. For the Gram-positive bacteria, 79.1% of E. faecalis were resistant to erythromycin while 70% of CoPS were resistant to cefoxitin, but no isolate was resistant (0%) to linezolid, and only 1% to teicoplanin. Except for Enterobacter spp that showed significant increase in resistance rates (by 250%) to piperacillin/tazobactam in 2019 over 2018, resistance rates of other Gram-negative isolates significantly decreased in 2019 compared to 2018 (p<0.05). For the Gram-positive isolates, resistance rates to many antibiotics tested significantly increased (by a factor of 36.5 - 2569%) in 2019 compared to 2018 among E. faecalis isolates in contrast to the rates for CoPS which significantly decreased by 16.7 - 65.7%, except for penicillin G which increased by a factor of 123%. Conclusion: Overuse and misuse of antibiotics, which is possible because of the easy access of the populace to these drugs, is a leading factor contributing to the high antibiotic resistance rates in this study. There is need to promote awareness of antimicrobial resistance in Lebanon among students especially in non-health related majors and enactment of govermental policy that will limit access to antibiotics. Keywords: antibiotic resistance; changing pattern; hospitalized patients; retrospective   French title: Une étude rétrospective des profils de résistance aux antibiotiques de pathogènes bactériens isolés de patients dans deux hôpitaux libanais pendant deux années consécutives (2018 et 2019) Contexte: La mauvaise utilisation des antibiotiques est le principal facteur favorisant l'émergence de la résistance bactérienne, une situation qui est devenue un sérieux défi de santé publique. Parmi les principales bactéries qui ont développé une résistance aux antibiotiques figurent Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae et Pseudomonas aeruginosa, qui ont provoqué des infections chez les patients, entraînant une mortalité considérable. L'objectif de cette étude rétrospective est d'évaluer les taux de résistance aux antibiotiques des pathogènes bactériens isolés à partir d'échantillons cliniques dans deux hôpitaux Libanais entre les années 2018 et 2019. Méthodologie: Les isolats bactériens prélevés sur des patients hospitalisés dans deux hôpitaux, Haroun et Bekaa, au Liban pour 2018 et 2019, ont été analysés. L'isolement et l'identification des bactéries ont été réalisés au laboratoire de chaque hôpital en utilisant des méthodes microbiologiques conventionnelles. Les tests de sensibilité aux antimicrobiens (AST) de chaque isolat bactérien aux antibiotiques ont été réalisés par le test de diffusion sur disque et interprétés selon les directives EUCAST, CLSI ou WHO/AST. Des comparaisons des taux moyens de résistance de chaque isolat à des antibiotiques individuels par année d'isolement ont été effectuées à l'aide du test Z et p<0,05 a été considéré comme statistiquement significatif. Résultats: Il y a eu un total de 1698 isolats de bactéries récupérés de patients hospitalisés dans les deux hôpitaux durant 2018 et 2019, dont 87,5% étaient à Gram négatif et 12,5% étaient des bactéries à Gram positif. Les isolats à Gram négatif les plus fréquents étaient E. coli (66,1%), suivis de P. aeruginosa (13,3%), K. pneumoniae (7,7%), Proteus mirabilis (6,7%) et Enterobacter spp (6,3%), tandis que les staphylocoques à coagulase positive CoPS (68,4%) et E. faecalis (31,6%) étaient les deux isolats Gram positifs. Parmi les isolats à Gram négatif sur la période de deux ans, 72,2% d'E. coli et 76,3% de K. pneumoniae étaient résistants à la ceftazidime, 93% de P. mirabilis à la colistine et 98% d'Enterobacter à la céfoxitine, mais faible les taux de résistance ont été démontrés par E. coli à l'imipénem (1%), K. pneumoniae à la tigécycline et à l'amikacine (0,9%), P. mirabilis à l'imipinem (2%) et Enterobacter à l'amikacine, à l'ertapénem et à la tigécycline (3%). La résistance de P. aeruginosa variait entre 2% à la colistine et 24% à la lévofloxacine. Pour les bactéries Gram positif, 79,1% des E. faecalis étaient résistantes à l'érythromycine tandis que 70% des CoPS étaient résistantes au céfoxitin, mais aucun isolat n'était résistant (0%) au linézolide et seulement 1% à la teicoplanine. À l'exception d'Enterobacter spp qui ont montré une augmentation significative des taux de résistance (de 250%) à la  pipéracilline/tazobactam en 2019 par rapport à 2018, les taux de résistance des autres isolats à Gram négatif ont considérablement  diminué en 2019 par rapport à 2018 (p<0,05). Pour les isolats Gram-positifs, les taux de résistance à de nombreux antibiotiques testés ont augmenté de manière significative (d'un facteur de 36,5 à 2569%) en 2019 par rapport à 2018 parmi les isolats d'E. faecalis contrairement aux taux de CoPS qui ont significativement diminué de 16,7 à 65,7%, à l'exception de la pénicilline G qui a augmenté d'un facteur de 123%. Conclusion: la surutilisation et la mauvaise utilisation des antibiotiques, ce qui est possible en raison de l'accès facile de la population à ces médicaments, est l'un des principaux facteurs contribuant aux taux élevés de résistance aux antibiotiques dans cette étude. Il est nécessaire de promouvoir la sensibilisation à la résistance aux antimicrobiens au Liban parmi les étudiants, en particulier dans les spécialisations non liées à la santé, et la promulgation d'une politique gouvernementale qui limitera l'accès non contrôlé aux antibiotiques. Mots clés: résistance aux antibiotiques; changement de modèle; patients hospitalisés; rétrospectiv

Pharmacokinetics of epinephrine in patients with septic shock: modelization and interaction with endogenous neurohormonal status

Introduction In septic patients, an unpredictable response to epinephrine may be due to pharmacodynamic factors or to non-linear pharmacokinetics. The purpose of this study was to investigate the pharmacokinetics of epinephrine and its determinants in patients with septic shock. Methods Thirty-eight consecutive adult patients with septic shock were prospectively recruited immediately before epinephrine infusion. A baseline blood sample (C0) was taken to assess endogenous epinephrine, norepinephrine, renin, aldosterone, and plasma cortisol levels before epinephrine infusion. At a fixed cumulative epinephrine dose adjusted to body weight and under steady-state infusion, a second blood sample (C1) was taken to assess epinephrine and norepinephrine concentrations. Data were analyzed using the nonlinear mixed effect modeling software program NONMEM. Results Plasma epinephrine concentrations ranged from 4.4 to 540 nmol/L at steady-state infusion (range 0.1 to 7 mg/hr; 0.026 to 1.67 μg/kg/min). A one-compartment model adequately described the data. Only body weight (BW) and New Simplified Acute Physiologic Score (SAPSII) at intensive care unit admission significantly influenced epinephrine clearance: CL (L/hr) = 127 × (BW/70)0.60 × (SAPS II/50)-0.67. The corresponding half-life was 3.5 minutes. Endogenous norepinephrine plasma concentration significantly decreased during epinephrine infusion (median (range) 8.8 (1 – 56.7) at C0 vs. 4.5 (0.3 – 38.9) nmol/L at C1, P < 0.001). Conclusions Epinephrine pharmacokinetics is linear in septic shock patients, without any saturation at high doses. Basal neurohormonal status does not influence epinephrine pharmacokinetics. Exogenous epinephrine may alter the endogenous norepinephrine metabolism in septic patients

Impact of Morbidity and Mortality Conferences on Analysis of Mortality and Critical Events in Intensive Care Practice

Background Morbidity and mortality conferences are a tool for evaluating care management, but they lack a precise format for practice in intensive care units.Objectives To evaluate the feasibility and usefulness of regular morbidity and mortality conferences specific to intensive care units for improving quality of care and patient safety. Methods For 1 year, a prospective study was conducted in an 18-bed intensive care unit. Events analyzed included deaths in the unit and 4 adverse events (unexpected cardiac arrest, unplanned extubation, reintubation within 24–48 hours after planned extubation, and readmission to the unit within 48 hours after discharge) considered potentially preventable in optimal intensive care practice. During conferences, events were collectively analyzed with the help of an external auditor to determine their severity, causality, and preventability. Results During the study period, 260 deaths and 100 adverse events involving 300 patients were analyzed. The adverse events rate was 16.6 per 1000 patient-days. Adverse events occurred more often between noon and 4 pm (P = .001).The conference consensus was that 6.1% of deaths and 36% of adverse events were preventable. Preventable deaths were associated with iatrogenesis (P = .008), human errors (P < .001), and failure of unit management factors or communication (P = .003). Three major recommendations were made concerning standardization of care or prescription and organizational management, and no similar incidents have recurred. Conclusion In addition to their educational value, regular morbidity and mortality conferences formatted for intensive care units are useful for assessing quality of care and patient safety

Ammoniacal nitrogen recovery from swine slurry using a gas-permeable membrane: pH control strategies and feed-to-trapping volume ratio

Gas-permeable membrane (GPM) technology is gaining interest to recover nitrogen from residual effluents due to its effectiveness, simple operation and capacity of producing a nutrient rich product with fertilising value. In this study, a GPM contactor was used at 25 °C to recover total ammoniacal nitrogen (TAN) from swine slurry as a concentrated (NH4)2SO4 solution. Firstly, a synthetic solution was tested on a wide pH range (6–12). Results showed that the ammonia mass transfer constants (Km) increased from 7.9·10−9 to 1.2·10−6 m/s as the pH increased. The reagent consumption to control the pH per mole nitrogen recovered had a minimum at pH 9, which showed a Km value of 3.0·10−7 m/s. Secondly, various pH control strategies were tested using swine slurry, including (i) no pH control, (ii) pH control at 8.5, 9.0 and 10.0, and (iii) an initial spike of the NaOH equivalent to the required to control the pH at 9. The test without pH control reached a TAN recovery of around 60%, which could be an interesting strategy when high nitrogen recoveries or short operating times are not required. The pH control at 9 stood out as the most favourable operating condition due to its high Km and lower reagent consumption. Thirdly, several feed-to-trapping volume ratios ranging from 1:1 to 15:1 were tested using swine slurry at pH 9. These assays revealed that a GPM process with a high feed-to-trapping volume ratio fastens the recovery of 99% of TAN as a high purity (NH4)2SO4 solution containing 40 g N/L

Gestión ambiental de los sistemas agroforestales en el Valle de Paraíba del Sur, Estado de Sao Paulo, Brasil.

En el año de 2011 se analizó el desempeño ambiental de la finca Coruputuba, en Pindamonhangaba, Estado de São Paulo, Brasil. La metodología utilizada fué el sistema APOIA-NovoRural, con 62 indicadores de sustentabilidad en el contexto para el análisis de la implementación de los sistemas agroforestales con Calophyllum braziliense y Acacia mangium. Antes de la implementación de los sistemas agroforestales, la finca estuvo plantada con arroz en el valle y eucalipto en las terrazas. Con el proyecto se logró sustituir 10 ha en el valle y 4 ha de terraza con Calophyllum, especie que ofrece una madera fina. Otra especie que se introdujo en la terraza fue la acacia (50 ha), sustituta del eucalipto. La finca aporta un valor agregado a la gestión dirigida a procesos de recuperación de la viabilidad económica y ambiental mediante el rescate de la vocación agrícola. Se fue reintroducido la Manihot esculenta, Maranta arundinaceae, Colocasia esculenta, Euterpe edulis, Musa sp., Cajanus cajan, y especies forestales en asociación con Calophyllum: Inga sp., Schinnus terebinthifolius, Alchornea triplinervia, Sesbania sp., repartidas entre 159 ha productivas y 50 ha para hábitats naturales de conservación. Las variables como efecto de los sistemas agroforestales estuvieron repartidas en suelos, caracteristicas productivas, apropiación y mejoramiento de las condicones de los trabajadores, aspectos ambientales y socioeconónicos que en conjunto arrojaron indices de desempeño para el sistema APOIA-NovoRural. Se encontraron contribuciones de los sistemas agroforestales para la sustentabilidad, destacándose la calidad del agua con índice (0,94) comparado con (0,85) obtenido en los sedimentos que drenan del cultivo de arroz; valores económicos (0,85) y de ecología del paisaje (0,77). El índice integrado medio, llegó a 0,79 en una escala de 0 a 10, con referencia de 0,70. La Finca Coruputuba estuvo entre los cinco valores más altos de desempeño ambiental de un universo de 178 casos

Comparison of verona integron-borne metallo-beta-lactamase (VIM) variants reveals differences in stability and inhibition profiles

DUZGUN, AZER OZAD/0000-0002-6301-611X; Abboud, Martine I./0000-0003-2141-5988; Brem, Jurgen/0000-0002-0137-3226; McDonough, Michael A/0000-0003-4664-6942; Rydzik, Anna/0000-0003-3158-0493; DUZGUN, AZER OZAD/0000-0002-6301-611X; McDonough, Michael/0000-0003-4664-6942; Schofield, Christopher/0000-0002-0290-6565; SANDALLI, Cemal/0000-0002-1298-3687WOS: 000376490800025PubMed: 26666919Metallo-beta-lactamases (MBLs) are of increasing clinical significance; the development of clinically useful MBL inhibitors is challenged by the rapid evolution of variant MBLs. the Verona integron-borne metallo-beta-lactamase (VIM) enzymes are among the most widely distributed MBLs, with > 40 VIM variants having been reported. We report on the crystallographic analysis of VIM-5 and comparison of biochemical and biophysical properties of VIM-1, VIM-2, VIM-4, VIM-5, and VIM-38. Recombinant VIM variants were produced and purified, and their secondary structure and thermal stabilities were investigated by circular dichroism analyses. Steady-state kinetic analyses with a representative panel of beta-lactam substrates were carried out to compare the catalytic efficiencies of the VIM variants. Furthermore, a set of metalloenzyme inhibitors were screened to compare their effects on the different VIM variants. the results reveal only small variations in the kinetic parameters of the VIM variants but substantial differences in their thermal stabilities and inhibition profiles. Overall, these results support the proposal that protein stability may be a factor in MBL evolution and highlight the importance of screening MBL variants during inhibitor development programs.Rhodes Trust; Scientific and Technology Council of Turkey; Recep Tayyip Erdogan Universitesi Research FundRecep Tayyip Erdogan University [BAP-2013.102.03.13]; Medical Research CouncilMedical Research Council UK (MRC) [MR/L007665/1]; Medical Research Council/Canadian Grant [G1100135]; Biochemical Society Krebs Memorial Award; Medical Research CouncilMedical Research Council UK (MRC) [G1100135, MR/N002679/1] Funding Source: researchfishThe Rhodes Trust provided funding to Anne Makena. Scientific and Technology Council of Turkey provided funding to Cemal Sandalli. Recep Tayyip Erdogan Universitesi Research Fund provided funding to Aysegul Saral, Aysegul C. Cicek, and Cemal Sandalli under grant number BAP-2013.102.03.13. Medical Research Council provided funding to Jurgen Brem, Michael A. McDonough, Anna M. Rydzik, and Christopher J. Schofield under grant number MR/L007665/1. Medical Research Council/Canadian Grant provided funding to Jurgen Brem, Michael A. McDonough, Anna M. Rydzik, and Christopher J. Schofield under grant number G1100135. Biochemical Society Krebs Memorial Award provided funding to Martine I. Abboud

The results of treatment of patients with an acute cholecystitis and perivesical complications

Objective. To improve the quality of diagnosis and results of treatment in patients, suffering an acute cholecystitis, complicated by formation of perivesicular infiltrate, abscess and Mirizzi’s syndrome. Materials and methods. Results of diagnosis and surgical treatment of 694 patients, suffering an acute cholecystitis, ageing 38 - 87 yrs old, admitted to the clinic in 2010 - 2019 yrs, were analyzed. The examination have included general clinical investigation, biochemical investigations of the blood, ultrasonographic investigation of a gallbladder and extrahepatic biliary ducts, and in accordance to certain indications – computer tomography, papilloscopy and endoscopic retrograde cholangiopancreaticography. Results. Of 694 patients, suffering an acute cholecystitis in 541 (78.0%) perivesical complications were revealed. In 215 (31.0%) patients perivesical infiltrate was formed, while in 76 (11.0%) – perivesical abscess. In 250 (36.0%) patients an acute cholecystitis have developed on background of obturation jaundice, caused by choledocholithiasis in 138 patients, while in 98 patients Mirizzi’s syndrome Type I was diagnosed, and in 14 - Mirizzi’s syndrome Type II. Of 215 patients with an acute cholecystitis and perivesical infiltrate in 84 laparoscopic cholecystectomy was performed after course of antibacterial therapy, while in 131 patients – open cholecystectomy. In all 76 patients with perivesical abscess open cholecystectomy was performed. Of 138 patients, suffering obturation jaundice on background of choledocholithiasis in 82 endoscopic retrograde cholangiopancreaticography with simultaneous lithoextraction and subsequent laparoscopic cholecystectomy was conducted. In 56 patients naso-biliary drainage was installed and was held in place till calculi from common biliary duct have gone away and subsequent laparoscopic cholecystectomy performed. Of 98 patients with an acute cholecystitis and confirmed Mirizzi’s syndrome Type I in 95 laparoscopic cholecystectomy was performed, while in 3 – the open one. Of 14 patients, suffering Mirizzi’s syndrome Type II, in 10 open operation was done with sanation of biliary ducts and plasty of a common biliary duct defect, while in 4 – laparoscopic cholecystocholedocholithotomy with restoration of the bile physiological passage. Conclusion. In 78.0% patients with an acute cholecystitis perivesical complications were diagnosed. Of 531 patients with perivesical infiltrate, choledocholithiasis and Mirizzi’s syndrome in 321 (60.5%) laparoscopic operations on biliary ducts were accomplished. Open laparotomy was performed in 210 (39.5%) patients. In all the patients, suffering Mirizzi’s syndrome of both Types, physiologic passage of bile was preserved

Impact of energy deficit calculated by a predictive method on outcome in medical patients requiring prolonged acute mechanical ventilation

To assess energy balance in very sick medical patients requiring prolonged acute mechanical ventilation and its possible impact on outcome, we conducted an observational study of the first 14 d of intensive care unit (ICU) stay in thirty-eight consecutive adult patients intubated at least 7 d. Exclusive enteral nutrition (EN) was started within 24 h of ICU admission and progressively increased, in absence of gastrointestinal intolerance, to the recommended energy of 125·5 kJ/kg per d. Calculated energy balance was defined as energy delivered − resting energy expenditure estimated by a predictive method based on static and dynamic biometric parameters. Mean energy balance was − 5439 (sem 222) kJ per d. EN was interrupted 23 % of the time and situations limiting feeding administration reached 64 % of survey time. ICU mortality was 72 %. Non-survivors had higher mean energy deficit than ICU survivors (P = 0·004). Multivariate analysis identified mean energy deficit as independently associated with ICU death (P = 0·02). Higher ICU mortality was observed with higher energy deficit (P = 0·003 comparing quartiles). Using receiver operating characteristic curve analysis, the best deficit threshold for predicting ICU mortality was 5021 kJ per d. Kaplan–Meier analysis showed that patients with mean energy deficit ≧5021 kJ per d had a higher ICU mortality rate than patients with lower mean energy deficit after the 14th ICU day (P = 0·01). The study suggests that large negative energy balance seems to be an independent determinant of ICU mortality in a very sick medical population requiring prolonged acute mechanical ventilation, especially when energy deficit exceeds 5021 kJ per d

Investigation of CO, C2H6 and aerosols in a boreal fire plume over eastern Canada during BORTAS 2011 using ground- and satellite-based observations, and model simulations

We present the results of total column measurements of CO, C2H6 and fine mode aerosol optical depth (AOD) during the "Quantifying the impact of BOReal forest fires on Tropospheric oxidants over the Atlantic using Aircraft and Satellites" (BORTAS-B) campaign over Eastern Canada. Ground-based observations, using Fourier transform spectrometers (FTSs) and sun photometers, were carried out in July and August 2011. These measurements were taken in Halifax, Nova Scotia, which is an ideal location to monitor the outflow of boreal fires from North America, and also in Toronto, Ontario. Measurements of fine mode AOD enhancements were highly correlated with enhancements in coincident trace gas (CO and C2H6) observations between 19 and 21 July 2011, which is typical for a smoke plume event. In this paper, we focus on the identification of the origin and the transport of this smoke plume. We use back-trajectories calculated by the Canadian Meteorological Centre as well as FLEXPART forward-trajectories to demonstrate that the enhanced CO, C2H6 and fine mode AOD seen near Halifax and Toronto originated from forest fires in Northwestern Ontario that occurred between 17 and 19 July 2011. In addition, total column measurements of CO from the satellite-borne Infrared Atmospheric Sounding Interferometer (IASI) have been used to trace the smoke plume and to confirm the origin of the CO enhancement. Furthermore, the emission ratio (ERC2H6/CO) and the emission factor (EFC2H6) of C2H6 (with respect to the CO emission) were estimated from these ground-based observations. These C2H6 emission results from boreal fires in Northwestern Ontario agree well with C2H6 emission measurements from other boreal regions, and are relatively high compared to fires from other geographical regions. The ground-based CO and C2H6 observations were compared with outputs from the 3-D global chemical transport model GEOS-Chem, using the Fire Locating And Monitoring of Burning Emissions (FLAMBE) inventory. Agreement within the stated measurement uncertainty was found for the magnitude of the enhancement of the total columns of CO (~3%) and C2H6 (~8%) between the measured and modelled results. However, there is a small shift in time (of approximately 6 h) of arrival of the plume over Halifax between the results

Cymantrene–Triazole "Click" Products: Structural Characterization and Electrochemical Properties

We report the first known examples of triazole-derivatized cymantrene complexes (η5-[4-substituted triazol-1-yl]cyclopentadienyl)tricarbonylmanganese(I), obtained via a “click” chemical synthesis, bearing a phenyl, 3-aminophenyl, or 4-aminophenyl moiety at the 4-position of the triazole ring. Structural characterization data using multinuclear NMR, UV–vis, ATR-IR, and mass spectrometric methods are provided, as well as crystallographic data for (η5-[4-phenyltriazol-1-yl]cyclopentadienyl)tricarbonylmanganese(I) and (η5-[4-(3-aminophenyl)triazol-1-yl]cyclopentadienyl)tricarbonylmanganese(I). Cyclic voltammetric characterization of the redox behavior of each of the three cymantrene–triazole complexes is presented together with digital simulations, in situ infrared spectroelectrochemistry, and DFT calculations to extract the associated kinetic and thermodynamic parameters. The trypanocidal activity of each cymantrene–triazole complex is also examined, and these complexes are found to be more active than cymantrene alone