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PubMed1996

Neurotoxicity of carbapenem antibacterials.

Similar to other beta-lactam antibacterials, carbapenems have a neurotoxic potential that seems to be higher than that of the penicillins and cephalosporins. Seizures have been reported in several large studies of patients treated with imipenem/cilastatin. However, it seems clear that the main factor increasing the risk of neurotoxicity with imipenem/cilastatin is administration of excessive dosages relative to bodyweight and/or renal function. If the manufacturer's dosage recommendations are followed, the risk of seizures in patients receiving this combination is minimal. With meropenem, a newly registered carbapenem, the safety margin with respect to neurotoxic reactions has been increased compared with imipenem and meropenem can be used at higher doses than imipenem/cilastatin. Since the neurotoxicity of beta-lactam antibacterials seems to be caused by an interaction with gamma-aminobutyric acid (GABA) receptors, other drugs with a similar mechanism of action, such as fluoroquinolone antibacterials, should be used with caution when combined with carbapenems.

Animals↗

PubMed1999

[Evidence-based medicine, health costs and treatment of intra-abdominal infection].

BACKGROUND: Anti-infectious drugs are among the most-prescribed medications in the community, in 1997 being more than 9% of all drugs prescribed by the Spanish National Health System. In the particular case of the treatment of patients with moderate or severe intra-abdominal infection, economic aspects are important. Antimicrobial therapy is responsible for as much as 50% of the drug budget in some Spanish hospitals. On the other hand, as more options become available for the treatment of intra-abdominal infection, it is important to know their clinical and economic consequences. Imipenem/cilastatin (IC) is a broad-spectrum beta-lactam antibiotic that has demonstrated its effectiveness in the treatment of nosocomial and community-acquired bacterial infections. OBJECTIVE: The objective of this study was to determine if IC has a favorable cost-effectiveness relation compared to other antibiotic therapies for the treatment of intra-abdominal infections. METHODS: A cost-effectiveness analysis was made based on retrospective information on the treatment of patients over 18 with clinical suspicion of moderate-to-severe intra-abdominal infection. Health-care results were measured in natural health units (percentage of clinically favorable cases) in a systematic review of the literature. Direct health-care costs associated with the treatments compared were calculated. The other options studied, apart from IC, included the most common and least expensive option (a combination of an aminoglycoside and an anaerobicide [AA]) and an antibiotic from the same family as IC, meropenem (M). RESULTS: The results, in terms of the percentage of patients with clinically favorable results, showed that the effectiveness of IC was equivalent to that of M (95.2% vs. 96.4%) and the AA association (88.0% vs. 86.6%). Analysis of cost minimization showed that the total cost per patient treated with the IC and M options was similar, but that the lower price of IC slightly reduced the total cost per patient treated (ptas. 455,320 IC and ptas. 483,404 M). In the comparison of IC and AA, the higher price of IC was compensated for by the lower cost associated with the duration of hospitalization in patients treated with IC (total cost per patients treated ptas. 844,678 IC and ptas. 1,009,180 AA). CONCLUSIONS: The results of the meta-analysis showed that imipenem/cilastatin was highly effective (more than 90% clinically favorable results) and that it can be considered a minimum equivalent to meropenem and to the combination of an aminoglycoside and anaerobicide for the treatment of patients with moderate or severe intra-abdominal infection. Given the equivalence in effectiveness of the options studied, analysis of cost minimization was used to study their relative effectiveness. This analysis showed that IC was accompanied by lower costs per patient than M and AA. The most relevant variables in the study of the efficiency of the treatment of intra-abdominal infections were, in conditions of equivalent effectiveness, days of hospitalization (and associated costs) and drug price.

Abdomen↗

PubMed1999

[In vitro antibacterial activities of carbapenems against clinical isolates].

Antibacterial activities of four carbapenems, imipenem, panipenem, meropenem, and biapenem, were determined using 353 strains belonging to 18 bacterial species which were isolated from clinical materials at Ehime University Hospital. The MIC values of these carbapenems against MRSA were widely distributed between 0.1 and 100 micrograms/ml, and MIC90 values of these 4 carbapenems were 25-50 micrograms/ml. Any of these carbapenems prevented the bacterial growth of enterobacteriaceae of 8 bacterial species excluding S. macrescens at concentrations of 1 microgram/ml or less. The MIC values against P. aeruginosa showed relatively wide distribution, being 0.39-25 micrograms/ml for imipenem, 0.2-25 micrograms/ml for panipenem, 0.1-12.5 micrograms/ml for meropenem, and 0.2-12.5 micrograms/ml for biapenem. From those results, it was confirmed that any of the carbapenems tested had a wide antibacterial spectrum and strong antibacterial activities.

Bacteria↗

PubMed1999

[In vitro activity of biapenem (BIPM) against clinically isolated respiratory pathogens in 1996-1998].

The in vitro antibacterial activity of biapenem (BIPM), a new carbapenem antibiotic, was compared with those of imipenem (IPM), panipenem (PAPM), meropenem (MEPM), ceftazidime (CAZ) and piperacillin (PIPC) against 280 isolates of 9 respiratory pathogens. The MIC90s of biapenem (BIPM) for methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), Streptococcus pneumoniae, Moraxella catarrhalis, Pseudomonas aeruginosa, and Haemophilus influenzae were 0.12, 32, 0.25, 0.06, 4 and 8 micrograms/ml, respectively. In comparison with other antibiotics, the activity of biapenem (BIPM) for P. aeruginosa was as potent as meropenem (MEPM), but for H. influenzae it was slightly less than those of other antibiotics, and for other respiratory pathogens it was as potent as those of other antibiotics. The MIC90s of biapenem (BIPM) for Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae and Serratia marcescens were 0.06, 1, 1, 0.5 microgram/ml, respectively, and which were equal to or somewhat lower than those of other antibiotics. Biapenem (BIPM) showed strong activity against Gram-positive and Gram-negative pathogens, especially P. aeruginosa in general. Based on these results, biapenem (BIPM) is seemed to be highly useful antibiotic for the treatment of respiratory infections with several organism.

Bacteria↗

PubMed2002

[Extended-spectrum beta-lactamase detection in Enterobacteriaceae and antibiotic susceptibility analysis].

OBJECTIVE: To detect the extended-spectrum beta-lactamases (ESBLs) in family Enterobacteriaceae and analyze the antibiotic susceptibility of those ESBLs-producing strains. METHODS: ESBLs were determined by the double-disk confirmatory test and 8 antibiotic susceptibilities were tested with the disk disffusion method in those strains producing ESBLs. RESULTS: Forty-seven ESBLs-producing strains comprised of 25 of E. coli, 14 of K. pneumoniae, 5 of E. cloacae, 1 of K. oxytoca, 1 of K. rhinoscleromatis, and 1 of S. liquefaciens. The susceptibility rates of those strains were: 100% for imipenem and meropenem, 89.4% for piperacillin/tazobactam, 72.4% for cefoxitin and 65.9% for cefotetan. CONCLUSION: E. coli and K. pneumoniae are the prime strains producing ESBLs in Enterobacteriaceae. Imipenem and meropenem are the best drugs to deal with those ESBLs-producing strains. Piperacillin/tazobactam is better than cephamycins and other beta-lactama/beta-lactamase inhibitor combination.

Anti-Bacterial Agents↗

PubMed2004

Appropriate use of the carbapenems.

The carbapenems are a group of broad-spectrum beta-lactam antibiotic agents of which there are three parenteral preparations currently available in South Africa, namely imimpenem/cilastatin, meropenem and ertapenem. Owing to the fact that imipenem/cilastatin and meropenem have a broad spectrum of activity that includes Pseudomonas and Acinetobacter species, they are ideal antibiotics for treatment of severe nosocomial infections. In contrast, ertapenem has limited in vitro activity against the latter non-fermentative gram-negative bacteria and is therefore more suitable for the treatment of certain severe community-acquired infections. This statement arises out of concerns about the general abuse of antibiotics such as the carbapenems, with the primary intention of highlighting the appropriate use of these agents.

Anti-Bacterial Agents↗

PubMed2004

[Investigation of the in-vitro effectiveness of ertapenem against Pseudomonas aeruginosa strains isolated from intensive care unit patients].

Pseudomonas aeruginosa is one of the important cause of infections in intensive care unit (ICU) patients. The aim of this study was to investigate the effectiveness of ertapenem prior to its use in Turkey, against multiple-resistant P. aeruginosa strains isolated from ICUs. Susceptibility tests were performed by using Kirby-Bauer disk diffusion method and MicroScan MERCH MIC 8 panel (MicroScan 96, Dade Behring, USA). While the resistance rates of ertapenem, imipenem and meropenem were 59.2%, 50% and 48.1% by disk diffusion method, they were 57.4%, 46.2% and 42.5% by MicroScan, respectively. Ertapenem was found less effective against multiple-resistant P. aeruginosa isolates by both of the methods when compared with imipenem and meropenem. Piperacillin/tazobactam was detected as the most effective agent against these isolates by both of the methods. As a result, although carbapenems are frequently used for infections caused by P. aeruginosa, ertapenem, which is a new carbapenem, is not effective as much as the others. In case of confirmation of our results by larger scale studies, the empiric treatment of ICU infections caused by P. aeruginosa with ertapenem, should be carefully evaluated.

Anti-Bacterial Agents↗

PubMed2005

Pneumococci: drug susceptibilities and preliminary epidemiological studies by penicillin binding protein genotyping.

A collection of 307 pneumococcal isolates form 84 children and 223 adults admitted to Siriraj Hospital were separated into two groups, penicillin-susceptible (PSSP) and penicillin-nonsusceptible (PNSP). Each group was tested for susceptibilities to 12 drugs (cefuroxime, amoxicillin, chloramphenicol, tetracycline, cefotaxime, ceftriaxone, imipenem, meropenem, ciprofloxacin, ofloxacin, erythromycin and co-trimoxazole). PSSP were susceptible to cefuroxime (87.5%), amoxicillin (100%), chloramphenicol (84.7%), tetracycline (45.8%), cefotaxime (99%), ceftriaxone (99%), imipenem (99%), meropenem (100%), ciprofloxacin (76%), ofloxacin (99%), erythromycin (94.8%) and co-trimoxazole (61.5%). PNSP were resistant to most drugs, except for amoxicillin (99%), ofloxacin (99%) and ciprofloxacin (86.3%). Twenty-two pneumococcal isolates belonging to the three most common serotypes (6, 19, 23) were randomly selected for studies of the pbp2b gene with RFLP. There were 7 distinct pbp2b RFLP patterns. RFLP pattern 1 was the most predominant resistant pattern. The RFLP pattern 2 was found only in PSSP.

Adolescent↗

PubMed2006

Clinical experience with three combination regimens for the treatment of high-risk febrile neutropenia.

INTRODUCTION: The objective of this study was to compare the safety and efficacy of ceftazidime (2 g every 8 h), piperacillin/tazobactam (4 g/500 mg every 6 h), and meropenem (1 g every 8 h), when combined with amikacin (15 mg/kg once daily), in the empirical treatment of high-risk febrile neutropenic episodes in patients with haematological malignancy. MATERIALS AND METHODS: A prospective, comparative study designed in the haematology unit of a university hospital in Turkey. RESULTS: A total of 89 febrile episodes in 60 neutropenic patients were treated; 29 febrile episodes in 23 patients with ceftazidime plus amikacin (group 1), 30 episodes in 25 patients with piperacillin/tazobactam plus amikacin (group 2), and 30 episodes in 25 patients with meropenem plus amikacin (group 3). The 3 groups were comparable in terms of age, sex, underlying malignancy, pretherapy neutrophil counts, duration of neutropenia and types of infections. Neutropenia, since the start of fever, persisted for > or =10 days in all of the episodes in the 3 study groups. Nearly all of the episodes were seen in patients with acute leukaemia. In 25.8% (23/89) of the febrile neutropenia episodes, an aetiologic organism was isolated, with gram-negative bacteria being the most commonly isolated. The success without modification rates were 34.5%, 30% and 36.7% for groups 1, 2 and 3, respectively (P >0.05). After modification with a different class of antimicrobial therapy, the response rates increased to 65.5%, 63.3% and 70% for groups 1, 2 and 3, respectively (P >0.05). The mean duration of treatment and the time to defervescence were also comparable in all groups. In all arms, side effects were minimal. CONCLUSIONS: It is concluded that the 3 regimens were equally effective and safe in the empirical treatment of high-risk febrile neutropenic episodes.

Adolescent↗

PubMed2006

[Metallo-beta-lactamase-producing gram-negative rods isolated from inpatients and outpatients, detected using Etest MBL].

The aim of presented study was to detect MBL-positive strains in a group of clinical carbapenem-resistant strains isolated from inpatients and outpatients during last four years. From the beginning of November 2001 to the end of October 2005, one hundred and four strains resistant to carbapenem antibiotics--imipenem and meropenem were cultured from clinical samples obtained from patients of the Infant Jesus Clinical Hospital Centre for Trauma Treatment in Warsaw and from patients of outpatient clinics. Strains were identified and their susceptibility to antibacterial agents was determined in the automatic ATB Expression system (bioMérieux). Resistance to imipenem and meropenem was confirmed with a disc diffusion method. Production of metallo-beta-lactamases (MBL) was examined with the use of Etest MBL (AB Biodisk, Sweden), and extended-spectrum beta-lactamases (ESBL) by means of following procedures: DDST and / or DD (four variants) (Oxoid Ltd., England). MBL-positive strains (36) were cultured in cases of infections in adult patients (35 strains) and in a child (1 strain). Majority of strains belonged to the species P. aeruginosa (27), several strains - to the species P. putida (6) and remaining strains--to P. stutzeri, A. xylosoxidans, and E. cloacae (1 strain of each species). Four strains were producers of MBL-type and ESBL-type beta-lactamases. According to our knowledge and accessible literature described strains (except one paediatric strain) are the first MBL-positive strains isolated from adult hospitalized patients and adult ambulatory patients in Poland. Additionally, MBL-positive E. cloacae strain is probably the first MBL producer isolated in Poland, which belongs to the group of enteric rods. MBL-producing strains of Gram-negative rods, detected by phenotypic Etest MBL method, will be verified with genetic procedures.

Anti-Bacterial Agents↗

PubMed1991

Adjunctive antimicrobials in surgery of soft tissue infections: evaluation of cephalosporins and carbapenems.

The authors report three trials of B-lactams and carbapenems for soft tissue infections treated on a surgical service: 1) cefmetazole versus cefoperazone, n = 44; 2) cefotetan versus cefoxitin, n = 24; and 3) meropenem versus imipenem, n = 44. A total of 138 hospitalized patients were enrolled with 112 meeting evaluability criteria. Four hundred twenty-three isolates were cultured (mean, three/patient) of which 67 per cent were aerobes and 33 per cent anaerobes. Cure rates for each trial were: 1) 93 per cent; 2) 92 per cent; 3) 100 per cent. Failures were caused by resistant organisms (Streptococcus group D, Bacteroides fragilis and Pseudomonas) appearing in incompletely drained infection sites. Three patients receiving meropenem had adverse effects (headache, nausea) and one receiving cefoxitin (truncal rash). Operative drainage and debridement remain the critical elements in therapy. Agents with longer half lives allowing twice daily dosing (cefmetazole and cefotetan) were as effective and less expensive than multiple doses of short-acting agents. The extended spectrum carbapenems are most useful for severe infections or resistant organisms.

Adult↗

PubMed1995

The treatment of pulmonary infection in cystic fibrosis.

The survival of cystic fibrosis patients has improved through an aggressive, multidisciplinary approach to the therapy of pulmonary sepsis. Intravenous antibiotics play a major role in the care of cystic fibrosis patients, even though it is not possible to achieve persistent bacterial eradication due to the complex microbiology and pathology of these patients. The most important pathogen in older patients is Pseudomonas aeruginosa. The increasing incidence of Pseudomonas cepacia, strains of which can be highly resistant to many antibiotics, also represents an important challenge to the efficacy of antibiotic therapy. Choice of appropriate antimicrobial therapy is hampered by the fact that a single patient may harbour several different pseudomonas phenotypes with variable resistance patterns. Carbapenem antibiotics possess a wide range of activity against most Gram-negative and Gram-positive bacteria and are therefore a useful addition to the antimicrobial armamentarium available to the clinician. The new carbapenem meropenem is well tolerated at high doses by both children and adults. Results from a comparative trial against ceftazidime suggests that meropenem has a place in the management of cystic fibrosis.

Adult↗

PubMed1993

[Effect of ciprofloxacin on the phagocytosis of Escherichia coli by human polymorphonuclear leukocytes].

BACKGROUND: Brief exposure of bacteria to high concentrations of some antimicrobials enhanced their susceptibility to phagocytic killing by human polymorphonuclear leucocytes. This effect was defined as Post Antibiotic Leukocyte Enhancement or PALE. In this study we have investigated the effect of prior exposure of E. coli for ten minutes to 0.99 mg/l of ciprofloxacin and 0.40 mg/l of meropenem. METHODS AND RESULTS: The pretreated bacteria were incubated for three hours in a mixture containing leukocytes and leukocytes plus serum (10% v/v). Leukocytes were prepared from blood of healthful volunteers and were extracting with ammonium chloride and differential centrifugation. At one hour intervals, aliquots were taken and added to basic water to dispute leukocytes and spread onto agar plates. Viable bacteria were counted. PALE of ciprofloxacin was higher than meropenem. CONCLUSION: Whether PALE is confirmed, it must be taken into consideration in dosage schedules.

Ciprofloxacin↗

PubMed1995

Outer membrane alterations in Pseudomonas aeruginosa after five-day exposure to quinolones and carbapenems.

A Pseudomonas aeruginosa strain (P.aeruginosa), recently isolated in clinical practice, was tested to evaluate the changes induced in the minimal inhibitory concentration (MIC) values and in the outer membrane (OM) components by a five-day exposure to sub-MIC concentrations of the quinolones ciprofloxacin and PD-131.628 and the carbapenems imipenem and meropenem. The treated strain showed a thirty two-fold increase in MIC values for quinolones and a sixteen-fold increase for carbapenems. The electrophoretic profile of the OM proteins of the strain treated with quinolones showed that ciprofloxacin induces loss of the 47 Kd protein band, whereas PD-131.628 modifies the protein pattern of the strain only after five days of exposure. The carbapenems engendered disappearance of the same protein band. Qualitative lipopolysaccaride (LPS) analysis did not reveal any change after antibiotic treatment of the strain, whereas the 2-keto-3-deoxyoctonic acid (KDO) assay showed considerable reduction in the strain treated with sub-MIC doses of meropenem. It can therefore be safely stated that the D2 protein plays an important though not exclusive role in enhancing strain resistance against the two classes of antibiotics tested in our study.

Anti-Infective Agents↗

PubMed1996

[In vitro and in vivo antibacterial activities of sulopenem, a new penem antibiotic].

The in vitro and in vivo antibacterial activities of sulopenem, a new penem, were evaluated in comparison with imipenem (IPM), meropenem (MEPM), ceftazidime (CAZ) and flomoxef (FMOX). Sulopenem had broad and potent antibacterial spectra against Gram-positive and Gram-negative bacteria, including Enterococcus faecalis, Proteus vulgaris, Morganella morganii, Enterobacter spp. and Citrobacter freundii. Sulopenem showed concentration-dependent bactericidal activities against Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae and Acinetobacter calcoaceticus. Morphological observation using phase-contrast microscope revealed that sulopenem induced spherical cell formation with E. coli and K. pneumoniae at lower concentrations and bacteriolysis at higher concentrations. Therapeutic efficacies of sulopenem against systemic infections in mice were almost equal to those of imipenem against Streptococcus pneumoniae. While its therapeutic efficacies were superior to those of meropenem, ceftazidime and flomoxef against S. aureus and S. pneumoniae, they were inferior to those of imipenem/cilastatin against S. aureus, K. pneumoniae and A. calcoaceticus.

Animals↗

PubMed1998

[Susceptibility of clinical strains of gram-positive bacteria to selected beta-lactam antibiotics].

The aim of the study was to determine the activity of four beta-lactam antibiotics against nosocomial strains of Gram-positive bacteria. Two antibiotics combined with beta-lactamase inhibitors: timentin (TIC/CLAV) and tazocin (PIP/TZB) and two carbapenems: imipenem and meropenem were applied. The clinical strains were isolated from patients hospitalized in surgical ward of the National Clinical Hospital No 1 in Warsaw. The strains were identified in the automatic ATB system using ID 32 STAPH, API STREP, API CORYNE and API 20 A strips. The susceptibility of isolates to antibacterial agents was determined in the automatic ATB system using ATB STAPH, ATB STREP and ATB ANA strips. The susceptibility of strains to timentin, tazocin, imipenem and meropenem was tested with disc diffusion method. 111 strains of Gram-positive bacteria were cultured. Staphylococci (49) and enterococci (44) dominated among isolated strains. 33 Staphylococcus spp. strains were identified as methicillin-resistant. The obtained results indicate a significant role of Gram-positive cocci (staphylococci and enterococci) in the aetiology of nosocomial infections. Antibiotics combined with beta-lactamase inhibitors and carbapenems demonstrate broad antibacterial spectrum against clinical strains of Gram-positive bacteria except E. faecium strains.

Anti-Bacterial Agents↗

PubMed2002

Susceptibility of Prevotella intermedia/Prevotella nigrescens (and Porphyromonas gingivalis) to propolis (bee glue) and other antimicrobial agents.

Black-pigmented gram-negative anaerobes such as Porphyromonas gingivalis and Prevotella intermedia are suspected pathogens in adult periodontitis, whereas Prevotella nigrescens has been associated with health. Antimicrobial resistance among bacteria from this group has been reported in the past decade. This research aimed to evaluate and compare the susceptibility profile of 17 P. intermedia/P. nigrescens isolates recovered from patients with periodontitis and three reference strains to six antimicrobials, prescribed in dentistry in Brazil, and propolis (bee glue). The antimicrobial agents tested were tetracycline, penicillin, clindamycin, erythromycin, metronidazole, meropenem and six ethanolic extracts of propolis (EEPs) from Brazil. The reference strains P. gingivalis ATCC 33277 and P. intermedia ATCC 25611 were used for determination of minimum bactericidal concentration (MBC) and for time-kill assay to the EEPs. All of the strains were susceptible to penicillin, erythromycin, meropenem, metronidazole and 95% of them (n=19) to tetracycline. Thirty six percent (n=7) of the P. intermedia/P. nigrescens strains tested were resistant to clindamycin. As for propolis activity, all strains were susceptible and the minimum inhibitory concentration values ranged from 64 to 256 microg/mL. For the reference strains P. gingivalis ATCC 33277 and Prevotella intermedia ATCC 25611 the MBC was 256 microg/mL and death was observed within 3 h of incubation for P. gingivalis and within 6 h for P. intermedia. The action of propolis (bee glue) against suspected periodontal pathogens suggests that it may be of clinical value.

Journal Article↗

PubMed1995

Lack of additive effect between mechanisms of resistance to carbapenems and other beta-lactam agents in Pseudomonas aeruginosa.

Eighty-nine clinical isolates resistant (n = 61) or susceptible (n = 28) to imipenem and exhibiting the main patterns of susceptibility to other beta-lactam agents (wild type pattern, penicillinase pattern, constitutive cephalosporinase pattern) were studied in order to investigate (i) the mechanism of resistance involved and (ii) whether resistance to carbapenems affects the level of resistance to other beta-lactam agents and, conversely, if resistance to other beta-lactam agents affects the level of resistance to carbapenems. For this purpose, the presence of OprD protein in the cell wall was detected by Western blot and beta-lactamase activity by spectrophotometric assay and isoelectric focusing. OprD expression was not detectable in the imipenem-resistant (MIC > or = 16 micrograms/ml) strains. It was decreased in half the strains for which MICs of imipenem were 2 to 8 micrograms/ml and was close to a normal level in the most susceptible strains (MIC < or = 1 microgram/ml), thus demonstrating a direct correlation between the level of susceptibility to imipenem and the level of OprD expression. No imipenemase activity was detected in imipenem-resistant strains. Synergy between imipenem or meropenem and BRL 42715 was observed for all of the strains, demonstrating the role of cephalosporinase in carbapenem resistance. Within each pattern of susceptibility, the mean MICs of beta-lactam agents other than carbapenems were similar, whether the strains were susceptible or resistant to imipenem. Conversely, the mean MICs of imipenem or meropenem for either the imipenem-resistant or the imipenem-susceptible strains were similar, regardless of the susceptibility of these strains to the other beta-lactam agents. Thus, when several mechanisms of resistance to beta-lactam agents are present in the same strain of Pseudomonas aeruginosa, there is no additive effect between these mechanisms.

Anti-Bacterial Agents↗