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JAC-antimicrobial Resistance Oct 2022Antimicrobials for bloodstream infections due to ESBL- and AmpC-producing and are significantly limited due to widespread antimicrobial resistance. Tebipenem, an oral...
BACKGROUND
Antimicrobials for bloodstream infections due to ESBL- and AmpC-producing and are significantly limited due to widespread antimicrobial resistance. Tebipenem, an oral carbapenem, exhibits stability against these resistance mechanisms and may prove an attractive alternative.
METHODS
The susceptibility of tebipenem was assessed against previously whole-genome sequenced ESBL- and AmpC-producing (274 isolates) and (42 isolates) derived from bloodstream infections using broth microdilution testing. Resulting tebipenem MICs were compared with those of other carbapenems previously tested against the isolate collection. Tebipenem activity was also compared against those isolates expressing co-resistance to the common oral antibiotics ciprofloxacin and trimethoprim/sulfamethoxazole.
RESULTS
The tebipenem MIC value was found to be 0.03 mg/L for and 0.125 mg/L for . For , the tebipenem MIC value was equivalent to that of meropenem, 2-fold lower than that of doripenem, and 8-fold and 4-fold lower than that of imipenem and ertapenem, respectively. For , the tebipenem MIC value was 2-fold higher than that of meropenem, equivalent to that of doripenem, and 4-fold and 2-fold lower than that of imipenem and ertapenem, respectively. Tebipenem MICs were also unaffected by the expression of co-resistance to ciprofloxacin and trimethoprim/sulfamethoxazole.
CONCLUSIONS
The activity of tebipenem was unaffected by the production of ESBL and AmpC enzymes. Tebipenem also retained its activity against those isolates expressing co-resistance to ciprofloxacin and trimethoprim/sulfamethoxazole. These findings therefore highlight tebipenem as a potential option for the treatment of invasive MDR infections.
PubMed: 36196442
DOI: 10.1093/jacamr/dlac105 -
New Microbes and New Infections Jul 2022The World Health Organization in 2017 listed carbapenem resistant Enterobacteriaceae (CRE) with critical priority for research. A research to assess carbapenem resistant...
The World Health Organization in 2017 listed carbapenem resistant Enterobacteriaceae (CRE) with critical priority for research. A research to assess carbapenem resistant (CREc) in coliuria among the outpatients and inpatients of a tertiary health institution was carried out using conventional methods, polymerase chain reaction, Sanger sequencing, and bioinformatics. There were 39 positive coliuria cases from the urine samples collected from a total of 126 patients with various genitourinary diseases. The enumeration (log CFU/mL) revealed that 82.1% (n = 32) of the samples showed significant coliuria, 12.8% (n = 5) showed non-significant coliuria while 5.1% (n = 2) showed indeterminate coliuria even when repeated. Significantly higher numbers (p > 0.05) of the sampled inpatients yielded positive coliuria (57.9%) than the outpatients. Though there were significantly more (P > 0.05) urology female patients (n = 77) than male (n = 49), coliuria was more prevalent in sampled male patients (34.9%) than female (28.6%). Highest prevalence of coliuria was observed among the age range (18-30) years. Selected CREc that was sequenced and the sequences submitted to GenBank of National Center for Biotechnological Information (NCBI) were AYO-WINI111 and AYO-WINI112 with accession number MT735391 and MT735392, respectively. High resistance was observed against ertapenem (53%), imipenem (62%), meropenem (48%), and doripenem (47%), while 7%-22% of the isolates showed phenotypic intermediate carbapenem resistance. Critically dangerous CREc are harboured by large number urology patients in the study area, depicting the need for more attention in the management of the condition, as CREc are close to achieving totally antibiotic resistance.
PubMed: 36176538
DOI: 10.1016/j.nmni.2022.101019 -
Antibiotics (Basel, Switzerland) Sep 2022In the context of difficult-to-treat carbapenem-resistant infections, we evaluated imipenem, meropenem, and doripenem combinations against eleven...
In the context of difficult-to-treat carbapenem-resistant infections, we evaluated imipenem, meropenem, and doripenem combinations against eleven carbapenemase-producing isolates. According to the widespread global distribution of high-risk clones and carbapenemases, four representative isolates were selected: ST175 (OXA-2/VIM-20), ST175 (VIM-2), ST235 (GES-5), and ST111 (IMP-33), for efficacy studies using a sepsis murine model. Minimum inhibitory concentration (mg/L) ranges were 64-256 for imipenem and 16-128 for meropenem and doripenem. In vitro, imipenem plus meropenem was synergistic against 72% of isolates and doripenem plus meropenem or imipenem against 55% and 45%, respectively. All combinations were synergistic against the ST175, ST235, and ST155 clones. In vivo, meropenem diminished the spleen and blood bacterial concentrations of four and three isolates, respectively, with better efficacy than imipenem or doripenem. The combinations did not show efficacy compared with the more active monotherapies, except for imipenem plus meropenem, which reduced the ST235 bacterial spleen concentration. Mortality decreased with imipenem plus meropenem or doripenem for the ST175 isolate. Results suggest that carbapenem combinations are not an alternative for severe infections by carbapenemase-producing . Meropenem monotherapy showed in vivo efficacy despite its high MIC, probably because its dosage allowed a sufficient antimicrobial exposure at the infection sites.
PubMed: 36139991
DOI: 10.3390/antibiotics11091212 -
Journal of Family Medicine and Primary... Jun 2022, serotype typhi, remains the predominant species causing enteric fever in India. The mode of transmission is considered to be predominantly vehicle-borne through...
BACKGROUND
, serotype typhi, remains the predominant species causing enteric fever in India. The mode of transmission is considered to be predominantly vehicle-borne through contaminated water or food. In India, the incidence of Salmonella typhi occurs between the months of April and June (dry season) followed by July and September (monsoon season). Typhoid fever may be difficult to distinguish clinically from other febrile illnesses and if left untreated, intestinal, neuropsychiatric, and other complications develop in some patients.
OBJECTIVE
The aim of this study was to determine the prevalence of in bloodstream infections and its antimicrobial susceptibility pattern among patients with febrile illness.
METHODOLOGY
Febrile patients admitted in the hospital who were prescribed blood culture tests and whose samples were sent to microbiology laboratory were included in the study. All blood samples (average 5 mL for adults and 2-3 mL for pediatric age group) were immediately inoculated into Bac-T ALERT aerobic blood culture bottles containing sodium polyethanol sulfonate as an anticoagulant (0.025%). If growth was isolated, isolated colony characteristics of growth and Gram stain were assessed. On Gram staining, typical nonlactose fermenting Gram negative bacilli were further subjected to species identification and detection of antimicrobial susceptibility pattern on the VITEK2.
RESULTS
In this study period, a total of 511 blood culture (paired) samples were processed, out of which 47 isolates of were obtained. Among these isolates, 33 (70.23%) were from males, and 14 (29.77%) were from females. Amongst these, 35 (74.4%) patients were from rural, 8 (17%) were from subrural, and 4 (8.5%) were from urban areas. Out of the total 47 isolates of , 42 (89.36%) were , 2 (4.25%) were A and B each, and 1 (2.12%) was . Antimicrobial susceptibility pattern of isolates revealed that all the isolates of species were highly susceptible (95%-100%) to third generation cephalosporins (ceftazidime, ceftriaxone, cefepime, cefoperazone-sulbactam) and other higher antibiotics such as betalactamase inhibitors - piperacillin tazobactam (95%-100%) and Ticarcillin-clavulanic acid (100%). They were also highly susceptible (100%) to carbapenams (imipenem, merpenem, doripenem, and ertapenem) but showed a fairly decreased susceptibility was towards nalidixic acid with 15% for and 50% for other isolates.
CONCLUSION
Surging drug-resistant cases, the level of resistance was not as high as predicted in our study population. Multidrug-resistant (MDR) trends may vary; therefore, drug susceptibility testing side-by-side to empirical therapy is mandatory, especially in developing countries where there is a practice of self-medication.
PubMed: 36119327
DOI: 10.4103/jfmpc.jfmpc_1976_21 -
Current Drug Research Reviews 2023Right from the breakthrough of carbapenems since 1976, many schemes on synthesis, structure-activity relationship (SAR), and biological activities have been carried out,... (Review)
Review
Right from the breakthrough of carbapenems since 1976, many schemes on synthesis, structure-activity relationship (SAR), and biological activities have been carried out, and several carbapenems have been developed, including parentally active carbapenems like imipenem, doripenem, biapenem, meropenem, ertapenem, panipenem, razupenem, tomopenem, and cilastatin, whereas orally active carbapenems like GV-118819, GV-104326, CS-834, L-084, DZ-2640, CL 191, 121, L-646, 591, S-4661, ER-35768, MK-826. Prodrugs of carbapenem with increased bioavailability include temopenem, tebipenem, sanfetrinem, LK-157, and CP 5484. Merck, Glaxo Welcome Research Group, Johnson & Johnson, Sankyo Group and Dai-ichi Group, and Wyeth-Ayerst Group were among the businesses that produced carbapenems. In this review Witting reaction, Mitsunobu reaction, Dieckmann reaction, palladium-catalyzed hydrogenolysis, E. coli-based cloned synthesis, as well as biosynthetic enzymes such as carbapenem synthetase (carA), carboxymethylproline synthase (carB), carbapenem synthase (carC) are included. Carbapenems are biologically mainly active in the infections like urinary tract infections, bloodstream infections, tuberculosis, intra-abdominal infections, and pathogens like anaerobes, gram-positive and gram-negative bacteria.
Topics: Humans; Anti-Bacterial Agents; Escherichia coli; Gram-Negative Bacteria; Gram-Positive Bacteria; Carbapenems
PubMed: 36082853
DOI: 10.2174/2589977514666220907141939 -
Archives of Toxicology Dec 2022Bile acid homeostasis plays an important role in many biological activities through the bile-liver-gut axis. In this study, two in vitro models were applied to further...
Bile acid homeostasis plays an important role in many biological activities through the bile-liver-gut axis. In this study, two in vitro models were applied to further elucidate the mode of action underlying reported in vivo bile acid changes induced by antibiotics (colistin sulfate, tobramycin, meropenem trihydrate, and doripenem hydrate). 16S rRNA analysis of rat fecal samples anaerobically incubated with these antibiotics showed that especially tobramycin induced changes in the gut microbiota. Furthermore, tobramycin was shown to inhibit the microbial deconjugation of taurocholic acid (TCA) and the transport of TCA over an in vitro Caco-2 cell layer used as a model to mimic intestinal bile acid reuptake. The effects induced by the antibiotics in the in vitro model systems provide novel and complementary insight explaining the effects of the antibiotics on microbiota and fecal bile acid levels upon 28-day in vivo treatment of rats. In particular, our results provide insight in the mode(s) of action underlying the increased levels of TCA in the feces upon tobramycin exposure. Altogether, the results of the present study provide a proof-of-principle on how in vitro models can be used to elucidate in vivo effects on bile acid homeostasis, and to obtain insight in the mode(s) of action underlying the effect of an antibiotic, in this case tobramycin, on bile acid homeostasis via effects on intestinal bile acid metabolism and reuptake.
Topics: Humans; Rats; Animals; Bile Acids and Salts; RNA, Ribosomal, 16S; Anti-Bacterial Agents; Colistin; Meropenem; Doripenem; Caco-2 Cells; Taurocholic Acid; Tobramycin
PubMed: 36074177
DOI: 10.1007/s00204-022-03373-4 -
Pharmaceutical Biology Dec 2022L. (Magnoliaceae) has been known since ancient times for its rich medicinal properties.
CONTEXT
L. (Magnoliaceae) has been known since ancient times for its rich medicinal properties.
OBJECTIVE
The ethanol extract of leaves (EEMC) was evaluated on depression and anxiety using and studies.
MATERIALS AND METHODS
Swiss albino mice were divided into control, standard, 100 and 200 mg/kg b.w. EEMC groups and for drug administration using oral gavage. The antidepressant activity was evaluated using forced swim test (FST) and tail suspension test (TST) whereas the anxiolytic activity through elevated plus maze and light and dark tests. The studies included molecular docking against human potassium channel KCSA-FAB and human serotonin transporter, and ADME/T analysis.
RESULTS
Open arm duration and entries were comparable between 200 mg/kg b.w. group (184.45 ± 1.00 s and 6.25 ± 1.11, respectively) and that of diazepam treated group (180.02 s ± 0.40 and 6.10 ± 0.05, respectively). Time spent in the light cubicle was higher (46.86 ± 0.03%), similar to that of diazepam (44.33 ± 0.64%), suggesting its potent anxiolytic activity. A delayed onset of immobility and lowered immobility time was seen at both the treatment doses (FST: 93.7 ± 1.70 and 89.1 ± 0.40 s; TST: 35.05 ± 2.75 and 38.50 ± 4.10 s) and the standard drug imipramine (FST: 72.7 ± 3.72 and TST: 30.01 ± 2.99 s), indicative of its antidepressant ability. studies predicted doripenem to induce anxiolytic and antidepressant activity by inhibiting human potassium channel KCSA-FAB and human serotonin transporter proteins, respectively.
CONCLUSIONS
EEMC is a rich source of bioactive compounds with strong antidepressant and anxiolytic properties.
Topics: Animals; Anti-Anxiety Agents; Antidepressive Agents; Depression; Diazepam; Humans; Magnoliaceae; Mice; Molecular Docking Simulation; Phytochemicals; Plant Extracts; Potassium Channels; Serotonin Plasma Membrane Transport Proteins
PubMed: 36052952
DOI: 10.1080/13880209.2022.2101669 -
Clinical Infectious Diseases : An... Feb 2023Traditional end points used in registrational randomized, controlled trials (RCTs) often do not allow for complete interpretation of the full range of potential clinical...
Improving Traditional Registrational Trial End Points: Development and Application of a Desirability of Outcome Ranking End Point for Complicated Urinary Tract Infection Clinical Trials.
BACKGROUND
Traditional end points used in registrational randomized, controlled trials (RCTs) often do not allow for complete interpretation of the full range of potential clinical outcomes. Desirability of outcome ranking (DOOR) is an approach to the design and analysis of clinical trials that incorporates benefits and risks of novel treatment strategies and provides a global assessment of patient experience.
METHODS
Through a multidisciplinary committee of experts in infectious diseases, clinical trial design, drug regulation, and patient experience, we developed a DOOR end point for infectious disease syndromes and demonstrated how this could be applied to 3 registrational drug trials (ZEUS, APEKS-cUTI, and DORI-05) for complicated urinary tract infections (cUTIs). ZEUS compared fosfomycin to piperacillin/tazobactam, APEKS-cUTI compared cefiderocol to imipenem, and DORI-05 compared doripenem to levofloxacin. Using DOOR, we estimated the probability of a more desirable outcome with each investigational antibacterial drug.
RESULTS
In each RCT, the DOOR distribution was similar and the probability that a patient in the investigational arm would have a more desirable outcome than a patient in the control arm had a 95% confidence interval containing 50%, indicating no significant difference between treatment arms. DOOR facilitated improved understanding of potential trade-offs between clinical efficacy and safety. Partial credit and subgroup analyses also highlight unique attributes of DOOR.
CONCLUSIONS
DOOR can effectively be used in registrational cUTI trials. The DOOR end point presented here can be adapted for other infectious disease syndromes and prospectively incorporated into future clinical trials.
Topics: Humans; Anti-Bacterial Agents; Urinary Tract Infections; Levofloxacin; Doripenem; Imipenem
PubMed: 36031403
DOI: 10.1093/cid/ciac692 -
Antibiotics (Basel, Switzerland) Aug 2022The aim of this study was to determine whether fingolimod could synergize the antibacterial activity of doripenem against carbapenem-resistant (CREC) and its potential...
The aim of this study was to determine whether fingolimod could synergize the antibacterial activity of doripenem against carbapenem-resistant (CREC) and its potential as an antibiotic adjuvant for doripenem. The used in this study had the gene and became resistant to many classes of antibiotics, particularly carbapenems. The minimum inhibitory concentrations (MICs) of fingolimod and doripenem were determined. To investigate the synergistic action between fingolimod and doripenem, synergy checkerboard, growth curve, and time-kill analyses were performed. A motility test was also performed using a semi-solid medium to determine whether fingolimod could inhibit the motility of , one of its virulence mechanisms. The expression levels of carbapenemase-, motility-, and efflux pump-related genes suppressed by fingolimod were analyzed by quantitative polymerase chain reaction (qPCR). Our study demonstrated that the combination of fingolimod and doripenem inhibited carbapenemase, biological activity and other CREC virulence factors. This study findings suggest the potential of fingolimod as an adjuvant to prevent antibiotic resistance in CREC.
PubMed: 36009912
DOI: 10.3390/antibiotics11081043 -
The American Journal of Tropical... Aug 2022Carbapenem-resistant Enterobacteriales has become a threat in Taiwan. This is the first local study focusing on the association between carbapenem-resistant...
Association between Antimicrobial Consumption and the Prevalence of Nosocomial Carbapenem-Resistant Escherichia coli and Klebsiella pneumoniae in a Tertiary Hospital in Northern Taiwan.
Carbapenem-resistant Enterobacteriales has become a threat in Taiwan. This is the first local study focusing on the association between carbapenem-resistant Enterobacteriales and antimicrobial consumption. From January 2012 to December 2020, data were collected in a tertiary care hospital in Taipei, Taiwan. Antimicrobial consumption was estimated by the defined daily dose/1,000 patient-days. During the same period, the prevalence of carbapenem-resistant Escherichia coli (CREC) and carbapenem-resistant Klebsiella pneumoniae (CRKP) were collected through routine surveillance data. The following retrospective analyses were conducted: 1) analysis of antimicrobial consumption over time, (2) analysis and forecast of CREC and CRKP prevalence over time, and 3) analysis of correlation between antimicrobial consumption and the prevalence of CREC and CRKP. The consumption of piperacillin/tazobactam (β = 0.615), fluoroquinolones (β = 0.856), meropenem (β = 0.819), and doripenem (β = 0.891) increased during the observation period (P < 0.001), and the consumption of aminoglycosides (β = -0.852) and imipenem/cilastatin (β = -0.851) decreased (P < 0.001). The prevalence of CRKP rose over time (β = 0.522, P = 0.001) and correlated positively with the consumption of fluoroquinolones, levofloxacin, penicillin/β-lactamase inhibitor, piperacillin/tazobactam, meropenem, and doripenem (P < 0.05). The prevalence of CRKP and CREC both correlated negatively with consumption of aminoglycosides (P < 0.01). The prevalence of CRKP in our hospital increased as the forecast predicted based on an autoregressive integrated moving average model. This study provides alarming messages for members participating in antimicrobial stewardship programs, including the increasing prevalence of CRKP, the increasing consumption of broad-spectrum antibiotics, and the positive correlation between them.
Topics: Humans; Tertiary Care Centers; Klebsiella pneumoniae; Retrospective Studies; Meropenem; Doripenem; Prevalence; Taiwan; Cross Infection; Anti-Bacterial Agents; Anti-Infective Agents; Carbapenems; Fluoroquinolones; Carbapenem-Resistant Enterobacteriaceae; Escherichia coli; Piperacillin, Tazobactam Drug Combination; Aminoglycosides; Klebsiella Infections; Microbial Sensitivity Tests
PubMed: 35895586
DOI: 10.4269/ajtmh.21-1242