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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 -
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 -
Pathogens (Basel, Switzerland) Jul 2022is ubiquitous in aquatic habitats and can cause life-threatening septicaemia in humans. However, limited data are available on their antimicrobial susceptibility...
is ubiquitous in aquatic habitats and can cause life-threatening septicaemia in humans. However, limited data are available on their antimicrobial susceptibility testing (AST) profiles. Hence, we aimed to examine their AST patterns using clinical ( = 94) and non-clinical ( = 23) isolates with dehydrated MicroScan microdilution. Carbapenem resistant isolates were further screened for genes related to carbapenem resistance using molecular assay. The isolates exhibited resistance to imipenem (76.9%), doripenem (62.4%), meropenem (41.9%), trimethoprim/sulfamethoxazole (11.1%), cefotaxime (8.5%), ceftazidime (6%), cefepime (1.7%) and aztreonam (0.9%), whereas all isolates were susceptible to amikacin. Clinical isolates showed significant association with resistance to doripenem, imipenem and meropenem compared to non-clinical isolates. These were detected in clinical isolates with resistance phenotypes: doripenem (67.2%, 45/67), imipenem (65.9%, 54/82) and meropenem (65.2%, 30/46). Our findings showed that the MicroScan microdilution method is suitable for the detection of carbapenem resistance in both clinical (48.9-87.2%) and non-clinical (4.3-13.0%) isolates. This study revealed that isolates had relatively high carbapenem resistance, which may lead to potential treatment failure. Continued monitoring of aquatic sources with a larger sample size should be carried out to provide further insights.
PubMed: 35894056
DOI: 10.3390/pathogens11080833 -
Journal of Clinical Medicine Jul 2022Clinically, doripenem therapy for nosocomial pneumonia remains a serious concern. The purpose of this meta-analysis was to explore the efficacy and the safety of... (Review)
Review
INTRODUCTION
Clinically, doripenem therapy for nosocomial pneumonia remains a serious concern. The purpose of this meta-analysis was to explore the efficacy and the safety of doripenem therapy for nosocomial pneumonia in comparison with other antimicrobial agents.
METHODS
Studies were eligible for inclusion only if they directly compared the clinical effectiveness of doripenem and other antimicrobial agent therapies for nosocomial pneumonia in adult patients between 1 January 2000 and 30 April 2022. All studies were included if they reported one or more of the following outcomes: clinical cure rate, microbiological cure rate, all-cause mortality, and adverse events.
RESULTS
Six randomized controlled trials and three retrospective studies were included in the meta-analysis. There were 952 patients in the doripenem group and 1183 patients in the comparator group. The comparator antimicrobial agents included imipenem/cilastatin, meropenem, and piperacillin/tazobactam. Seven studies had a high risk of bias. Doripenem therapy for nosocomial pneumonia had a microbiological cure rate, a clinical cure rate, an all-cause mortality, and adverse events similar to those of comparators.
CONCLUSIONS
The efficacy and the safety of doripenem therapy for nosocomial pneumonia were comparable with those of comparators. Randomized controlled trials are needed to confirm the role of doripenem in nosocomial pneumonia therapy.
PubMed: 35887777
DOI: 10.3390/jcm11144014 -
Antibiotics (Basel, Switzerland) Jul 2022The aim of this study was to investigate the pharmacokinetics (PK) of doripenem in healthy Chinese subjects and evaluate the optimal dosage regimens of doripenem. A...
The aim of this study was to investigate the pharmacokinetics (PK) of doripenem in healthy Chinese subjects and evaluate the optimal dosage regimens of doripenem. A randomized, single-dose, three-period, self-crossover controlled extended-infusion clinical trial was conducted with 12 healthy Chinese subjects. Plasma and urine samples were collected to determine doripenem concentrations. Non-compartmental and population PK analysis were performed to characterize the PK of doripenem. The Monte Carlo simulation was employed to optimize dosing regimens based on the probability of target attainment of doripenem against pathogens with different minimum inhibitory concentrations (MIC). All 12 healthy Chinese subjects completed the study, and the doripenem was well tolerated. The study showed linearity relationships in the peak plasma concentration and the area under the concentration-time curve after intravenous infusion of doripenem from 0.25 g to 1.0 g. The cumulative urinary recovery rate of doripenem was 68.1-72.0% within 24 h. PPK modeling showed a two-compartmental model, with first-order elimination presenting the best fit for doripenem PK. Monte Carlo simulation results showed that 1.0 g q12h or 0.5 g q8h was an optimal regimen for pathogens susceptible to doripenem (MIC ≤ 1 mg/L); while high dose and extended infusion (1 g, q8h, 4 h infusion) was proposed for unsusceptible pathogens (2 ≤ MIC ≤ 8 mg/L). In the dose range of 0.25 to 1.0 g, doripenem showed linear pharmacokinetics. Doripenem at 1.0 g with a prolonged infusion time of 4 h was predicted to be effective against pathogens with MICs as high as 8 mg/L.
PubMed: 35884212
DOI: 10.3390/antibiotics11070958