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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 -
Expert Opinion on Investigational Drugs May 2008Potent new drugs against multidrug-resistant Gram-negative bacteria, namely Pseudomonas aeruginosa and Acinetobacter spp. and pan-drug-resistant Klebsiella pneumoniae,... (Review)
Review
BACKGROUND
Potent new drugs against multidrug-resistant Gram-negative bacteria, namely Pseudomonas aeruginosa and Acinetobacter spp. and pan-drug-resistant Klebsiella pneumoniae, which constitute an increasing medical threat, are almost absent from the future pharmaceutical pipeline.
OBJECTIVE
This drug evaluation focuses on the position of doripenem, a novel forthcoming carbapenem. Mechanisms of resistance and new drugs with anti-Gram-negative activity are also briefly reviewed.
METHODS
Literature search was performed for new carbapenems, new antibiotics, doripenem, metallo-beta-lactamase inhibitors, multidrug-resistant pathogens, antipseudomonal antibiotics and multidrug-resistant epidemiology.
RESULTS
Doripenem possesses a broad spectrum of activity against Gram-negative bacteria, similar to that of meropenem, while retaining the spectrum of imipenem against Gram-positive pathogens. Against P. aeruginosa, doripenem exhibits rapid bactericidal activity with 2 - 4-fold lower MIC values, compared to meropenem. Exploitation of pharmacokinetic/pharmacodynamic applications could offer a treatment opportunity against strains exhibiting borderline resistance to doripenem. Stability against numerous beta-lactamases, low adverse event potential and more potent in vitro antibacterial activity against P. aeruginosa and A. baumanni compared to the existing carbapenems, are its principal features.
Topics: Animals; Anti-Bacterial Agents; Carbapenems; Clinical Trials, Phase III as Topic; Doripenem; Drug Evaluation; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Microbial Sensitivity Tests; Molecular Structure
PubMed: 18447600
DOI: 10.1517/13543784.17.5.749 -
Journal of Chemotherapy (Florence,... Aug 2010Carbapenems are the most potent group of beta-lactam agents, having a broad spectrum of bactericidal activity against both Gram-negative and Gram-positive bacteria... (Review)
Review
Carbapenems are the most potent group of beta-lactam agents, having a broad spectrum of bactericidal activity against both Gram-negative and Gram-positive bacteria including anaerobes. Doripenem is a new carbapenem endowed with excellent bactericidal activity, a wide spectrum of antibacterial activity against difficult nosocomial pathogens, including extended-spectrum beta-lactamase producers. Its high stability in solution render it extremely flexible for dosing and infusion time. It is the only carbapenem which has been registered officially for administration as an extended infusion of more than 4 hours, which can thus enhance its potential clinical efficacy against difficult bacterial pathogens with MICs of 4-8 mg/L.
Topics: Animals; Anti-Bacterial Agents; Carbapenems; Doripenem; Humans
PubMed: 20685624
DOI: 10.1179/joc.2010.22.4.219 -
Expert Review of Anti-infective Therapy Oct 2007The threat of antibacterial resistance continues to increase globally, and therapeutic options for the treatment of some serious infectious diseases are diminishing. The... (Review)
Review
The threat of antibacterial resistance continues to increase globally, and therapeutic options for the treatment of some serious infectious diseases are diminishing. The carbapenems are a potent class of broad-spectrum drugs, and their stability against hydrolysis by many important beta-lactamases make them an important weapon in the treatment of beta-lactamase-producing bacterial pathogens. This review focuses on four carbapenems of clinical importance in the USA: imipenem, meropenem, ertapenem and doripenem. After a historical review of carbapenem development, these four carbapenems are evaluated based on their mechanism of action, spectrum of activity, potency, pharmacodynamics, clinical pharmacokinetics, clinical profiles and toxicity issues.
Topics: Anti-Bacterial Agents; Bacterial Infections; Carbapenems; Clinical Trials as Topic; Doripenem; Drug Resistance, Multiple, Bacterial; Ertapenem; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests; Structure-Activity Relationship; Thienamycins; United States; beta-Lactams
PubMed: 17914914
DOI: 10.1586/14787210.5.5.793 -
Medecine Et Maladies Infectieuses Dec 2009Doripenem is a new member of the carbapenem family. Its spectrum is a little wider than meropenem and it is active on some Pseudomonas aeruginosa strains resistant to... (Review)
Review
Doripenem is a new member of the carbapenem family. Its spectrum is a little wider than meropenem and it is active on some Pseudomonas aeruginosa strains resistant to other carbapenems and on Burkholderia cepacia. Doripenem was evaluated in nosocomial pneumonia including ventilator-acquired pneumonia, complicated intra-abdominal infection, and complicated urinary tract infection. In nosocomial pneumonia, doripenem showed an interesting activity in P. aeruginosa infected patients. This data, along with the global increase in multiresistance, may be an opportunity to optimize our therapeutic options with a new molecule.
Topics: Animals; Anti-Bacterial Agents; Bacterial Infections; Burkholderia cepacia; Carbapenems; Clinical Trials as Topic; Cross Infection; Doripenem; Drug Evaluation, Preclinical; Drug Resistance, Multiple, Bacterial; Humans; Nervous System Diseases; Peritonitis; Pneumonia, Bacterial; Pseudomonas aeruginosa; Urinary Tract Infections
PubMed: 19875257
DOI: 10.1016/j.medmal.2009.08.014 -
Infectious Disease Clinics of North... Dec 2009This article reviews the new beta-lactam (beta-lactam) antibiotics doripenem, ceftobiprole, and ceftaroline. It covers pharmacokinetic and pharmacodynamic properties,... (Review)
Review
This article reviews the new beta-lactam (beta-lactam) antibiotics doripenem, ceftobiprole, and ceftaroline. It covers pharmacokinetic and pharmacodynamic properties, dosing, in vitro activities, safety, and clinical trial results. Doripenem (Doribax) has been approved by the US Food and Drug Administration (FDA) for the treatment of complicated intra-abdominal and urinary tract infections. At this writing, ceftobiprole is under review by the FDA for approval based on results of phase 3 clinical trials, whereas at least one phase 3 clinical trial of ceftaroline has been completed. The article also reviews recent data suggesting increased overall mortality with Cefepime (Maxipime) use compared with other beta-lactam antibiotics and the potential risk for neurotoxicity in the setting of renal failure.
Topics: Anti-Bacterial Agents; Bacteria; Bacterial Infections; Humans; beta-Lactams
PubMed: 19909894
DOI: 10.1016/j.idc.2009.06.007 -
Pharmacotherapy Jul 2020Biliary tract infections (BTIs), including cholangitis and cholecystitis, are common causes of bacteremia. Bacteremic BTIs are associated with a mortality rate of 9-12%.... (Review)
Review
Biliary tract infections (BTIs), including cholangitis and cholecystitis, are common causes of bacteremia. Bacteremic BTIs are associated with a mortality rate of 9-12%. The extent to which antibiotics are excreted in the bile and the ratio of their exposure to the minimum inhibitory concentration of the infecting organism are among the important factors for the treatment of BTIs. This review updates health care professionals on the distribution of antibiotics in the common bile duct, gallbladder, and gallbladder wall. Antibiotic efficacy in treating BTIs based on the latest available clinical studies is also discussed. The efficacy and pharmacokinetics of 50 antibiotics are discussed. Overall, most antibiotic classes exhibit biliary penetration that translates into clinical efficacy. Only seven antibiotics (amoxicillin, cefadroxil, cefoxitin, ertapenem, gentamicin, amikacin, and trimethoprim/sulfamethoxazole) had poor biliary penetration profiles. Three antibiotics (ceftibuten, ceftolozane/tazobactam, and doripenem) had positive clinical outcomes despite the lack of pharmacokinetic studies on their penetration into the biliary tract. Conflicting efficacy data were reported for ampicillin despite adequate biliary penetration, whereas conflicting pharmacokinetic data were reported with cefaclor and moxifloxacin. Even in the absence of supportive clinical studies, antibiotics with good biliary penetration profiles may have a place in the treatment of BTIs.
Topics: Anti-Bacterial Agents; Bacteremia; Biliary Tract; Biliary Tract Diseases; Gallbladder; Humans
PubMed: 32485056
DOI: 10.1002/phar.2431 -
The Lancet. Infectious Diseases Jan 2020
Topics: Cephalosporins; Cross Infection; Doripenem; Double-Blind Method; Humans; Meropenem; Pneumonia, Ventilator-Associated; Tazobactam
PubMed: 31876489
DOI: 10.1016/S1473-3099(19)30717-0 -
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 -
Diagnostic Microbiology and Infectious... Apr 2009Doripenem, a synthetic 1-beta-methyl carbapenem, has a broad-spectrum of activity against almost all species of anaerobic bacteria, including all Bacteroides fragilis... (Review)
Review
Doripenem, a synthetic 1-beta-methyl carbapenem, has a broad-spectrum of activity against almost all species of anaerobic bacteria, including all Bacteroides fragilis group species, most with MIC(90) results at
doripenem when compared with meropenem, but in vitro against the anaerobes, it was "more potent than meropenem, ertapenem, ... and similar to imipenem". Doripenem activity against anaerobes seems comparable with the other extant carbapenems. Although resistance among anaerobic bacteria to this agent is possible, it remains relatively rare. Topics: Animals; Anti-Bacterial Agents; Bacteria, Anaerobic; Bacterial Infections; Carbapenems; Clinical Trials as Topic; Doripenem; Humans; Microbial Sensitivity Tests; Rats
PubMed: 19249176
DOI: 10.1016/j.diagmicrobio.2009.01.022