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Clinical Infectious Diseases : An... Sep 2020Cefazolin and ertapenem combination therapy was used successfully to salvage 11 cases (6 endocarditis) of persistent methicillin-susceptible Staphylococcus aureus (MSSA)...
Cefazolin and ertapenem combination therapy was used successfully to salvage 11 cases (6 endocarditis) of persistent methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia, including immediate clearance (≤24 hours) in 8 cases. While in vitro synergy was modest, cefazolin plus ertapenem exhibited synergistic action in a rat model of MSSA endocarditis. The combination of cefazolin and ertapenem provides potent in vivo activity against MSSA beyond what is predicted in vitro and warrants further clinical study in the treatment of refractory MSSA bacteremia and endocarditis.
Topics: Animals; Anti-Bacterial Agents; Bacteremia; Cefazolin; Ertapenem; Methicillin; Rats; Salvage Therapy; Staphylococcal Infections; Staphylococcus aureus
PubMed: 31773134
DOI: 10.1093/cid/ciz995 -
Antimicrobial Agents and Chemotherapy Nov 2011In this review, we summarize the current "state of the art" of carbapenem antibiotics and their role in our antimicrobial armamentarium. Among the β-lactams currently... (Review)
Review
In this review, we summarize the current "state of the art" of carbapenem antibiotics and their role in our antimicrobial armamentarium. Among the β-lactams currently available, carbapenems are unique because they are relatively resistant to hydrolysis by most β-lactamases, in some cases act as "slow substrates" or inhibitors of β-lactamases, and still target penicillin binding proteins. This "value-added feature" of inhibiting β-lactamases serves as a major rationale for expansion of this class of β-lactams. We describe the initial discovery and development of the carbapenem family of β-lactams. Of the early carbapenems evaluated, thienamycin demonstrated the greatest antimicrobial activity and became the parent compound for all subsequent carbapenems. To date, more than 80 compounds with mostly improved antimicrobial properties, compared to those of thienamycin, are described in the literature. We also highlight important features of the carbapenems that are presently in clinical use: imipenem-cilastatin, meropenem, ertapenem, doripenem, panipenem-betamipron, and biapenem. In closing, we emphasize some major challenges and urge the medicinal chemist to continue development of these versatile and potent compounds, as they have served us well for more than 3 decades.
Topics: Anti-Bacterial Agents; Carbapenems; Cilastatin; Cilastatin, Imipenem Drug Combination; Doripenem; Drug Combinations; Ertapenem; Humans; Imipenem; Thienamycins; beta-Alanine; beta-Lactams
PubMed: 21859938
DOI: 10.1128/AAC.00296-11 -
Clinical Microbiology and Infection :... Jan 2015The aim of this study was to determine whether ertapenem, being highly protein bound, is less effective than other carbapenems in the presence of hypoalbuminemia. In a...
The aim of this study was to determine whether ertapenem, being highly protein bound, is less effective than other carbapenems in the presence of hypoalbuminemia. In a prospective cohort study, we included adults with clinically and microbiologically documented infections caused by carbapenem-susceptible Enterobacteriaceae who were hospitalized in a tertiary medical center from March 2010 to September 2012. We tested whether hypoalbuminemia (serum albumin <2.5 g/dL) had a larger effect on 30-day mortality in subjects treated with ertapenem compared to those treated with meropenem or imipenem (I/M). Logistic regression analysis was used to identify independent risk factors for death including the carbapenem drug and the interaction between albumin and the carbapenem. Of 279 individual subjects included, 173 were treated with ertapenem and 106 with I/M. The odds ratio (OR) for 30-day mortality with hypoalbuminemia was 4.6 (95% confidence interval (CI) 2.1-10.1) among subjects with ertapenem versus 1.2 (95% CI 0.5-2.70) with I/M (p = 0.02 for difference between groups). In the regression model, the interaction between carbapenem type and albumin levels was significant (p = 0.03); for ertapenem lower albumin levels were associated with increased 30-day mortality (OR 2.45, 95% CI 1.19-5.05), while for I/M the change was not significant (OR 0.67, 95% CI 0.31-1.41). The model suggests that the risk of death for ertapenem-treated subjects quintupled when albumin was 2 g/dL compared to 4 g/dL. Hypoalbuminemia was associated with mortality significantly more among subjects treated with ertapenem compared to subjects treated with I/M. The effectiveness of current dosing schemes of ertapenem in subjects with significant hypoalbuminemia should be revisited.
Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Carbapenems; Drug Resistance, Bacterial; Enterobacteriaceae; Enterobacteriaceae Infections; Ertapenem; Humans; Hypoalbuminemia; Israel; Middle Aged; Prospective Studies; Risk Factors; beta-Lactams
PubMed: 25636928
DOI: 10.1016/j.cmi.2014.08.003 -
Antimicrobial Agents and Chemotherapy Nov 2016Ertapenem and cefazolin were used in combination to successfully clear refractory methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia. In addition, recent...
Ertapenem and cefazolin were used in combination to successfully clear refractory methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia. In addition, recent work has demonstrated activity of combination therapy with beta-lactams from different classes against methicillin-resistant S. aureus (MRSA). The ertapenem-plus-cefazolin combination was evaluated for synergy in vitro and in vivo in a murine skin infection model using an index MSSA bloodstream isolate from a patient in whom persistent bacteremia was cleared with this combination and against a cadre of well-described research strains and clinical strains of MSSA and MRSA. Against the index MSSA bloodstream isolate, ertapenem and cefazolin showed synergy using both checkerboard (fractional inhibitory concentration [FIC] index = 0.375) and time-kill assays. Using a disk diffusion ertapenem potentiation assay, the MSSA isolate showed a cefazolin disk zone increased from 34 to 40 mm. In vitro pharmacokinetic/pharmacodynamic modeling at clinically relevant drug concentrations demonstrated bactericidal activity (>3 log-CFU/ml reduction) of the combination but bacteriostatic activity of ether drug alone at 48 h. A disk diffusion potentiation assay showed that ertapenem increased the cefazolin zone of inhibition by >3 mm for 34/35 (97%) MSSA and 10/15 (67%) MRSA strains. A murine skin infection model of MSSA showed enhanced activity of cefazolin plus ertapenem compared to monotherapy with these agents. After successful use in clearance of MSSA bacteremia, the combination of ertapenem and cefazolin showed synergy against MSSA in vitro and in vivo This combination may warrant consideration for future clinical study in MSSA bacteremia.
Topics: Aged, 80 and over; Animals; Anti-Bacterial Agents; Bacteremia; Cefazolin; Disease Models, Animal; Disk Diffusion Antimicrobial Tests; Drug Synergism; Drug Therapy, Combination; Ertapenem; Female; Humans; Methicillin-Resistant Staphylococcus aureus; Mice; Staphylococcal Infections; Staphylococcal Skin Infections; beta-Lactams
PubMed: 27572414
DOI: 10.1128/AAC.01192-16 -
BMJ Case Reports Jun 2020Neurotoxicity is an unusual side effect of carbapenems, and it has been reported most commonly presenting as seizures, encephalopathy and hallucinations. Ertapenem...
Neurotoxicity is an unusual side effect of carbapenems, and it has been reported most commonly presenting as seizures, encephalopathy and hallucinations. Ertapenem neurotoxicity most classically presents as seizures in patients with end-stage renal disease (estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m). We present a patient with a baseline eGFR of 30-59 mL/min/1.73 m with acute kidney injury who developed non-seizure neurotoxicity after ertapenem exposure. This patient is a middle-aged Caucasian man who received intravenous ertapenem for treatment of empyema. Although the empyema improved, he developed delirium beginning on day 7 of ertapenem. The delirium progressed to constant agitation and visual hallucinations requiring transfer to the intensive care unit with eventual intubation for airway protection. No improvement in mental status was observed with cessation of other medications. Ertapenem was discontinued and within 24 hours, he was extubated, and his mental status returned to baseline. He was discharged from the hospital the following day. The timely resolution after ertapenem discontinuation makes ertapenem-induced encephalopathy the most likely explanation for this patient's course.
Topics: Akathisia, Drug-Induced; Anti-Bacterial Agents; Delirium; Empyema; Ertapenem; Hallucinations; Humans; Male; Middle Aged; Neurotoxicity Syndromes; Treatment Outcome; Withholding Treatment
PubMed: 32487528
DOI: 10.1136/bcr-2019-231875 -
BMC Infectious Diseases Jun 2017Due to limited therapeutic options, the spread of extended-spectrum beta-lactamases (ESBLs) have become a major public health concern. We conducted a prospective,... (Randomized Controlled Trial)
Randomized Controlled Trial
Randomized controlled trial of piperacillin-tazobactam, cefepime and ertapenem for the treatment of urinary tract infection caused by extended-spectrum beta-lactamase-producing Escherichia coli.
BACKGROUND
Due to limited therapeutic options, the spread of extended-spectrum beta-lactamases (ESBLs) have become a major public health concern. We conducted a prospective, randomized, open-label comparison of the therapeutic efficacy of piperacillin-tazobactam (PTZ), cefepime, and ertapenem in febrile nosocomial urinary tract infection with ESBL-producing Escherichia coli (ESBL-EC).
METHODS
This study was conducted at three university hospitals between January 2013 and August 2015. Hospitalized adult patients presenting with fever were screened for healthcare-associated urinary tract infection (HA-UTI). When ESBL-EC was solely detected and susceptible to a randomized antibiotic in vitro, the case was included in the final analysis. Participants were treated for 10-14 days with PTZ, cefepime, or ertapenem.
RESULTS
A total of 66 participants were evenly assigned to the PTZ and ertapenem treatment groups. After the recruitment of six participants, assignment to the cefepime treatment group was stopped because of an unexpectedly high treatment failure rate. The baseline characteristics of these participants did not differ from participants in other treatment groups. The clinical and microbiological response to PTZ treatment was estimated to be 94% and was similar to the response to ertapenem treatment. The efficacy of cefepime was 33.3%. In the cefepime group, age, Charlson comorbidity index, genotype, and minimal inhibitory concentration (MIC) did not significantly affect the success of treatment. Similarly, genotype seemed to be irrelevant with respect to clinical outcome in the PTZ group. Expired cases tended to involve septic shock with a high Charlson comorbidity index and high MIC.
CONCLUSION
Results from this study suggest that PTZ is effective in the treatment of urinary tract infection caused by ESBL-EC when the in vitro test indicates susceptibility. In addition, cefepime should not be used as an alternative treatment for urinary tract infection caused by ESBL-EC.
TRIAL REGISTRATION
The trial was registered with the Clinical Research Information Service of Korea Centers for Disease Control and Prevention. (KCT0001895).
Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Cefepime; Cephalosporins; Cross Infection; Ertapenem; Escherichia coli; Escherichia coli Infections; Female; Genotype; Humans; Male; Middle Aged; Penicillanic Acid; Piperacillin; Piperacillin, Tazobactam Drug Combination; Prospective Studies; Republic of Korea; Tazobactam; Urinary Tract Infections; beta-Lactamase Inhibitors; beta-Lactamases; beta-Lactams
PubMed: 28592240
DOI: 10.1186/s12879-017-2502-x -
Clinical Infectious Diseases : An... Jan 2023Sulopenem is a thiopenem antibiotic being developed for the treatment of multidrug-resistant infections. The availability of both intravenous (IV) and oral formulations... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Sulopenem is a thiopenem antibiotic being developed for the treatment of multidrug-resistant infections. The availability of both intravenous (IV) and oral formulations will facilitate earlier hospital discharge.
METHODS
Hospitalized adults with pyuria, bacteriuria, and signs and symptoms of complicated urinary tract infection (cUTI) were randomized to 5 days of IV sulopenem followed by oral sulopenem etzadroxil/probenecid or 5 days of IV ertapenem followed by oral ciprofloxacin or amoxicillin-clavulanate, depending on uropathogen susceptibility. The primary end point was overall combined clinical and microbiologic response at the test-of-cure visit (day 21).
RESULTS
Of 1392 treated patients, 444 and 440 treated with sulopenem and ertapenem, respectively, had a positive baseline urine culture and were eligible for the primary efficacy analyses. Extended-spectrum β-lactamase-producing organisms were identified in 26.6% of patients and fluoroquinolone-nonsusceptible pathogens in 38.6%. For the primary end point, noninferiority of sulopenem to the comparator regimen was not demonstrated, 67.8% vs 73.9% (difference, -6.1%; 95% confidence interval, -12.0 to -.1%). The difference was driven by a lower rate of asymptomatic bacteriuria in the subgroup of ertapenem-treated patients who stepped down to ciprofloxacin. No substantial difference in overall response was observed at any other time point. Both IV and oral formulations of sulopenem were well-tolerated and compared favorably to the comparator.
CONCLUSIONS
Sulopenem followed by oral sulopenem-etzadroxil/probenecid was not noninferior to ertapenem followed by oral step-down therapy for the treatment of cUTIs, driven by a lower rate of asymptomatic bacteriuria in those who received ciprofloxacin. Both formulations of sulopenem were well-tolerated.
CLINICAL TRIAL REGISTRATION
NCT03357614.
Topics: Adult; Humans; Ertapenem; Bacteriuria; Urinary Tract Infections; Anti-Bacterial Agents; Pyelonephritis; Ciprofloxacin
PubMed: 36068705
DOI: 10.1093/cid/ciac704 -
The Journal of Antimicrobial... 2015Enterococcus faecalis (Efc) and Enterococcus faecium (Efm) are frequently resistant to vancomycin and β-lactams (BLs). In vitro data suggest synergy between several BLs...
OBJECTIVES
Enterococcus faecalis (Efc) and Enterococcus faecium (Efm) are frequently resistant to vancomycin and β-lactams (BLs). In vitro data suggest synergy between several BLs and glycopeptides or lipopeptides against resistant pathogens. Our objective was to conduct combination MIC and time-kill experiments to evaluate BL synergy with daptomycin against enterococci.
METHODS
Fifteen Efc and 20 Efm strains were evaluated for daptomycin enhancement via combination MICs. Daptomycin MICs were obtained by microdilution in the absence and presence of ceftaroline, ertapenem, cefepime, ceftriaxone, cefotaxime, cefazolin and ampicillin. Two Efc strains (R6981 and R7808) and one isogenic daptomycin-susceptible/daptomycin-non-susceptible Efm pair (8019/5938) were evaluated in time-kill experiments. Daptomycin at 0.5 × MIC was used in combination with BL at biological free concentration. Strain 5938 was evaluated for enhancement of daptomycin binding in fluorescently labelled daptomycin (BoDipy) experiments.
RESULTS
Ceftaroline reduced daptomycin MIC values the most against all strains. In time-kill experiments, ceftaroline, ertapenem, cefepime, ceftriaxone and ampicillin demonstrated synergy with daptomycin against all strains, cefazolin demonstrated none and cefotaxime demonstrated synergy against only R7808. Bacterial reduction at 24 h was greater for daptomycin + ceftaroline, ertapenem, cefepime, ceftriaxone or ampicillin for all strains compared with any single agent or daptomycin + cefazolin or cefotaxime (P < 0.001). In BoDipy daptomycin experiments, ceftaroline enhanced daptomycin binding most compared with all other agents (P < 0.001).
CONCLUSIONS
The data support the potential use of daptomycin/BL combination therapy in infections caused by VRE. Combination regimens, other than those involving cefazolin and cefotaxime, provide better kill compared with daptomycin alone. Further clinical research involving daptomycin combinations is warranted.
Topics: Daptomycin; Drug Synergism; Enterococcus faecalis; Enterococcus faecium; Humans; Microbial Sensitivity Tests; Microbial Viability; Vancomycin-Resistant Enterococci; beta-Lactams
PubMed: 25645208
DOI: 10.1093/jac/dkv007