Oral Tebipenem Pivoxil Hydrobromide in Complicated Urinary Tract Infection.

BACKGROUND: There is a need for oral antibiotic agents that are effective against multidrug-resistant gram-negative uropathogens. Tebipenem pivoxil hydrobromide is an orally bioavailable carbapenem with activity against uropathogenic Enterobacterales, including extended-spectrum beta-lactamase-producing and fluoroquinolone-resistant strains. METHODS: In this phase 3, international, double-blind, double-dummy trial, we evaluated the efficacy and safety of orally administered tebipenem pivoxil hydrobromide as compared with intravenous ertapenem in patients with complicated urinary tract infection or acute pyelonephritis. Patients were randomly assigned, in a 1:1 ratio, to receive oral tebipenem pivoxil hydrobromide (at a dose of 600 mg every 8 hours) or intravenous ertapenem (at a dose of 1 g every 24 hours) for 7 to 10 days (or up to 14 days in patients with bacteremia). The primary efficacy end point was overall response (a composite of clinical cure and favorable microbiologic response) at a test-of-cure visit (on day 19, within a ±2-day window) in the microbiologic intention-to-treat population. The noninferiority margin was 12.5%. RESULTS: A total of 1372 hospitalized adult patients were enrolled; 868 patients (63.3%) were included in the microbiologic intention-to-treat population (50.8% of whom had complicated urinary tract infections and 49.2% of whom had pyelonephritis). An overall response was seen in 264 of 449 patients (58.8%) who received tebipenem pivoxil hydrobromide, as compared with 258 of 419 patients (61.6%) who received ertapenem (weighted difference, -3.3 percentage points; 95% confidence interval [CI], -9.7 to 3.2). Clinical cure at the test-of-cure visit was observed in 93.1% of the patients in the microbiologic intention-to-treat population who received tebipenem pivoxil hydrobromide and 93.6% of patients who received ertapenem (weighted difference, -0.6 percentage point; 95% CI, -4.0 to 2.8); the majority of patients with microbiologic response failures at the test-of-cure visit were asymptomatic patients with recurrent bacteriuria. Secondary and subgroup analyses were supportive of the primary analysis. Adverse events were observed in 25.7% of patients who received tebipenem pivoxil hydrobromide and in 25.6% of patients who received ertapenem; the most common adverse events were mild diarrhea and headache. CONCLUSIONS: Oral tebipenem pivoxil hydrobromide was noninferior to intravenous ertapenem in the treatment of complicated urinary tract infection and acute pyelonephritis and had a similar safety profile. (Funded by Spero Therapeutics and the Department of Health and Human Services; ADAPT-PO ClinicalTrials.gov number, NCT03788967.).

A short course of antimicrobial therapy for asymptomatic bacteriuria is safe and effective before urologic procedures.

INTRODUCTION: In the presence of asymptomatic bacteriuria (ASB) before the urological procedure, the duration of antimicrobial treatment is controversial. This study aims to evaluate whether a short course of antimicrobial therapy is safe and effective in cases with ASB before urological procedures. METHODOLOGY: We retrospectively reviewed adult patients who had ASB before undergoing several urological procedures between 2011 and 2019. The patients received a single dose of an appropriate parenteral antibiotic, determined by antimicrobial sensitivity testing, 30 to 60 minutes before the urological procedure. If a urinary catheter was placed post-procedure, a second dose was given. RESULTS: A total of 293 patients who had ASB before undergoing several urological procedures were included in the study. The total number of procedures was 328. Female/male ratio was 92 (31.4%)/201 (68.6%). The mean age was 63.7 ± 14.9 years. The most common isolated microorganisms were Escherichia coli (155 [47%]), Klebsiella pneumoniae (38 [11.6%]), and Pseudomonas aeruginosa (28 [8.5%]). The most common antimicrobial used was ertapenem. A second dose antimicrobial was given for 290 procedures due to a urinary catheter after a urological procedure. The mean hospitalization time was 3.97 ± 3.42 days. None of the patients developed infectious complications. CONCLUSIONS: This study has demonstrated that a single dose of parenteral antimicrobial drug administered 30-60 minutes before the urologic procedures and a second dose in the presence of a post-procedure catheter, was adequate to prevent post-procedure septicemia and urinary tract infection.

Ertapenem Neurotoxicity in Hemodialysis Patients-Safe and Effective Dosing Is Still Needed: A Retrospective Study and Literature Review.

BACKGROUND: The approved dosing of ertapenem in patients with chronic kidney disease stage 5 utilizing dialysis (CKD-5D) is 0.5 g intravenous daily. Several reports associated this dosing strategy with neurotoxicity. OBJECTIVE: The purpose of this study is to identify the incidence of neurotoxicity in this population and the risk factors associated with this toxicity. The secondary objective was to review the literature and discuss a safer/cost-effective dosing strategy based on available data. METHODS: A retrospective study was conducted screening all patients who received ertapenem and hemodialysis at our quaternary hospital between May 2015 and March 2019. Patients' demographics, comorbidities, concomitant drugs (known to induce neurotoxicity), and seizure history were collected. RESULTS: A total of 99 eligible patients were identified; 10 of them (10%) developed neurotoxicity. The patients who developed neurotoxicity were all male; mean age was 74 ± 9 years as compared with 68.9 ± 13 years in the sample. Bivariate relationships between all predictors and the seizures (dichotomously coded) were estimated to investigate the risk factors. The following were the significant predictors of seizures: male sex (17%; P = 0.014), dementia (27%; P = 0.012), and concomitant use of ß-lactams, aminoglycosides, or fluoroquinolones (19.6%; P = 0.042). CONCLUSION AND RELEVANCE: The currently approved ertapenem dose imposes a risk of developing neurotoxicity in patients with CKD-5D. Utilizing the published data in this population, alternative post-dialysis dosing strategies administered through dialysis access such as 1 g loading dose, followed by either 0.5 g (for the 48 hours interdialytic time) or 1 g (for the 72 hours interdialytic time) might warrant further investigation for efficacy and safety.

Ertapenem and Faropenem against Mycobacterium tuberculosis: in vitro testing and comparison by macro and microdilution.

BACKGROUND: Interest in carbapenems has been rising in the last few years due to the emergence of drug resistant tuberculosis. Ertapenem (ETP), given once a day parenteral, and faropenem (FAR), oral, have a better administration profile than meropenem (MEM), imipenem (IPM) and doripenem (DOR). The addition of amoxicillin-clavulanate (AMC) inhibits the hydrolysis by the carbapenemase present in Mycobacterium tuberculosis (MTB). The aim of this study was to determine the in vitro activity of ETP and FAR against susceptible and resistant clinical MTB strains by two widely use methodologies, the BACTEC960 MGIT and microdilution. RESULTS: 19 clinical isolates with different susceptibility profiles and H37Rv were included. Minimal inhibitory concentration (MIC) testing was performed using two methods of different concentrations of ETP and FAR with and without AMC. MIC50 was 2 and 8 for FAR with and without AMC by both methods. MIC90 was > 16 and > 8 by microdilution and MGIT respectively and did not change after AMC addition. 18/20 samples were resistant to the highest concentration of ETP, with and without AMC. Half of the samples had some susceptibility to FAR; addition of AMC further reduced the MIC level in seven isolates. 10/20 isolates showed susceptibility to FAR and the addition of AMC further reduced the MIC in 7 isolates. However, most of the MICs were near the limit of effectiveness (8 µg/mL). Resistance to FAR was associated with resistance to MEM (p = 0.04) but not to resistance profiles of other drugs, including M/XDR status. CONCLUSIONS: The lack of ETP activity may be associated with its degradation, independent of carbapenemase, during incubation. No susceptibility pattern to traditional drugs can predict susceptibility to FAR and susceptibility testing is not routinely available. PK/PD studies are needed as reaching the concentrations tested in these experiments may be challenging. This work highlighted some of the limitations of carbapenem use. More evidence is needed to clarify their true impact in TB treatment and outcome, considering the financial burden, complications and microbiota changes associated with their use.

Highly effective prophylaxis with ertapenem for transrectal ultrasound-guided prostate biopsy: effects on overall antibiotic use and inpatient hospital exposure.

BACKGROUND: Ertapenem prophylaxis for transrectal ultrasound-guided prostate biopsy (TRUS-PB) has proven highly effective at our institution. A subsequent study showed no selection for carbapenem resistance, but antimicrobial stewardship concerns remained. AIM: To assess the effects of this prophylaxis on overall antibiotic consumption and exposure to the hospital environment. METHODS: All men undergoing TRUS-PB from November 2006 to July 2019 were included. Hospital records of men presenting within 30 days of biopsy were searched to determine whether post-biopsy infection (PBI) occurred, antibiotic usage, and duration of hospitalization. Prophylaxis during the pre-ertapenem period (period 1: 2006 to 2012) was oral ciprofloxacin for three days, with oral amoxicillin-clavulanate added in 2009. During the subsequent period (period 2: 2012 to 2019) a single intramuscular dose of ertapenem was used. FINDINGS: From periods 1 and 2, 1663 and 2357 men, respectively, were included. Median age was 65 years for both groups. Between periods 1 and 2, PBI incidence decreased from 2.65% to 0.34% (risk ratio: 0.13; 95% confidence interval (CI): 0.06, 0.27), and PBI-related bacteraemia from 1.14% to 0.04% (0.04; 0.01, 0.22), with a single bacteraemia during period 2. PBI treatment antibiotic consumption decreased from 57.6 to 4.3 defined daily doses (DDDs) per 100 biopsies (mean difference: -53.3; 95% CI: -73.1, -33.5) and overall consumption (treatment plus prophylaxis) decreased from 580.8 to 104.3 DDDs per 100 biopsies (mean difference: -476.5). PBI-related hospitalized bed-days per 100 biopsies decreased from 9.44 to 0.89 (mean difference: -8.55; 95% CI: -12.31, -4.79). CONCLUSION: Ertapenem prophylaxis was highly effective and resulted in marked reductions in overall antibiotic consumption and inpatient bed-days. Effective prophylaxis has advantages from an antimicrobial stewardship perspective.

Ertapenem-induced encephalopathy.

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 m2). We present a patient with a baseline eGFR of 30-59 mL/min/1.73 m2 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.

Mechanistic Insights Into the Differential Efficacy of Daptomycin Plus ß-Lactam Combinations Against Daptomycin-Resistant Enterococcus faecium.

BACKGROUND: The combination of daptomycin (DAP) plus ampicillin (AMP), ertapenem (ERT), or ceftaroline has been demonstrated to be efficacious against a DAP-tolerant Enterococcus faecium strain (HOU503). However, the mechanism for the efficacy of these combinations against DAP-resistant (DAP-R) E. faecium strains is unknown. METHODS: We investigated the efficacy of DAP in combination with AMP, ERT, ceftaroline, ceftriaxone, or amoxicillin against DAP-R E. faecium R497 using established in vitro and in vivo models. We evaluated pbp expression, levels of penicillin-binding protein (PBP) 5 (PBP5) and ß-lactam binding affinity in HOU503 versus R497. RESULTS: DAP plus AMP was the only efficacious regimen against DAP-R R497 and prevented emergence of resistance. DAP at 8, 6, and 4 mg/kg in combination with AMP was efficacious but showed delayed killing compared with 10 mg/kg. PBP5 of HOU503 exhibited amino acid substitutions in the penicillin-binding domain relative to R497. No difference in pbp mRNA or PBP5 levels was detected between HOU503 and R497. labeling of PBPs with Bocillin FL, a fluorescent penicillin derivative, showed increased ß-lactam binding affinity of PBP5 of HOU503 compared with that of R497. CONCLUSIONS: Only DAP (10 mg/kg) plus AMP or amoxicillin was efficacious against a DAP-R E. faecium strain, and pbp5 alleles may be important contributors to efficacy of DAP plus ß-lactam therapy.

Subcutaneously administered antibiotics.

The subcutaneous route is a widely used route of administration in routine clinical practice, particularly in elderly patients, when the intravenous route cannot be used. This review of the literature highlights the lack of randomized studies and the lack of pharmacokinetic data on the use of this route of administration. Three antibiotics administered subcutaneously can be used for severe infections, with acceptable pharmacokinetic and pharmacodynamic data, when the intravenous administration is not possible: ceftriaxone, ertapenem, and teicoplanin.

Is the subcutaneous route an alternative for administering ertapenem to older patients? PHACINERTA study.

BACKGROUND: Antibiotic administration by subcutaneous (SC) injection is common practice in French geriatric wards as an alternative to the intravenous (IV) route, but few pharmacokinetic/pharmacodynamic data are available. Ertapenem is useful for the treatment of infections with ESBL-producing enterobacteria. OBJECTIVES: To report and compare ertapenem pharmacokinetic data between IV and SC routes in older persons. METHODS: Patients >65 years of age receiving ertapenem (1 g once daily) for at least 48 h (IV or SC, steady-state) were prospectively enrolled. Total ertapenem concentrations [residual (C0), IV peak (C0.5) and SC peak (C2.5)] were determined by UV HPLC. Individual-predicted AUC0-24 values were calculated and population pharmacokinetic analyses were performed. Using the final model, a Monte Carlo simulation involving 10 000 patients evaluated the influence of SC or IV administration on the PTA. Tolerance to ertapenem and recovery were also monitored. ClinicalTrials.gov identifier: NCT02505386. RESULTS: Ten (mean ± SD age=87±7 years) and 16 (age=88±5 years) patients were included in the IV and SC groups, respectively. The mean C0 and C2.5 values were not significantly different between the IV and SC groups (C0=12±5.9 versus 12±7.4 mg/L, P=0.97; C2.5=97±42 versus 67±41 mg/L, P=0.99). The mean C0.5 was higher in the IV group compared with the SC group (C0.5=184±90 versus 51±66 mg/L, P=0.001). The mean individual AUCs (1126.92±334.99 mg·h/L for IV versus 1005.3±266.0 mg·h/L for SC, P=0.38) and PTAs were not significantly different between groups. No severe antibiotic-related adverse effects were noted. CONCLUSIONS: SC administration of ertapenem is an alternative to IV administration in older patients.

Shortening duration of ertapenem in outpatient parenteral antimicrobial therapy for complicated urinary tract infections: A retrospective study.

BACKGROUND: The incidence of multi-drug resistant ESBL-associated urinary tract infections (UTIs) is increasing globally. Patients with abnormal renal tract anatomy and other co-morbidities are at increased risk of complicated UTI and ESBL-associated infections. The duration and safety of OPAT for this cohort of patients is unknown. OBJECTIVES: This study aims to provide an evidence base to support decision-making regarding duration of antibiotic treatment for complicated UTIs. METHODS: We retrospectively reviewed all patients receiving ertapenem with or without adjunctive fosfomycin for complicated UTIs in the OPAT service of our tertiary infectious diseases hospital. All data had been collected prospectively as part of routine clinical care. Our primary outcomes were microbiological and clinical cure of UTI. RESULTS: We identified 33 treatment episodes of ertapenem use for UTIs. 76% episodes related to pyelonephritis or urosepsis diagnoses. Renal tract abnormalities or prior urological surgery were present in 45% of patients. The median duration of appropriate parenteral antibiotic therapy in our study was 6 days. Clinical cure was achieved with short-course parenteral treatment alone in 81% of patients and this increased to 96% when adjunctive fosfomycin was used. There was a single treatment failure resulting in hospital admission. CONCLUSIONS: Short duration ertapenem via OPAT with or without adjunctive fosfomycin is safe and effective for the treatment of complicated UTIs. Further studies are required to inform optimal treatment strategies and publication of guidelines in this field.

Activity of Ceftazidime-Avibactam Alone and in Combination with Ertapenem, Fosfomycin, and Tigecycline Against Carbapenemase-Producing Klebsiella pneumoniae.

The aim of this study was to investigate the synergy between ceftazidime-avibactam, ertapenem, fosfomycin, and tigecycline against carbapenemase-producing Klebsiella pneumoniae using the E test MIC:MIC (minimum inhibitory concentration) ratio synergy method. The results were interpreted using fractional inhibitory concentration index (FICI) to describe the effects of antimicrobial combinations in vitro. To assess the clinical significance of each antibiotic combination, the susceptible breakpoint index (SBPI) was calculated for each combination, and within each strain. The FICI method revealed that the most synergistic combinations against carbapenemase-producing K. pneumoniae were ceftazidime-avibactam with ertapenem and ceftazidime-avibactam with fosfomycin. This effect was demonstrated in 47% (9/19) of all tested clinical K. pneumoniae isolates. Considering the effects of all drug combinations in K. pneumoniae harboring blaKPC, blaNDM, and blaOXA-48 genes, we observed that the combination of ceftazidime-avibactam with fosfomycin was the most synergistic in New Delhi metallo-ß-lactamase (NDM)-producing K. pneumoniae, and the combination of ceftazidime-avibactam with ertapenem was the most synergistic in K. pneumoniae carbapenemase (KPC)-producing K. pneumoniae. In addition, all tested combinations were synergistic against oxacillinase (OXA)-48-producing K. pneumoniae, except the combination of ceftazidime-avibactam with tigecycline. The SBPI index showed that ceftazidime-avibactam in combination with fosfomycin reduced the MIC to less than the susceptibility breakpoint among all tested carbapenemase-producing K. pneumoniae. Moreover, the combinations of ceftazidime-avibactam with ertapenem, and ceftazidime-avibactam with tigecycline were able to reduce the MIC to less than the susceptibility breakpoint in all KPC- and OXA-48-producing K. pneumoniae.

Cost analysis of antibiotic therapy versus appendectomy for treatment of uncomplicated acute appendicitis: 5-year results of the APPAC randomized clinical trial.

BACKGROUND: The efficacy and safety of antibiotic treatment for uncomplicated acute appendicitis has been established at long-term follow-up with the majority of recurrences shown to occur within the first year. Overall costs of antibiotics are significantly lower compared with appendectomy at short-term follow-up, but long-term durability of these cost savings is unclear. The study objective was to compare the long-term overall costs of antibiotic therapy versus appendectomy in the treatment of uncomplicated acute appendicitis in the APPAC (APPendicitis ACuta) trial at 5 years. METHODS AND FINDINGS: This multicentre, non-inferiority randomized clinical trial randomly assigned 530 adult patients with CT-confirmed uncomplicated acute appendicitis to appendectomy or antibiotic treatment at six Finnish hospitals. All major costs during the 5-year follow-up were recorded, whether generated by the initial visit and subsequent treatment or possible recurrent appendicitis. Between November 2009 and June 2012, 273 patients were randomized to appendectomy and 257 to antibiotics. The overall costs of appendectomy were 1.4 times higher (p<0.001) (€5716; 95% CI: €5510 to €5925) compared with antibiotic therapy (€4171; 95% CI: €3879 to €4463) resulting in cost savings of €1545 per patient (95% CI: €1193 to €1899; p<0.001) in the antibiotic group. At 5 years, the majority (61%, n = 156) of antibiotic group patients did not undergo appendectomy. CONCLUSIONS: At 5-year follow-up antibiotic treatment resulted in significantly lower overall costs compared with appendectomy. As the majority of appendicitis recurrences occur within the first year after the initial antibiotic treatment, these results suggest that treating uncomplicated acute appendicitis with antibiotics instead of appendectomy results in lower overall costs even at longer-term follow-up.

Poly (bromocresol green) flakes-decorated pencil graphite electrode for selective electrochemical sensing applications and pharmacokinetic studies.

A square wave voltammetric method for selective determination of meropenem (MRP) and ertapenem (ERP) was developed using pencil graphite electrode modified with poly (bromocresol green) (PGE/PBCG). The modified electrode film was characterized by scanning electron microscopy and electro-chemical impedance spectroscopy. Under the optimized conditions, the prepared electrode has good linearity over concentration range 1.0-60.0 and 0.3.0-75.0 µM for MRP and ERP, respectively. The developed method was validated according to ICH guidelines. In addition, the diffusion co-efficients of MRP and ERP were estimated to be 1.24 × 10-6 and 9.09 × 10-6 cm2 s-1, respectively using chronoamperometric technique. The developed method was highly sensitive and selective for the determination of MRP or ERP in the presence of their corresponding open beta-lactam ring degradation products. Consequently, it was successfully utilized for in-vitro and in-vivo applications in spiked and real plasma samples of healthy rabbits for their pharmacokinetic studies. Furthermore, the method was applied for the assay of the available dosage forms of both drugs.

[Clinical impact of ertapenem de-escalation in critically-ill patients with Enterobacteriaceae infections]. / Impacto clínico del desescalamiento a ertapenem en pacientes críticos con infecciones por Enterobacteriaceae.

BACKGROUND: Ertapenem has proven to be effective for extended-spectrum beta-lactamases-producing Enterobacteriaceae but lacks activity against non-fermenters; de-escalation to this antibiotic may reduce the selection of resistance to Pseudomonas aeruginosa and improve clinical outcomes. AIM: To evaluate the clinical impact of de-escalation from broad-spectrum anti-pseudomonal agents to ertapenem, a non-pseudomonal antibiotics for Enterobacteriaceae infections in critically-ill patients. METHODS: We conducted a prospective cohort study in adult patients admitted to intensive care units (ICUs) who had Enterobacteriaceae infections and were de-escalated from empiric anti-pseudomonal coverage to non-pseudomonal antibiotics. Cox proportional hazards models were performed comparing all-cause mortality and length of hospital stay between patients who remained on anti-pseudomonal coverage versus those who were de-escalated to ertapenem. RESULTS: 105 patients in the anti-pseudomonal group were compared to 148 patients in the ertapenem de-escalation group. De-escalation was associated with lower all-cause mortality compared to patients who remained on anti-pseudomonal coverage (adjusted Hazard Ratio 0.24; 95% CI: 0.12-0.46). The length of ICU stay was similar between the groups. DISCUSSION: ICU patients with Enterobacteriaceae infections de-escalated to ertapenem therapy had better outcomes compared to patients who remained on broad-spectrum, anti-pseudomonal therapy, suggesting that de-escalation is a safe approach amongst ICU patients.

Modeling Ertapenem: the impact of body mass index on distribution of the antibiotic in the body.

Ertapenem is an antibiotic commonly used to treat a broad spectrum of infections and is part of a broader class of antibiotics called carbapenems. Unlike other carbapenems, ertapenem has a longer half-life and thus only has to be administered once a day. Previously, a physiologically-based pharmacokinetic (PBPK) model was developed to investigate the uptake, distribution, and elimination of ertapenem following a single one gram dose in normal height, normal weight males. Due to the absorption properties of ertapenem, the amount of fat in the body can influence how the drug binds, how quickly the drug passes through the body, and thus how effective the drug might be. Thus, we have revised the model so that it is applicable to males and females of differing body mass index (BMI). Simulations were performed to consider the distribution of the antibiotic in males and females with varying body mass indexes. These results could help to determine if there is a need for altered dosing regimens in the future.

Detection in the United Kingdom of the Neisseria gonorrhoeae FC428 clone, with ceftriaxone resistance and intermediate resistance to azithromycin, October to December 2018.

We describe detection in the United Kingdom (UK) of the drug-resistant Neisseria gonorrhoeae FC428 clone, with ceftriaxone resistance and intermediate azithromycin resistance. Two female patients developed infection following contact with UK-resident men from the same sexual network linked to travel to Ibiza, Spain. One case failed treatment with ceftriaxone, and azithromycin and gentamicin, before successful treatment with ertapenem. Both isolates had indistinguishable whole-genome sequences. Urgent action is essential to contain this drug-resistant strain.

Fenómeno de la orina purpura / Purple urine bag syndrome

No disponible

Impacto clínico del desescalamiento a ertapenem en pacientes críticos con infecciones por Enterobacteriaceae / Clinical impact of ertapenem de-escalation in critically-ill patients with Enterobacteriaceae infections

Resumen Introducción: Ertapenem ha demostrado eficacia frente a Enterobacteriaceae productoras de β-lactamasas de espectro extendido, pero carece de actividad contra bacterias no fermentadoras; el desescalamiento a este antimicrobiano cuando no existe la presencia de P. aeruginosa podría reducir la presión selectiva contra esta bacteria y mejorar los resultados clínicos. Objetivo: Evaluar el impacto clínico del desescalamiento de antimicrobianos con cobertura anti-pseudomonas a ertapenem, un agente sin este espectro, en pacientes críticos con infecciones por Enterobacteriaceae. Métodos: Se realizó un estudio de cohorte prospectivo en adultos admitidos a Unidades de Cuidado Intensivo (UCI) con infecciones por Enterobacteriaceae, que habían sido desescalados de una cobertura anti-pseudomonas, a un antimicrobiano sin la misma (ertapenem). Se realizó un modelo de riesgo proporcional de Cox comparando mortalidad por cualquier causa y duración de estancia hospitalaria entre aquellos pacientes que permanecieron con cobertura anti-pseudomonas versus aquellos que fueron desescalados a ertapenem. Resultados: 105 pacientes en el grupo anti-pseudomonas fueron comparados con 148 pacientes del grupo de desescalamiento a ertapenem. El desescalamiento estuvo asociado con una menor mortalidad por cualquier causa comparado con los pacientes que permanecieron con cobertura anti-pseudomonas (hazard ratio ajustado 0,24; IC 95%: 0,12-0,46). La estancia hospitalaria en UCI fue similar en ambos grupos. Discusión: Los pacientes de UCI con infecciones por Enterobacteriaceae desescalados a terapia con ertapenem, tuvieron mejores resultados clínicos comparados con aquellos que permanecieron en terapia anti-pseudomonas, sugiriendo que el desescalamiento es una práctica segura en esta población.

Background: Ertapenem has proven to be effective for extended-spectrum beta-lactamases-producing Enterobacteriaceae but lacks activity against non-fermenters; de-escalation to this antibiotic may reduce the selection of resistance to Pseudomonas aeruginosa and improve clinical outcomes. Aim: To evaluate the clinical impact of de-escalation from broad-spectrum anti-pseudomonal agents to ertapenem, a non-pseudomonal antibiotics for Enterobacteriaceae infections in critically-ill patients. Methods: We conducted a prospective cohort study in adult patients admitted to intensive care units (ICUs) who had Enterobacteriaceae infections and were de-escalated from empiric anti-pseudomonal coverage to non-pseudomonal antibiotics. Cox proportional hazards models were performed comparing all-cause mortality and length of hospital stay between patients who remained on anti-pseudomonal coverage versus those who were de-escalated to ertapenem. Results: 105 patients in the anti-pseudomonal group were compared to 148 patients in the ertapenem de-escalation group. De-escalation was associated with lower all-cause mortality compared to patients who remained on anti-pseudomonal coverage (adjusted Hazard Ratio 0.24; 95% CI: 0.12-0.46). The length of ICU stay was similar between the groups. Discussion: ICU patients with Enterobacteriaceae infections de-escalated to ertapenem therapy had better outcomes compared to patients who remained on broad-spectrum, anti-pseudomonal therapy, suggesting that de-escalation is a safe approach amongst ICU patients.

Pharmacokinetics and investigation of optimal dose ertapenem in intermittent hemodialysis patients.

BACKGROUND: Previous pharmacokinetic studies demonstrated an increase in serum ertapenem concentrations with decreasing kidney function, including patients receiving renal replacement therapy. This study evaluated the pharmacokinetic parameters of ertapenem in patients receiving hemodialysis. METHODS: This prospective, single-center, open-label study examined the pharmacokinetics of a single intravenous (IV) dose of ertapenem 1 g in seven hospitalized noninfected patients undergoing hemodialysis. Blood samples were collected prior to ertapenem administration and at 0.5, 1, 2, 6, 12 and 48 hours (h) after administration. Ertapenem concentrations were determined by validated liquid chromatography mass spectrometry assay. RESULTS: Following an IV bolus of 1 g ertapenem, plasma concentrations declined relatively slowly with a mean ±standard deviation (SD) elimination half-life of 19.3 ±6.6 h. Plasma concentrations were similar in all subjects, with maximum mean plasma concentration observed of 343±48 µg/mL postdose. The mean ±SD values for systemic plasma clearance (CL) and volume of distribution at steady state (Vss) were 2±0.5 mL/min and 3295±1187 mL, respectively. The area under the curve for 0 h-∞ (AUCinf) was 7494 ±1424 h•µg/mL. No gender effect was observed and no serious adverse events were reported. CONCLUSIONS: Ertapenem half-life was prolonged in hemodialysis patients. Considering the nonrenal clearance and the expected 70% removal with high-efficacy hemodialysis, the dose of 1 g ertapenem, three times weekly, after hemodialysis may produce pharmacodynamically sufficient exposure for potential antimicrobial efficacy. Further studies are warranted to assess the clinical efficacy and safety of this dose with prolonged duration of therapy.