Evaluation of Oral Tebipenem as a Step-Down Therapy following Intravenous Ertapenem against Extended-Spectrum ß-Lactamase-Producing Escherichia coli in a Hollow-Fiber In Vitro Infection Model.

Tebipenem is an orally bioavailable carbapenem in development for the treatment of patients with complicated urinary tract infections. Herein, we describe the results of studies designed to evaluate tebipenem's potential as an oral (p.o.) transition therapy from intravenous (i.v.) ertapenem therapy for the most common uropathogen, Escherichia coli. These studies utilized a 7-day hollow-fiber in vitro infection model and 5 extended-spectrum ß-lactamase-producing E. coli challenge isolates. Human free-drug serum concentration-time profiles for tebipenem 600 mg p.o. every 8 h and ertapenem 1 g i.v. every 24 h were simulated in the hollow-fiber in vitro infection model. Samples were collected for bacterial density and drug concentration determination over the 7-day study period. Generally, ertapenem monotherapy resulted in a greater reduction in bacterial density than did tebipenem monotherapy. In the treatment arms in which ertapenem dosing was stopped following dosing for 1 or 3 days, immediate bacterial regrowth occurred and matched that of the growth control. Finally, in the treatment arms in which ertapenem dosing was stopped following dosing for 1 or 3 days and tebipenem dosing was initiated for the remainder of the 7-day study, the intravenous-to-oral transition regimen reduced bacterial burdens and prevented regrowth. Given that transition from intravenous to oral antibiotic therapy has been shown to reduce hospital length of stay, nosocomial infection risk, and cost, and improve patient satisfaction, these data demonstrate tebipenem's potential role as an oral transition agent from intravenous antibiotic regimens within the antibiotic stewardship paradigm.

Ertapenem blood concentration: A retrospective cohort study to analyse risk of neurotoxicity.

AIMS: Several cases of ertapenem-related neurotoxicity have been published in the current literature. However, studies evaluating the ertapenem blood concentration (EBC) as a risk of these adverse events are scarce. We aimed to evaluate the relationship between the trough EBC and the risk of neurological toxicity. METHODS: This was a retrospective study, including patients who underwent ertapenem treatment between October 2019 and February 2021. We excluded patients in the critical care unit and those whose blood samples were not properly taken in order to analyse ertapenem trough concentration. We also excluded patients whose clinical follow-up was not properly realized for the entire period of ertapenem treatment. The main outcome was the presence of any suspicious neurological side effect owing to ertapenem administration and its relationship with the plasma concentration. Secondary outcomes were to identify clinical and analytical data contributing to a higher risk of neurotoxicity. RESULTS: The initial cohort comprised 158 individuals. For the final analysis we evaluated 102 patients, reporting a neurological alteration in 13/102 (12.7%). Mean trough EBC was significantly higher in patients showing neurotoxicity in comparison with those who did not (37.8 mcg mL-1 , standard deviation [SD] ± 35.7 vs. 14.6 mcg mL-1 , SD ± 15.2; P = .002). In multivariable logistic regression analysis, EBC (odds ratio [OR] = 1.07; P = .006), a moderate renal insufficiency (OR = 9.2; P = .02) and a history of previous neurologic disease (OR = 9.9; P = .02) were identified as risk factors of neurological alteration during ertapenem treatment. CONCLUSIONS: In patients at risk, determining the ertapenem plasma concentration may help to minimize the risk of neurotoxicity.

Perianal abscess in children: an evaluation of microbiological etiology and the effectiveness of antibiotics.

PURPOSE: We aimed to evaluate the demographic characteristics of children with perianal abscess, distribution of microbiological etiology, antibiotic susceptibility, and identify the effectiveness and coverage of antibiotics due to culture results. METHODS: A retrospective study was designed to evaluate pediatric patients with perianal abscesses between January 2013 and December 2022. RESULTS: A total of 197 episodes in 135 patients were evaluated. The median age of the patients was 10 months (22 days-17 years). The isolated microorganisms were Gram-positive bacteria in 56 (28.4%) patients and Gram-negative bacteria in 141 (71.6%) patients. The most common isolated species was Escherichia coli (n = 70, 35.5%), followed by Klebsiella spp. (n = 48, 24.4%), Staphylococcus aureus (n = 37, 18.9%), and Enterobacter spp. (n = 9, 4.5%). Forthy-two percent (n = 58) of isolates were positive for extended-spectrum beta-lactamase, 8% (n = 11) were carbapenem-resistant in Gram-negative bacteria, and 37.5% (n = 21) were methicillin-resistant, 7.1% (n = 4) were vancomycin-resistant in Gram-positive bacteria. According to bacterial culture results, ertapenem plus glycopeptide had the highest antimicrobial coverage rate (92.3%), followed by ertapenem plus clindamycin (89.8%), ertapenem (81.7%), third-generation cephalosporin plus glycopeptide (82.2%), third-generation cephalosporin plus clindamycin (69.5%). CONCLUSION: Ertapenem can be a good choice in the empirical treatment of perianal abscesses in children due to its high coverage rate.

In Vitro Activity of Ertapenem against Neisseria gonorrhoeae Clinical Isolates with Decreased Susceptibility or Resistance to Extended-Spectrum Cephalosporins in Nanjing, China (2013 to 2019).

Neisseria gonorrhoeae isolates collected in Nanjing, China, that possessed decreased susceptibility (or resistance) to extended-spectrum cephalosporins (ESCs) were examined for susceptibility to ertapenem, and their sequence types were determined. Ceftriaxone and cefixime MICs of ≥0.125 mg/L and ≥0.25 mg/L, respectively, were first determined in 259 strains isolated between 2013 and 2019, and then MICs of ertapenem were measured using the antimicrobial gradient Epsilometer test (Etest). Also, genetic determinants of ESC resistance were identified and N. gonorrhoeae multiantigen sequence typing (NG-MAST) was performed to analyze associations with ertapenem susceptibility. All isolates displayed ertapenem MICs between 0.006 mg/L and 0.38 mg/L; the overall MIC50 and MIC90 were 0.032 mg/L and 0.125 mg/L, respectively. Forty-four (17.0%) isolates displayed ertapenem MICs of ≥0.125 mg/L; 10 (3.9%) had MICs of ≥0.25 mg/L. The proportion of isolates with ertapenem MICs of ≥0.125 mg/L increased from 4.0% in 2013 to 20.0% in 2019 (χ2 = 24.144, P < 0.001; chi-square test for linear trend). The penA mosaic allele was present in a significantly higher proportion of isolates with ertapenem MICs of ≥0.125 mg/L than of isolates with MICs of ≤0.094 mg/L) (97.7% versus 34.9%, respectively; χ2 = 58.158, P < 0.001). ST5308 was the most prevalent NG-MAST type (8.5%); ST5308 was also significantly more common among isolates with ertapenem MICs of ≥0.125 mg/L than isolates with MICs of ≤0.094 mg/L (22.7% and 5.6%, respectively; χ2 = 13.815, P = 0.001). Ertapenem may be effective therapy for gonococcal isolates with decreased susceptibility or resistance to ESCs and isolates with identifiable genetic resistance determinants.

Thirty-Day Mortality Rates in Patients with Extended-Spectrum ß-Lactamase-Producing Enterobacterales Bacteremia Receiving Ertapenem versus Other Carbapenems.

Ertapenem is one of the carbapenems recommended for treating extended-spectrum ß-lactamase (ESBL)-producing Enterobacterales. However, efficacy data are limited. We compared 30-day mortality rates for patients receiving ertapenem and other carbapenems for treatment of ESBL-producing Enterobacterales bacteremia. A multicenter, retrospective study was performed from January 2013 to December 2020 at three hospitals. Patients who received only members of one group of carbapenems (group 1 or group 2) throughout their treatment for ESBL-producing Escherichia coli or Klebsiella pneumoniae bacteremia were enrolled. To compare 30-day all-cause mortality rates in the two groups, propensity score matching was used to control for selection bias. Subgroup analyses were performed for several subgroups. Secondary outcomes included Clostridioides difficile infection (CDI) and the emergence of multidrug-resistant Gram-negative bacteria within 90 days after initiation of carbapenem treatment. One-to-one propensity score matching yielded 162 pairs of patients from the total of 603 patients included. There was no difference in 30-day mortality rates between ertapenem and the other carbapenems in adjusted analyses (hazard ratio, 0.60 [95% confidence interval [CI], 0.29 to 1.22]) of the propensity score-matched cohorts. A similar result was obtained in a subgroup analysis of patients who suffered severe sepsis or septic shock and those who did not (P = 0.54 for interaction). Emergence of CDI (odds ratio [OR], 0.99 [95% CI, 0.44 to 2.20]) and carbapenem-resistant Enterobacterales (OR, 1.31 [95% CI, 0.51 to 3.53]) did not differ between the two groups. Our study suggests that the efficacy of ertapenem may be comparable to that of the other carbapenems in treatment of ESBL-producing E. coli and K. pneumoniae bacteremia.

Ertapenem-induced neurotoxicity in an end-stage renal disease patient on intermittent haemodialysis: a case report.

BACKGROUND: Carbapenem-induced neurotoxicity is an unusual side effect, with seizure being the most commonly reported symptom. Among the carbapenems, imipenem-cilastin is classically associated with the most severe neurotoxicity side effects. Carbapenem is mainly excreted by the kidney and its half-life is significantly increased in patients with chronic kidney disease (CKD). Therefore, dose adjustment is necessary in such patients. Ertapenem-associated neurotoxicity is increasingly being reported in CKD patients, but rarely seen in patients with recommended dose adjustment. CASE PRESENTATION: We report a case of a 56-year-old male patient with chronic kidney disease 5 on dialysis(CKD 5D). The patient presented with a history of fever, chills and rigours during a session of haemodialysis (HD). He was diagnosed with Enterobacter cloacae catheter-related blood stream infection and was started on ertapenem. After 13 days of ertapenem, he experienced an acute confusional state and progressed to having auditory and visual hallucinations. His blood investigations and imaging results revealed no other alternative diagnosis. Hence a diagnosis of ertapenem-induced neurotoxicity was made. He had complete resolution of symptoms after 10 days' discontinuation of ertapenem. CONCLUSION: Our case draws attention to the risk of potentially serious toxicity of the central nervous system in HD patients who receive the current recommended dose of ertapenem. It also highlights that renal dosing in CKD 5D patients' needs to be clinically studied to ensure antibiotic safety.

Oxacillin plus ertapenem rapidly clears persistent left ventricular assist device-related methicillin-susceptible Staphylococcus aureus bacteremia.

There is an increasing use of left ventricular assist devices (LVADs) as bridge to transplantation or permanent destination therapy in the heart failure patient population. Infection remains a common complication in LVADs, with Gram-positive skin flora as predominant pathogens implicated, including Staphylococcus aureus. While there is emerging evidence for synergistic antibiotic combinations with methicillin resistant S. aureus, there remains a significant gap in the literature for persistent methicillin susceptible S. aureus bacteremia. In this article, we describe the first successful treatment of persistent LVAD-related bacteremia with salvage oxacillin plus ertapenem. The salvage therapy described here must be balanced by the risks for toxicity, impact on resistance, microbiota disruption, drug shortages, and patient costs. This combination warrants further evaluation in the clinical setting to better establish its role in our expanding patient population.

Bio-analytically fluorimetric method for estimation of ertapenem in real human plasma and commercial samples; application to pharmacokinetics study.

Ertapenem (EPM) has been recently approved by the United States Food and Drug Administration (US-FDA) as an antimicrobial drug. EPM has a broad spectrum of action against different bacterial strains and is most commonly prescribed in Egypt for the treatment of Klebsiella pneumonia. In this study, EPM was estimated using a sensitive and selective spectrofluorimetric method for human plasma and pharmaceutical vials. The measured fluorescence (at 540 nm) was obtained from reaction of EPM with 0.05% w/v benzofurazan (NBD-Cl) using 0.1 M borate buffer pH 8.8 after excitation at 460 nm. The fluorometric linear range was stable from 10 to 350 ng ml-1 . The lower limit of detection and the lower limit of quantitation were found to be 2.13 and 6.47 ng ml-1 respectively. Many factors such as pH, temperature, heating time, and NBD-Cl concentration were optimized. The presented work was validated according to International Council for Harmonisation guidelines and bio-analytically validated using FDA recommendations. The significant finding of this study, sensitivity, was successfully applied in Egypt for a pharmacokinetic application and commercial vials. Pharmacokinetic parameters were studied and the result, recorded as Cmax of EPM, was found to be 83.60 µg ml-1 after infusion of 0.5 g of Invanz® for 30 min. AUC0-∞ was found to be 320 ± 30.2 µ.h ml-1 .

Propensity Score and Desirability of Outcome Ranking Analysis of Ertapenem for Treatment of Nonsevere Bacteremic Urinary Tract Infections Due to Extended-Spectrum-Beta-Lactamase-Producing Enterobacterales in Kidney Transplant Recipients.

There are scarce data on the efficacy of ertapenem in the treatment of bacteremia due to extended-spectrum-beta-lactamase (ESBL)-producing Enterobacterales (ESBL-E) in kidney transplant (KT) recipients. We evaluated the association between treatment with ertapenem or meropenem and clinical cure in KT recipients with nonsevere bacteremic urinary tract infections (B-UTI) caused by ESBL-E. We performed a registered, retrospective, international (29 centers in 14 countries) cohort study (INCREMENT-SOT, NCT02852902). The association between targeted therapy with ertapenem versus meropenem and clinical cure at day 14 (the principal outcome) was studied by logistic regression. Propensity score matching and desirability of outcome ranking (DOOR) analyses were also performed. A total of 201 patients were included; only 1 patient (treated with meropenem) in the cohort died. Clinical cure at day 14 was reached in 45/100 (45%) and 51/101 (50.5%) of patients treated with ertapenem and meropenem, respectively (adjusted OR 1.29; 95% CI 0.51 to 3.22; P = 0.76); the propensity score-matched cohort included 55 pairs (adjusted OR for clinical cure at day 14, 1.18; 95% CI 0.43 to 3.29; P = 0.74). In this cohort, the proportion of cases treated with ertapenem with better DOOR than with meropenem was 49.7% (95% CI, 40.4 to 59.1%) when hospital stay was considered. It ranged from 59 to 67% in different scenarios of a modified (weights-based) DOOR sensitivity analysis when potential ecological advantage or cost was considered in addition to outcome. In conclusion, targeted therapy with ertapenem appears as effective as meropenem to treat nonsevere B-UTI due to ESBL-E in KT recipients and may have some advantages.

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.

Subcutaneous ertapenem delivered by an Australian outpatient parenteral antimicrobial therapy service: a retrospective comparative efficacy study.

Subcutaneous (SC) administration of ertapenem in outpatient parenteral antimicrobial therapy (OPAT) services may be a practical alternative to intravenous delivery for complicated infections. The clinical features and outcomes according to route of administration were compared from a large Australian OPAT service. Chronic renal impairment was more common in the SC group, reflecting an opportunity for route of administration as a vein preservation strategy. Adverse events were uncommon and successful outcomes were not different between the groups.

Cefazolin plus ertapenem and heart transplantation as salvage therapy for refractory LVAD infection due to methicillin-susceptible Staphylococcus aureus: A case series.

The use of left ventricular assist devices (LVADs) is increasingly more common as the availability of donor organs in relation to failing hearts is outstandingly limited. Infections are the most common complications in LVAD recipients, particularly those caused by Staphylococcus spp. Refractory LVAD-related infections are not uncommon as achieving adequate source control is often not feasible before heart transplantation. Evidence suggest that cefazolin plus ertapenem is effective in refractory methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia, but this approach has not been described in LVAD recipients. In this article, we report two cases of refractory MSSA bacteremia in LVAD recipients that were successfully treated with salvage therapy with cefazolin plus ertapenem and subsequent heart transplantation. This treatment strategy should be considered in patients with refractory LVAD-associated infection due to MSSA that are not responding to standard treatment.

Microbiological efficiency of the combinations of two carbapenems against antibiotic resistant Klebsiella pneumoniae strains.

Combined antibiotic therapy is widely used for infections caused by carbapenem-resistant K. pneumoniae. The objective of this work was to identify the synergistic activity of combinations of two carbapenems against multidrug- and extensively drug-resistant K. pneumoniae strains producing various types of carbapenemases. For 60 antibiotic-resistant K. pneumoniae strains isolated in 8 cities of Belarus, the minimum inhibitory concentrations (MIC) of colistin and carbapenems were determined by subsequent broth microdilution method, and the genes of carbapenemases and phosphoethanolamine transferases were detected. The checkerboard method was used to determine the sensitivity to the combination of ertapenem and doripenem. High MIC values of carbapenems were revealed for NDM carbapenemase-producing strains (MIC50 of meropenem 64 mg/L, MIC50 of doripenem 64 mg/L). Doripenem was more active; MIC of doripenem ≤ 16 mg/L (low level of resistance) was determined in 28 (46.7%) strains, MIC of meropenem ≤ 16 mg/L - in 8 (13.3% of strains). The effect of potentiating the activity of doripenem with ertapenem at a fixed pharmacokinetic / pharmacodynamic concentration was observed for 20.0% of the strains producing KPC carbapenemase and 29.0% of the strains producing OXA-48 carbapenemase. The potentiating effect was independent of the presence of colistin resistance. Thus, the ability of ertapenem to potentiate the antimicrobial activity of doripenem and meropenem against some of the strains producing serine carbapenemases (KPC and OXA-48) was confirmed. The necessity of routine determination of the true MIC values of carbapenems was shown to optimize their dosage regimens and select the combination antibiotic therapy regimens.

Cefazolin and Ertapenem Salvage Therapy Rapidly Clears Persistent Methicillin-Susceptible Staphylococcus aureus Bacteremia.

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.

Personalized Ertapenem Prophylaxis for Carriers of Extended-spectrum ß-Lactamase-producing Enterobacteriaceae Undergoing Colorectal Surgery.

BACKGROUND: Carriers of extended-spectrum ß-lactamase-producing Enterobacteriaceae (ESBL-PE) who receive cephalosporin-based prophylaxis have twice the risk of surgical site infection (SSI) following colorectal surgery as noncarriers. We tested whether ESBL-PE screening and personalized prophylaxis with ertapenem reduces SSI risk among carriers. METHODS: We conducted a prospective nonrandomized, nonblinded, interventional study in 3 hospitals in Israel, Switzerland, and Serbia. Patients were screened for ESBL-PE carriage before elective colorectal surgery. During the baseline phase, departmental guidelines advised prophylaxis with a cephalosporin plus metronidazole. In the intervention phase, guidelines were changed for ESBL-PE carriers to receive ertapenem. The primary outcome was any type of SSI within 30 days. We calculated adjusted risk differences (ARDs) following logistic regression. RESULTS: The intention-to-treat analysis compared 209 ESBL-PE carriers in the baseline phase to 269 in the intervention phase. SSI rates were 21.5% and 17.5%, respectively (ARD, -4.7% [95% confidence interval {CI}, -11.8% to 2.4%]). Unplanned crossover was high (15%), so to assess efficacy we performed an as-treated analysis comparing 247 patients who received cephalosporin-based prophylaxis with 221 who received ertapenem. SSI rates were 22.7% and 15.8%, respectively (ARD, -7.7% [95% CI, -14.6% to -.8%]), and rates of SSI caused by ESBL-PE were 6.5% and 0.9%, respectively (ARD, -5.6% [95% CI, -8.9% to -2.3%]). There was no significant difference in the rate of deep SSI. The number needed to treat to prevent 1 SSI in ESBL-PE carriers was 13. CONCLUSIONS: Screening for ESBL-PE carriage before colorectal surgery and personalizing prophylaxis for carriers is efficacious in reducing SSI.

Comparative Plasma Pharmacokinetics of Ceftriaxone and Ertapenem in Normoalbuminemia, Hypoalbuminemia, and Albumin Replacement in a Sheep Model.

Optimal concentrations of unbound antimicrobials are essential for a maximum microbiological effect. Although hypoalbuminemia and albumin fluid resuscitation are common in critical care, the effects of different albumin concentrations on the unbound concentrations of highly protein-bound antimicrobials are not known. The aim of this study was to compare the effects of different albumin states on total and unbound concentrations of ertapenem and ceftriaxone using an ovine model. The study design was a prospective, three-phase intervention observational study. The subjects were healthy Merino sheep. Eight sheep were subjected to three experimental phases: normoalbuminemia, hypoalbuminemia using plasmapheresis, and albumin replacement using a 25% albumin solution. In each phase, ceftriaxone at 40 mg/kg of body weight and ertapenem at 15 mg/kg were given intravenously. Blood samples were collected at predefined intervals and analyzed using an ultrahigh-performance liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters such as the area under the curve from 0 to 24 h (AUC0-24), plasma clearance (CL), and apparent volume of distribution in the terminal phase (V) were estimated and compared between the phases. The protein and albumin concentrations were significantly different between phases. Hypoalbuminemia resulted in a significantly lower AUC0-24 and higher CL of total and unbound concentrations of ceftriaxone than in the other phases, whereas albumin replacement led to higher AUC0-24 and lower CL than in the other phases for both drugs. The V values for total drug concentrations for both drugs were significantly lower with albumin replacement. For highly protein-bound drugs such as ceftriaxone and ertapenem, both hypoalbuminemia and albumin replacement may affect unbound drug exposure.

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.

Valproate Interaction With Carbapenems: Review and Recommendations.

Introduction: Valproic acid is a commonly used antiepileptic drug. Combining valproate derivatives with carbapenem antibiotics is associated with a potential drug interaction that decreases serum concentration of valproate and may expose the patient to uncontrolled seizure risk from valproate subtherapeutic concentration. Raising awareness of this drug interaction among health care providers including emergency department physicians, neurologists, and pharmacists is highly needed. The aim of this article was to review the current literature about the potential drug interaction resulting from combining valproate derivatives with carbapenem antibiotics and to establish therapeutic recommendations regarding their use together. Methods: A review of the literature was conducted using Medline (through PubMed), Ovid, Embase, Cochrane library using the following keywords: valproate, valproic acid, carbapenem, ertapenem, doripenem, meropenem, imipenem, and valproate drug interaction. In addition, a manual search through major journals for articles referenced in PubMed was performed. Related publications from January 1998 till November 2018 were included in the initial search. Relevant publications were reviewed, and data regarding patients, type of carbapenem used, valproic acid dosing and level, interaction severity, and clinical outcome were summarized. Results and Discussion: Few clinical trials and multiple case reports have shown that carbapenem antibiotics including meropenem, ertapenem, imipenem, and doripenem can decrease the serum concentration of valproate derivatives leading to a subtherapeutic serum concentration and seizures in some patients. Valproic acid serum concentration may be significantly decreased with addition of a carbapenem antibiotic but generally return toward normal shortly after discontinuation of the carbapenem antibiotic. Conclusions: Generally, the concurrent use of carbapenem antibiotics with valproate derivatives should be avoided due to the potential of drug-drug interaction that results in subtherapeutic valproate serum concentration. Other antimicrobial agents should be considered as alternatives to carbapenems but if a concurrent carbapenem is necessary, using an additional antiepileptic agent is recommended. Therapeutic drug monitoring of valproate serum concentrations is warranted when a carbapenem-valproic acid combination therapy is unavoidable.

Pharmacokinetic-Pharmacodynamic Evaluation of Ertapenem for Patients with Hospital-Acquired or Ventilator-Associated Bacterial Pneumonia.

Ertapenem provides activity against many pathogens commonly associated with hospital-acquired and ventilator-associated bacterial pneumoniae (HABP and VABP, respectively), including methicillin-susceptible Staphylococcus aureus and numerous Gram-negative pathogens with one major gap in coverage, Pseudomonas aeruginosa Pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses were conducted to evaluate ertapenem against the most prevalent Enterobacteriaceae causing HABP/VABP. The objective of these analyses was to provide dose selection support for and demonstrate the appropriateness of ertapenem to empirically treat patients with HABP/VABP when administered with murepavadin, a novel targeted antimicrobial exhibiting a highly specific spectrum of activity against P. aeruginosa A previously developed population pharmacokinetic model, a total-drug epithelial lining fluid (ELF) to free-drug serum penetration ratio, contemporary in vitro surveillance data for ertapenem against Enterobacteriaceae, and percentage of the dosing interval for which drug concentrations exceed the MIC value (%T>MIC) targets associated with efficacy were used to conduct Monte Carlo simulations for five ertapenem regimens administered over short or prolonged durations of infusion. Overall total-drug ELF percent probabilities of PK-PD target attainment based on a %T>MIC target of 35% among simulated patients with HABP/VABP arising from Enterobacteriaceae based on pathogen prevalence data for nosocomial pneumonia ranged from 89.1 to 92.7% for all five ertapenem regimens evaluated. Total-drug ELF percent probabilities of PK-PD target attainment ranged from 99.8 to 100%, 97.9 to 100%, 10.6 to 74.1%, and 0 to 1.50% at MIC values of 0.06, 0.12, 1, and 4 µg/ml, respectively (MIC90 values for Escherichia coli, Serratia marcescens, Enterobacter species, and Klebsiella pneumoniae, respectively). Results of these analyses provide support for the evaluation of ertapenem in combination with murepavadin for the treatment of patients with HABP/VABP.

Evaluation of Carbapenems for Treatment of Multi- and Extensively Drug-Resistant Mycobacterium tuberculosis.

Multi- and extensively drug-resistant tuberculosis (M/XDR-TB) has become an increasing threat not only in countries where the TB burden is high but also in affluent regions, due to increased international travel and globalization. Carbapenems are earmarked as potentially active drugs for the treatment of Mycobacterium tuberculosis To better understand the potential of carbapenems for the treatment of M/XDR-TB, the aim of this review was to evaluate the literature on currently available in vitro, in vivo, and clinical data on carbapenems in the treatment of M. tuberculosis and to detect knowledge gaps, in order to target future research. In February 2018, a systematic literature search of PubMed and Web of Science was performed. Overall, the results of the studies identified in this review, which used a variety of carbapenem susceptibility tests on clinical and laboratory strains of M. tuberculosis, are consistent. In vitro, the activity of carbapenems against M. tuberculosis is increased when used in combination with clavulanate, a BLaC inhibitor. However, clavulanate is not commercially available alone, and therefore, it is impossible in practice to prescribe carbapenems in combination with clavulanate at this time. Few in vivo studies have been performed, including one prospective, two observational, and seven retrospective clinical studies to assess the effectiveness, safety, and tolerability of three different carbapenems (imipenem, meropenem, and ertapenem). We found no clear evidence at the present time to select one particular carbapenem among the different candidate compounds to design an effective M/XDR-TB regimen. Therefore, more clinical evidence and dose optimization substantiated by hollow-fiber infection studies are needed to support repurposing carbapenems for the treatment of M/XDR-TB.