Treatment Of Complicated Intra-abdominal Infections Research Articles

The Efficacy and Safety of Eravacycline in the Treatment of Complicated Intra-Abdominal Infections: A Systemic Review and Meta-Analysis of Randomized Controlled Trials.

This study aims to assess the clinical efficacy and safety of eravacycline for treating complicated intra-abdominal infection (cIAI) in adult patients. The PubMed, Web of Science, EBSCO, Cochrane databases, Ovid Medline, Embase, and ClinicalTrials.gov were searched up to May 2019. Only randomized controlled trials (RCTs) that evaluated eravacycline and other comparators for the treatment of cIAI were included. The primary outcome was the clinical cure rate at the test-of-cure visit based on modified intent-to-treat population, microbiological intent-to-treat population, clinically evaluable population, and microbiological evaluable population, and the secondary outcomes were clinical failure rate and the risk of adverse event. Three RCTs were included. Overall, eravacycline had a clinical cure rate (88.7%, 559/630) at test-of-cure in modified intent-to-treat population similar to comparators (90.1%, 492/546) in the treatment of cIAIs (risk ratio (RR), 0.99; 95% confidence interval (CI), 0.95–1.03; I2 = 0%, Figure 3). In the microbiological intent-to-treat, clinically evaluable, and microbiological evaluable populations, no difference was found between eravacycline and comparators in terms of clinical cure rate at test-of-cure (microbiological intent-to-treat population, RR, 0.99; 95% CI, 0.95–1.04; I2 = 0%, clinically evaluable population, RR, 1.00; 95% CI, 0.97–1.03; I2 = 0%, microbiological evaluable population, RR, 0.98; 95% CI, 0.95–1.02; I2 = 0%). In addition, eravacycline had clinical failure rate similar to comparators at test-of-cure in modified intent-to-treat population (RR, 1.01; 95% CI, 0.61–0.69; I2 = 0%), microbiological intent-to-treat population (RR, 1.34; 95% CI, 0.77–2.31; I2 = 16%), clinically evaluable population (RR, 1.03; 95% CI, 0.61–1.76; I2 = 0%), and microbiological evaluable population (RR, 1.32; 95% CI, 0.75–2.32; I2 = 10%). Although eravacycline was associated with higher risk of treatment-emergent adverse event than comparators (RR, 1.34; 95% CI, 1.13–1.58; I2 = 0%), no significant differences were found between eravacycline and comparators for the risk of serious adverse event (RR, 1.04; 95% CI, 0.65–1.65; I2 = 0%), discontinuation of study drug because of adverse event (RR, 0.68; 95% CI, 0.23–1.99; I2 = 13%), and all-cause mortality (RR, 1.09; 95% CI, 0.41–2.9; I2 = 28%). In conclusion, the clinical efficacy of eravacycline is as high as that of the comparator drugs in the treatment of cIAIs and this antibiotic is as well tolerated as the comparators.

Eravacycline, a newly approved fluorocycline.

Complicated intra-abdominal infections (cIAIs) are commonly associated with multimicroorganisms and treatment choices are becoming narrower due to developing resistance, especially in the gram-negative Enterobacteriaceae species. Eravacycline is a newly developed, fully synthetic tetracycline derivative that has shown potent broad-spectrum activity against a wide variety of microorganisms, including those such as extended spectrum β-lactamase producing Enterobacteriaceae and Acinetobacter. Eravacycline has shown activity against many gram-positive organisms such as methicillin-resistant S. aureus and vancomycin resistant Enterococcus faecalis and Enterococcus faecium (VRE), gram-negative organisms such as Escherichia coli, and anaerobic species of microorganisms such as Bacteroides. This fluorocycline has been compared to ertapenem and meropenem for the treatment of complicated intra-abdominal infections and levofloxacin for the treatment of complicated urinary tract infections. Eravacycline was shown to be noninferior to ertapenem but did not meet noninferiority criteria in comparison to levofloxacin. Oral and IV formulations on eravacycline were tested in clinical trials, but at this time, only the IV formulation is FDA approved. Eravacycline has been noted to have a half-life of 20h with protein binding around 80%; AUC over minimum inhibitory concentration (MIC) has also been shown to be eravacycline's best predictor of efficacy. Of note, eravacycline does not require any renal dose adjustments, as the majority of its clearance is by nonrenal pathways.

Eravacycline: The Tetracyclines Strike Back.

Objective: To review the pharmacology, pharmacokinetics, efficacy, safety, and place in therapy of eravacycline, a novel fluorocycline antibiotic from the tetracycline family. Data Sources: A PubMed search was conducted for data between 1946 and March 2019 using MeSH terms eravacycline and TP-434. An internet search was conducted for unpublished clinical research. Study Selection and Data Extraction: The literature search was limited to English-language studies that described clinical efficacy, safety, and pharmacokinetics in humans and animals. Abstracts featuring prepublished data were also evaluated for inclusion. Data Synthesis: Eravacycline has in vitro activity against multidrug-resistant organisms, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus, extended-spectrum β-lactamase-producing and carbapenem-resistant Enterobacteriaceae, and Acinetobacter. It was approved for the treatment of complicated intra-abdominal infections (cIAIs) in adults following favorable results of 2 phase III trials, IGNITE 1 and IGNITE 4, compared with ertapenem and meropenem, respectively. The most common adverse drug events associated with eravacycline were infusion site reactions (7.7%), nausea (6.5%), vomiting (3.7%), and diarrhea (2.3%). Relevance to Patient Care and Clinical Practice: Eravacycline will likely be most useful for resistant infections when lack of tolerability, resistant phenotypes, or allergies prevent the use of β-lactams. Conclusions: Eravacycline is a new tetracycline antibiotic with a broad spectrum of activity that has demonstrated efficacy in the treatment of cIAIs. Although it has activity against multidrug-resistant organisms, data are limited for other indications.

Clinical Pharmacokinetics and Pharmacodynamics of Eravacycline.

On 27 August, 2018, the US Food and Drug Administration approved eravacycline, a fluorocycline antimicrobial agent within the tetracycline class of antibacterial drugs, for the treatment of complicated intra-abdominal infections in patients aged 18years and older. This decision was based on substantial clinical and pre-clinical data, including rigorous pharmacokinetic and pharmacodynamic work. This paper examines the in-vivo pharmacokinetic/pharmacodynamic work that led to the approval of eravacycline and explores how this important new antibiotic may be used to treat aggressive multidrug-resistant infections in the years ahead.

Dose Selection and Validation for Ceftazidime-Avibactam in Adults with Complicated Intra-abdominal Infections, Complicated Urinary Tract Infections, and Nosocomial Pneumonia.

Avibactam is a non-β-lactam β-lactamase inhibitor that has been approved in combination with ceftazidime for the treatment of complicated intra-abdominal infections, complicated urinary tract infections, and nosocomial pneumonia, including ventilator-associated pneumonia. In Europe, ceftazidime-avibactam is also approved for the treatment of Gram-negative infections with limited treatment options. Selection and validation of the ceftazidime-avibactam dosage regimen was guided by an iterative process of population pharmacokinetic (PK) modelling, whereby population PK models for ceftazidime and avibactam were developed using PK data from clinical trials and updated periodically. These models were used in probability of target attainment (PTA) simulations using joint pharmacodynamic (PD) targets for ceftazidime and avibactam derived from preclinical data. Joint PTA was calculated based on the simultaneous achievement of the individual PK/PD targets (50% free time above the ceftazidime-avibactam MIC for ceftazidime and free time above a critical avibactam threshold concentration of 1 mg/liter for avibactam). The joint PTA analyses supported a ceftazidime-avibactam dosage regimen of 2,000 + 500 mg every 8 h by 2-h intravenous infusion for patients with creatinine clearance (CLCR) >50 ml/min across all approved indications and modified dosage regimens for patients with CLCR ≤50 ml/min. Subgroup simulations for individual phase 3 patients showed that the dosage regimen was robust, with high target attainment (>95%) against MICs ≤8 mg/liter achieved regardless of older age, obesity, augmented renal clearance, or severity of infection. This review summarizes how the approved ceftazidime-avibactam dosage regimens were developed and validated using PK/PD targets, population PK modeling, and PTA analyses.

Mass Balance and Drug Interaction Potential of Intravenous Eravacycline Administered to Healthy Subjects.

Eravacycline is a novel, fully synthetic fluorocycline that is approved for the treatment of complicated intra-abdominal infections (cIAI) in adult patients. We report results from three studies in healthy subjects that investigated the distribution, metabolism, and excretion of intravenous (i.v.) eravacycline and the effect of a CYP3A4 inhibitor (itraconazole) and inducer (rifampin) on the pharmacokinetics (PK) of i.v. eravacycline. In the mass balance study, the majority of total radioactivity from [14C]eravacycline was recovered in the feces, suggesting biliary/fecal elimination is the major route of excretion for eravacycline and its metabolites after IV administration. The volume of distribution (217 liters) was greater than that of extracellular fluid, which suggests distribution beyond the central compartment. In the drug-drug interaction studies, mean area under the concentration-time curve from 0 h to the last time point (AUC0-t ) and half-life were increased approximately 30% to 40% after a concomitant dose of i.v. eravacycline and itraconazole and clearance (CL) was decreased. A reduction in total eravacycline exposure (AUC) of approximately 25% to 35% and an increase in CL of approximately 50% occurred with concomitant eravacycline and rifampin treatment. The dose of eravacycline should be increased to 1.5 mg/kg of body weight every 12 h when coadministered with a strong CYP3A inducer.

Eravacycline: A Review in Complicated Intra-Abdominal Infections.

Eravacycline (Xerava™), a novel fully synthetic fluorocycline, consists of the tetracyclic core scaffold with unique modifications in the tetracyclic D ring; consequently, it exhibits potent in vitro activity against Gram-positive and -negative bacterial strains expressing certain common tetracycline-specific acquired resistance mechanisms. In vitro, eravacycline exhibits potent activity against a broad spectrum of clinically relevant Gram-positive and -negative aerobic and anaerobic bacteria. Intravenous eravacycline is approved in several countries for the treatment of complicated intra-abdominal infections (cIAIs) in adult patients. In two pivotal double-blind, multinational trials in this patient population, eravacycline (infusion ≈ 1 h) was noninferior to intravenous ertapenem or meropenem at the test-of-cure visit in terms of clinical response rates in all prespecified populations. Eravacycline had an acceptable tolerability profile, with infusion site reactions, nausea, vomiting and diarrhoea the most commonly reported adverse reactions, most of which were of mild to moderate severity. Given its broad spectrum of activity against common clinically relevant pathogens (including those expressing certain tetracycline- and other antibacterial-specific acquired resistance mechanisms) and its more potent in vitro activity and better tolerability profile than tigecycline, eravacycline provides a novel emerging option for the treatment of adult patients with cIAIs, especially as empirical therapy when coverage of resistant pathogens is required.

New possibilities in antibacterial treatment of intra-abdominal infections caused by multiresistant microflora

To determine the place of new drugs with activity against multidrug resistant strains of microorganisms in the treatment of complicated intraabdominal infections. The incidence and distribution of pathogens isolated from intra-abdominal specimens in patients with intra-abdominal infections are analyzed. The current situation on the growth of resistant strains among pathogens causing intra-abdominal infections is rewied. New combined drugs for the treatment of multidrug resistant infections - ceftolozane/tazobactam and ceftazidim/avibactam plus metronidazole, has been suggested. Their potential role in empiric and targeted antibacterial treatment of complicated intraabdominal infections is defined. Taking into consideration local monitoring data and risk factors of multi resistant strains Ceftolozane/tazobactam in combination with metronidazole can be used in empiric regime of treatment. Due to the high activity on carbapenem resistant strains of Klebsiella pneumonia and the lack of alternatives, it is advisable to use Ceftazidim/avibactam for the targeted therapy.

The Role of Ertapenem for the Treatment of Complicated Intra-abdominal Infections With a Positive Culture for Enterococcus faecalis.

Controversy remains as to whether Enterococcus faecalis recovered from intra-abdominal infections (IAIs) requires targeted therapy. In a multicenter study comparing patients with IAIs from which E. faecalis was identified in intra-abdominal cultures, no difference in clinical outcomes was observed between patients receiving ertapenem vs those receiving piperacillin/tazobactam.

1963. Combined Microbiological Response Rates From Two Phase 3 Trials Demonstrating the Activity of Eravacycline in the Treatment of Complicated Intra-abdominal Infections: A Pooled Analysis of IGNITE1 and IGNITE4

BackgroundIGNITE1 and IGNITE4 were randomized, double-blind, double-dummy, multicenter studies which demonstrated the efficacy and safety of eravacycline (ERV) compared with a carbapenem in subjects with complicated intra-abdominal infections (cIAIs). The primary objective of this analysis was to compare the microbiological response at the test-of-cure (TOC) visit for subjects in the two treatment groups.MethodsAppropriate aerobic and anaerobic specimens for culture at the time of the initial procedure were collected from the site of infection and directly inoculated into transport media. Blood and intra-abdominal specimens were cultured, and species identified according to local laboratory practice. Pure cultures of isolates were sent to a reference laboratory for susceptibility analysis to ERV and comparators. Favorable microbiological response rates at the TOC visit were determined for each baseline pathogen isolated from blood and/or intra- or extra-abdominal specimens in the micro-ITT population.ResultsFor subjects with infections caused by Enterobacteriaceae, the overall favorable microbiological response rates for ERV-treated subjects were 86.3% and 91.8% for IGNITE1 and IGNITE4, respectively. The favorable microbiological response rates among pooled ERV-treated subjects are shown in the Table.Baseline PathogenERV No./Total No. (%)Baseline PathogenERV No/Total No. (%) Enterobacteriaceae 277/314 (88.2) Streptococcus viridans group109/120 (90.8) E. coli 223/253 (88.1) E. faecalis 45/54 (83.3) E. cloacae 18/21 (85.7) E. faecium 39/45 (86.7) K. pneumoniae 38/39 (97.4) S. aureus 24/24 (100) A. baumannii 13/13 (100) B. fragilis 74/84 (88.1)ConclusionIn IGNITE1 and IGNITE4 studies, high favorable microbiological responses were observed for ERV. More than 88% of five Enterobacteriaceae spp. and B. fragilis, the most common bacteria associated with intraabdominal infections, were eradicated by ERV. Comparable eradication rates were observed following ertapenem and meropenem therapy, further establishing that ERV was at least as effective as carbapenem treatments. These data support in vitro observations that ERV has broad-spectrum activity against common isolates found in intra-abdominal infections.Disclosures J. Newman, Tetraphase Pharmaceuticals: Employee, Salary. S. Izmailyan, Tetraphase Pharmaceuticals: Employee, Salary. C. Fyfe, Tetraphase Pharmaceuticals: Employee, Salary. L. Tsai, Tetraphase Pharmaceuticals: Employee and Shareholder, Salary.

1978. Efficacy of Eravacycline in Secondary Bacteremia: A Post Hoc Analysis of Two Phase 3 studies of Complicated Intra-Abdominal Infection

BackgroundEravacycline is a novel, fully synthetic fluorocycline antibiotic that was evaluated for the treatment of complicated intra-abdominal infections (cIAI) in two Phase 3 (IGNITE1 and IGNITE4) clinical trials. The objective of this analysis was to evaluate microbiological response at the test of cure (TOC) visit in patients with baseline bacteremia who received eravacycline vs. comparators (ertapenem and meropenem).MethodsPooled data from IGNITE1 and IGNITE4 studies were analyzed. All patients enrolled were randomized (1:1) to receive eravacycline (1 mg/kg IV q12h) or ertapenem 1 g IV q24h, (IGNITE1 study) or meropenem 1g IV q8h, (IGNITE4 study) for 4–14 days. Blood (aerobic and anaerobic bottles) and intra-abdominal samples were collected from all patients. Clinical outcome at the TOC visit (28 days after randomization) in the microbiological-intention to treat population (micro-ITT) was the primary efficacy endpoint.ResultsFour hundred fifteen patients were treated with eravacycline and 431 with comparators of which 39 (9.4%) and 40 (9.3%), respectively, had concurrent bacteremia. Demographic and baseline characteristics were similar among the groups. In the micro-ITT population, the pooled clinical response at the TOC visit for eravacycline vs. comparators was 88.7% and 89.3% (−0.7; 95% CI, −4.9, 3.6), respectively. The baseline pathogens associated with concurrent bacteremia and the microbiological eradication for selected pathogens are presented in Table 1.Table 1.Microbiological Eradication at the Test of Cure Visit by Baseline Pathogen from Blood SpecimenEravacycline, (N = 415), n (%)Comparatorsa, (N = 431), n (%)Gram-negative14/15 (93.3)14/15 (93.3) E. coli 5/6 (83.3)6/7 (85.7)Gram-positive15/15 (100)11/11 (100) Streptococcus spp.8/8 (100)4/4 (100) Enterococcus spp.2/2 (100)5/5 (100)Anaerobes9/9 (100)13/14 (92.9) Bacteroides spp.6/6 (100)8/8 (100) aMeropenem and ertapenem.ConclusionEravacycline demonstrated a similar microbiological eradication rate as comparator agents in patients with cIAI associated with secondary bacteremia.Disclosures K. Lawrence, Tetraphase Pharmaceuticals: Employee, Salary. M. Olesky, Tetraphase Pharmaceuticals: Employee and Shareholder, Salary. S. Izmailyan, Tetraphase Pharmaceuticals: Employee, Salary. L. Tsai, Tetraphase Pharmaceuticals: Employee and Shareholder, Salary.

1976. Pooled Analysis of Safety Data From Phases 2 and 3 Clinical Trials Evaluating Eravacycline in Complicated Intra-Abdominal Infections

BackgroundEravacycline is a novel, fully synthetic fluorocycline antibiotic that was evaluated in three comparator-controlled studies for the treatment of complicated intra-abdominal infections (cIAI). The objective of this analysis was to evaluate the safety profile of eravacycline 1 mg/kg IV q12h for the treatment of cIAI.MethodsPooled data from one phase 2 and two phase 3 (IGNITE1 and IGNITE4) clinical trials in cIAI were analyzed. Patients in the trials were randomized to receive eravacycline 1 mg/kg IV q12h, ertapenem 1 g IV q24h, or meropenem 1 g IV q8h for 4–14 days. Overall treatment-emergent adverse events (TEAEs), serious TEAEs, and laboratory assessments were evaluated.ResultsFive hundred seventy-six patients were treated with eravacycline 1 mg/kg IV q12h and 547 patients with comparators (ertapenem and meropenem). Demographic and baseline characteristics were similar among the groups. Overall summary and common TEAEs are presented in Table 1. None of the serious TEAEs or those leading to death were related to the study drug. Clinically notable laboratory abnormalities were relatively uncommon and occurred at similar frequencies in eravacycline- and comparator-treated patients.Table 1.Overall Summary of Treatment Emergent Adverse Events—Eravacycline Phases 2 and 3 Clinical StudiesEravacycline 1 mg/kg IV q12h, N = 576, n (%)Comparatorsa, N = 547, n (%)Any TEAEs217 (37.7)152 (27.8) Nausea40 (6.9)5 (0.9) Vomiting20 (3.5)13 (2.4) Diarrhea13 (2.3)8 (1.5) Infusion phlebitis13 (2.3)1 (0.2) Pyrexia11 (1.9)11 (2.0) Anemia7 (1.2)12 (2.2)Treatment-related TEAEs71 (12.3)20 (3.7)TEAEs leading to discontinuation from study drug9 (1.6)12 (2.2)Serious TEAEs33 (5.7)33 (6.0)TEAEs leading to death7 (1.2)7 (1.3) aComparators include ertapenem 1 g IV q24h and meropenem 1 g IV q8h.ConclusionThis pooled analysis demonstrated that eravacycline 1 mg/kg IV q12h was generally well tolerated for the treatment of cIAI when compared with ertapenem and meropenem. Results of the analysis are consistent with those of individual clinical studies and no new safety signals were identified.Disclosures E. Efimova, Tetraphase Pharmaceuticals: Employee, Salary. M. Olesky, Tetraphase Pharmaceuticals: Employee and Shareholder, Salary. S. Izmailyan, Tetraphase Pharmaceuticals: Employee, Salary. L. Tsai, Tetraphase Pharmaceuticals: Employee and Shareholder, Salary.

FDA Approval of Eravacycline for Complicated Intra-Abdominal Infections

The FDA recently approved eravacycline (Xerava) for treatment of complicated intra-abdominal infections (cIAIs) in adults. Eravacycline is a

Clinical Pharmacokinetics and Pharmacodynamics of Ceftazidime-Avibactam Combination: A Model-Informed Strategy for its Clinical Development.

Avibactam is a non-β-lactam, β-lactamase inhibitor of the diazabicyclooctane class that covalently acylates its β-lactamase targets, encompassing extended spectrum of activities that cover serine β-lactamases but not metallo-β-lactamases. Ceftazidime and avibactam have complementary pharmacokinetic (PK) profiles. Both drugs have a half-life of approximately 2 h, making them suitable to be combined in a fixed-dose combination ratio of 4:1 (ceftazidime:avibactam). Renal clearance is the primary elimination pathway of both ceftazidime and avibactam, and dose adjustment is required in patients with moderate and severe renal impairment. Population PK models of ceftazidime and avibactam were developed separately and incorporated body weight, disease state, ethnicity, and renal function (creatinine clearance) as covariates of clearance and volume of distribution. The clinical dosing regimen of ceftazidime/avibactam combination was determined from population PK model simulations in the patient population for dosing regimens that can achieve sufficient joint probability of target attainment for ceftazidime minimum inhibitory concentration (MIC) of 8mg/L at a fixed 4mg/L avibactam concentration (MIC ≤ 8/4mg/L); 8mg/L is the breakpoint of ceftazidime in Enterobacteriaceae and Pseudomonas aeruginosa for the target pharmacodynamic indices of ceftazidime and avibactam of 50% time at which the free ceftazidime concentration is above the MIC (fT > MIC) and 50% time at which the free avibactam is above a threshold concentration of 1mg/L (fT > CT). Whereas the static index approach does not take into account the changing potency of ceftazidime in the presence of changing avibactam concentration, a mathematical model based on kill-curve kinetics was utilized to validate the dose selection in humans. The clinical dosing regimen of 2/0.5g ceftazidime/avibactam administered every 8h as a 2-h intravenous infusion in patients with normal renal function, with dose adjustment in renal impairment, demonstrated statistical non-inferiority to carbapenem in phase III studies on the treatment of complicated intra-abdominal infection, complicated urinary tract infection, and nosocomial pneumonia, including ceftazidime non-susceptible Gram-negative pathogens. The success of the phase III studies validated the dose selection and exposure target that were associated with efficacy based on a model-informed approach.

A Review of Ceftolozane/Tazobactam for the Treatment of Infections Caused by Multidrug-Resistant Pathogens

Abstract Multidrug-resistant (MDR) gram-negative bacterial infection is a serious and growing public health threat, in part due to limited treatment options. A novel cephalosporin and β-lactamase inhibitor, ceftolozane/tazobactam, has a broad spectrum of activity against MDR pathogens and is approved for the treatment of complicated intra-abdominal infections in combination with metronidazole and complicated urinary tract infections, including pyelonephritis. This article reviews published data on the clinical pharmacology, spectrum of activity, pharmacokinetics/pharmacodynamics, clinical efficacy and safety, and dosing and administration of ceftolozane/tazobactam. Searches of MEDLINE from January 2000 to April 2017 were conducted using the following keywords: ceftolozane, tazobactam, and ceftolozane tazobactam. Additional references were identified from a review of the retrieved articles' citations. Ceftolozane is active against organisms producing AmpC β-lactamases and MDR Pseudomonas aeruginosa. The addition of tazobactam enhances activity against extended-spectrum β-lactamase–producing organisms. Data from phase III trials using ceftolozane/tazobactam for the treatment of complicated intra-abdominal infection and complicated urinary tract infections have yielded positive results. Ceftolozane/tazobactam has demonstrated noninferior or superior efficacy to comparators in clinical trials. It has a favorable safety profile and few drug-drug interactions. This novel combination agent has a role in treating MDR infections, particularly P. aeruginosa, although its use should be reserved for patients without other treatment options to limit the risk of resistance. Although case reports of successful treatment have been reported, further investigation is needed into the utility of ceftolozane/tazobactam for the treatment of bacteremia and pneumonia caused by MDR pathogens.

PIN36 - Cost-Effectiveness of Ceftolozane/Tazobactam Plus Metronidazole as Empiric Therapy for the Treatment of Complicated Intra-Abdominal Infections in Colombia

PIN36 - Cost-Effectiveness of Ceftolozane/Tazobactam Plus Metronidazole as Empiric Therapy for the Treatment of Complicated Intra-Abdominal Infections in Colombia

Ceftolozane/tazobactam dose regimens in severely/morbidly obese patients with complicated intra-abdominal infection or complicated urinary tract infection

Ceftolozane/tazobactam is approved for treatment of complicated intra-abdominal infection (cIAI) and complicated urinary tract infection (cUTI) with renal function-based dose adjustment. Given that creatinine clearance, body weight and sex are highly correlated in severely/morbidly obese patients, this study investigated whether approved dosing regimens for ceftolozane/tazobactam are appropriate in severely/morbidly obese patients based on simulated pharmacokinetic/pharmacodynamic target attainment, with confirmation from observed clinical outcomes data from the phase 3 clinical development programme. Using a previously published population pharmacokinetic model, 1000 patients were randomly sampled from an internal pooled database of 201 severely/morbidly obese patients (BMI ≥ 35 kg/m2) and were used for Monte Carlo simulation to test whether the labelled dose regimens can achieve ≥90% probability of a target of 32.2% (1-log kill) time above free ceftolozane concentration against pathogens at an MIC up to 8 mg/L. Clinical outcomes data for severely/morbidly obese patients with cIAI or cUTI from pivotal phase 3 studies were summarised to calculate clinical and composite cure rates as a complimentary support. With the approved renal function-based dosing regimens, >90% target attainment of bactericidal activity was achieved at MICs up to 8 mg/L in the simulated severely/morbidly obese patients with cIAI or cUTI, similar to target attainment in non-obese patients and further confirmed by phase 3 outcomes where cure rates in severely/morbidly obese patients and non-obese patients are similar. Approved dosing regimens of ceftolozane/tazobactam, adjusted according to renal function, can achieve adequate target attainment and high clinical cure rates in severely/morbidly obese patients with cIAI or cUTI.

Efficacy and safety of ceftazidime-avibactam in the treatment of complicated intra-abdominal infections (CIAIs) and complicated urinary tract infections (CUTIs): A meta-analysis of randomized controlled trials

The aim of this study was to assess the efficacy and safety of ceftazidime-avibactam in the treatment of complicated intra-abdominal infections (CIAIs) and complicated urinary tract infections (CUTIs) with meta-analysis method. We included six randomized clinical trials identified from Medline, Embase, Cochrane Library, "ISRCTN Register" and "ClinicalTrials.gov" which compared ceftazidime-avibactam with comparison group. The meta-analysis was performed using Review Manager software version 5.3. Ceftazidime-avibactam versus active comparisons demonstrated a statistically significant higher rate of microbiological response success on microbiological evaluable populations at the test-of-cure visit (95CI 1.10-2.38, p=0.02) and late-follow-up visit (95CI 1.09-2.23, p=0.02) for the treatment of CUTIs. Ceftazidime-avibactam versus active comparisons demonstrated a statistically significant higher rate of microbiological response success on EME populations at the test-of-cure visit (95CI 1.08-4.27, p=0.03) and late-follow-up visit (OR=1.75, 95CI 1.33-2.29, p<0.0001) for the treatment of CUTIs. Similar results were obtained at the late-follow-up visit (OR = 1.58, 95CI 1.26-1.97, p<0.0001) on microbiologically modified intent-to-treat (mMITT) populations for the treatment of CUTIs. We can find better eradication rates for E. coli and Klebsiella pneumoniae based on mMITT populations. In terms of AEs, SAEs and mortality, ceftazidime-avibactam had a safety and tolerability profile broadly similar to the comparison group. This meta-analysis provides evidence of the efficacy of ceftazidime-avibactam as a potential alternative for the treatment of patients with CUTIs, and CIAIs.

Цефтолозан/тазобактам – новый игрок на поле борьбы с полирезистентными возбудителями

Ceftolozane/tazobactam is a new combined antibacterial agent for the treatment of infections caused by gram-negative microorganisms, *P. aeruginosa* in particular, including strains resistant to other clinically available antimicrobials. In this paper we reviewed the data on antimicrobial activity, pharmacokinetics, clinical efficacy and safety of ceftolozane/tazobactam, as well as its potential role for the treatment of complicated intra-abdominal infections and urinary tract infections.

Imipenem-Relebactam and Meropenem-Vaborbactam: Two Novel Carbapenem-β-Lactamase Inhibitor Combinations.

Relebactam (formerly known as MK-7655) is a non-β-lactam, bicyclic diazabicyclooctane, β-lactamase inhibitor that is structurally related to avibactam, differing by the addition of a piperidine ring to the 2-position carbonyl group. Vaborbactam (formerly known as RPX7009) is a non-β-lactam, cyclic, boronic acid-based, β-lactamase inhibitor. The structure of vaborbactam is unlike any other currently marketed β-lactamase inhibitor. Both inhibitors display activity against Ambler class A [including extended-spectrum β-lactamases (ESBLs), Klebsiella pneumoniae carbapenemases (KPCs)] and class C β-lactamases (AmpC). Little is known about the potential for relebactam or vaborbactam to select for resistance; however, inactivation of the porin protein OmpK36 in K. pneumoniae has been reported to confer resistance to both imipenem-relebactam and meropenem-vaborbactam. The addition of relebactam significantly improves the activity of imipenem against most species of Enterobacteriaceae [by lowering the minimum inhibitory concentration (MIC) by 2- to 128-fold] depending on the presence or absence of β-lactamase enzymes. Against Pseudomonas aeruginosa, the addition of relebactam also improves the activity of imipenem (MIC reduced eightfold). Based on the data available, the addition of relebactam does not improve the activity of imipenem against Acinetobacter baumannii, Stenotrophomonas maltophilia and most anaerobes. Similar to imipenem-relebactam, the addition of vaborbactam significantly (2- to>1024-fold MIC reduction) improves the activity of meropenem against most species of Enterobacteriaceae depending on the presence or absence of β-lactamase enzymes. Limited data suggest that the addition of vaborbactam does not improve the activity of meropenem against A. baumannii, P. aeruginosa, or S. maltophilia. The pharmacokinetics of both relebactam and vaborbactam are described by a two-compartment, linear model and do not appear to be altered by the co-administration of imipenem and meropenem, respectively. Relebactam's approximate volume of distribution (V d) and elimination half-life (t ½) of~18L and 1.2-2.1h, respectively, are similar to imipenem. Likewise, vaborbactam's V d and t½ of~18L and 1.3-2.0h, respectively, are comparable to meropenem. Like imipenem and meropenem, relebactam and vaborbactam are both primarily renally excreted, and clearance correlates with creatinine clearance. In vitro and in vivo pharmacodynamic studies have reported bactericidal activity for imipenem-relebactam and meropenem-vaborbactam against various Gram-negative β-lactamase-producing bacilli that are not inhibited by their respective carbapenems alone. These data also suggest that pharmacokinetic-pharmacodynamic parameters correlating with efficacy include time above the MIC for the carbapenems and overall exposure for their companion β-lactamase inhibitors. Phase II clinical trials to date have reported that imipenem-relebactam is as effective as imipenem alone for treatment of complicated intra-abdominal infections and complicated urinary tract infections, including acute pyelonephritis. Imipenem-relebactam is currently in two phase III clinical trials for the treatment of imipenem-resistant bacterial infections, as well as hospital-associated bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP). A phase III clinical trial has reported superiority of meropenem-vaborbactam over piperacillin-tazobactam for the treatment of complicated urinary tract infections, including acute pyelonephritis. Meropenem-vaborbactam has recently demonstrated higher clinical cure rates versus best available therapy for the treatment of carbapenem-resistant Enterobacteriaceae (CRE), as well as for HABP and VABP. The safety and tolerability of imipenem-relebactam and meropenem-vaborbactam has been reported in various phase I pharmacokinetic studies and phase II and III clinical trials. Both combinations appear to be well tolerated in healthy subjects and hospitalized patients, with few serious drug-related treatment-emergent adverse events reported to date. In conclusion, relebactam and vaborbactam serve to broaden the spectrum of imipenem and meropenem, respectively, against β-lactamase-producing Gram-negative bacilli. The exact roles for imipenem-relebactam and meropenem-vaborbactam will be defined by efficacy and safety data from further clinical trials. Potential roles in therapy for these agents include the treatment of suspected or documented infections caused by resistant Gram-negative bacilli-producing ESBL, KPC, and/or AmpC β-lactamases. The usage of these agents in patients with CRE infections will likely become the standard of care. Finally, increased activity of imipenem-relebactam against P. aeruginosa may be of clinical benefit to patients with suspected or documented P. aeruginosa infections.