Treatment Of cIAI Research Articles

Comparison of efficacy and safety between elacycline and polymyxin for complicated intra-abdominal infections caused by multidrug-resistant bacteria

Objective: To compare the efficacy and safety of eravacycline and polymyxin drugs in the treatment of multidrug-resistant complicated intra-abdominal infections(cIAI). Methods: The cIAI patients diagnosed or highly suspected of multidrug resistant bacterial infection who received eravacycline treatment at Sir Run Run Shaw Hospital and Shulan (Hangzhou) Hospital from June to August 2023 were prospectively included as the elacycline group. The cIAI patients with cIAI caused by multidrug resistant bacteria who received treatment with polymyxin (B or E) from January 2021 to August 2023 were retrospectively collected. The acute physiology and chronic health scores and age were matched with those of the elacrinid group, and they were included in the polymyxin group. The study mainly analyzed the clinical efficacy, microbial clearance rate, comprehensive efficacy, and safety of the two groups at the end of treatment and discharge. Results: A total of 72 patients with cIAI were included in the study, including 53 males and 19 females, aged (56.0±15.4) years. Among them, there were 28 cases in the eravacycline group and 44 cases in the polymyxin group. There was no statistically significant differences in the baseline, the proportion of patients who used combined drugs, the strains, the infection sites and infection conditions of patients between the two groups(all P>0.05).The clinical efficacy rate at the end of treatment [89.3% (25/28) vs 56.8%(25/44), P=0.004] and discharge [(88.5%(23/26) vs 63.6%,(28/44), P=0.024], microbial clearance rate at the end of treatment [(88.9% (24/27) vs 47.6%(20/42), P=0.001] and discharge [(91.3%(21/23) vs 59.5%(25/42), P=0.007], and overall recovery rate at the end of treatment [(89.3%(25/28) vs 52.3%(23/44), P=0.001] and discharge [(88.5%(23/26) vs 63.6%(28/44), P=0.024] in the erythromycin group were higher than those in the polymyxin drug group. In terms of safety, only 2 cases of mild vasculitis were observed in the eravacycline group. Conclusions: Combined regimens based on eravacycline showed better clinical effect in the treatment of cIAI caused by multidrug-resistant bacteria. The clinical effective rate, microbial clearance rate and comprehensive efficacy were significantly higher than those of polymyxin drugs at the end of treatment and discharge with good safety.

669. Real World Use of Ceftazidime/Avibactam for the Treatment of Multidrug Resistant Gram Negative Bacilli Infections: A Real World Experience from Two Centers in Mexico

Abstract Background Ceftazidime-avibactam (C-A) is effective against many carbapenem resistant Enterobacteriaceae (CRE) and some carbapenem resistant Pseudomonas aeruginosa (CRPsa), indicated in complicated urinary tract infections (cUTI), complicated intra-abdominal infections (cIAI), and hospital-acquired pneumonia. To our knowledge, in Mexico, there is no data regarding the clinical efficacy (clinical cure) of its use in the treatment of cIAI, cUTI, hospital-acquired pneumonia, and the treatment of CRE and CRPsa. Methods this is a descriptive, observational, retrospective study, including infections in which ceftazidime avibactam was the definitive therapy for CRE and CRPsa, and empiric treatment of cUTI, cIAI, Hospital-acquired pneumonia. The study includes patients from 2 centers, between April 2019 and february 2020. Demographic, clinical and microbiological data were obtained. Clinical cure was defined as the absence of fever, leukocytosis, tachycardia, systolic pressure < 90mmHg or use of vasopressors, and lowering of C-reactive protein by at least 60% after 5 days of treatment. Results Seventy patients in which C-A was the definitive antimicrobial treatment were evaluated. UTI accounts for 24 cases (34.2%), followed by primary and secondary peritonitis (28.5%), soft tissue infection (12.8%), bacteremia (12.8%) and hospital-acquired pneumonia (11.4%). Of all infections 39.9% were secondary to CRPsa, and 60.1% were due to CRE (30.3% Klebsiella pneumoniae, 21.2% Escherichia coli and 6% for Klebsiella oxytoca, Enterobacter cloacae and Proteus mirabilis). Clinical cure was achieved in 64 patients (91.4%). Six patients died, but only one was associated to CRPsa infection. Conclusion To the best of our knowledge, this is the first study of Mexican experience with C-A. Our study brings relevant information on the treatment of carbapenem resistant GNB infections with C-A in our population. More studies, specifically RCTs are needed to prove the antibiotic efficacy in our media. Disclosures All Authors: No reported disclosures.

POSA122 Budget Impact Analysis of Introducing Ceftolozane/Tazobactam Injection for Treatment of Complicated Intra-Abdominal Infections and Complicated Urinary Tract Infections in the Ministry of Health Malaysia Facilities

Growing prevalence of multidrug-resistant (MDR) pathogens is a major problem specifically in cases of complicated intra-abdominal infections (cIAIs) and complicated urinary tract infections (cUTIs) associated with increasing mortality, morbidity and healthcare costs leading to the need of new effective and safe treatment options. The aim of this study is to estimate the budget impact (BI) of introducing Ceftolozane/Tazobactam as treatment of cIAIs and cUTIs in public facilities under Ministry of Health Malaysia (MoHM).

110. A Phase 3, Multicenter, Double-blind, Randomized Clinical Trial to Evaluate the Efficacy and Safety of Ceftolozane/Tazobactam Plus Metronidazole Versus Meropenem in Chinese Participants With Complicated Intra-abdominal Infections

BackgroundIn China, the prevalence of infections due to multidrug-resistant gram-negative bacteria is high and additional treatment options for complicated intra-abdominal infections (cIAI) are needed. This study compared the efficacy and safety of ceftolozane/tazobactam (C/T) + metronidazole (MTZ) versus meropenem (MEM) + placebo (pbo) for the treatment of cIAI in adult Chinese participants.MethodsThis was a phase 3, double-blind study conducted at 21 centers in China (NCT03830333). Participants aged 18-75 years with cIAI requiring surgical intervention within 24 hours of study drug administration were stratified by site of infection and randomized 1:1 to receive 1.5 g C/T (1 g ceftolozane and 0.5 g tazobactam) + 0.5 g MTZ administered intravenously (IV) every 8 hours (q8h) or 1 g MEM + pbo administered IV q8h for 4-14 days. The primary endpoint was clinical cure at test of cure (TOC) in the clinically evaluable (CE) population. Secondary endpoints included rates of clinical cure, per-participant microbiologic response, per-pathogen microbiologic response, and adverse events (AE). Non-inferiority for clinical cure at TOC in the CE population was confirmed if the lower bound of the 2-sided 95% CI for the between-treatment difference in the clinical cure rate was larger than −12.5%.ResultsA total of 134 participants were randomized to each treatment group. Demographics and baseline characteristics were generally well balanced between treatment groups (Table 1). The median (range) age in the ITT population was 50 (18-75) years and 61% were men. The most frequent sites of infection were the appendix (C/T + MTZ, 50.0%; MEM + pbo, 49.3%) and gallbladder (C/T + MTZ, 27.6%; MEM + pbo, 29.1%). Overall, the most frequently isolated pathogens were Escherichia coli (61.4%) and Klebsiella pneumoniae (17.3%); few anaerobes were isolated (Table 1). C/T + MTZ was non-inferior to MEM + pbo for clinical cure in the CE population (C/T + MTZ, 95.2%; MEM + pbo, 93.1%; difference, 2.1% [95% CI, −4.7% to 8.8%]). Results for key secondary endpoints were comparable between treatment groups (Table 2). Rates of AEs were generally similar between treatment groups (Table 3). ConclusionC/T + MTZ was non-inferior to MEM + pbo in the treatment of adult Chinese participants with cIAI and demonstrated a favorable safety profile.Disclosures Xiaofei Chen, n/a, MSD, China (Employee) Xiaoling Du, n/a, MSD, China (Employee) Ye Wang, n/a, MSD, China (Employee) Hui Wang, n/a, MSD, China (Employee) Fang Sun, n/a, MSD, China (Employee) Matthew G. Johnson, MD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee) Mekki Bensaci, PhD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee) Jennifer A. Huntington, PharmD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee) Christopher Bruno, MD, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (Employee)

Cost-effectiveness of ceftolozane/tazobactam for the treatment of complicated intraabdominal and urinary tract infections in Colombia

Objective: To evaluate the cost-effectiveness of ceftolozane/tazobactam + metronidazole (C/T+M) and ceftolozane/tazobactam (C/T) compared with 8 alternatives used in the treatment of complicated intraabdominal infection (cIAI) and complicated urinary tract infection (cUTI) respectively. Methods: A Monte Carlo simulation decision model was used for the estimation and comparison of treatment-related costs, and quality adjusted life years for patients with cIAI treated with C/T+M in comparison with cefepime + metronidazole, ciprofloxacin + metronidazole, doripenem, levofloxacin + metronidazole, meropenem, piperacillin/tazobactam, ceftazidime + metronidazole or imipenem/cilastatin and patients with cUTI treated with C/T in comparison with cefepime, ciprofloxacin, doripenem, levofloxacin, meropenem, piperacillin/tazobactam, ceftazidime or imipenem/cilastatin. Local costs were estimated using base cases identified by experts and consulting local databases. Sensitivity values of the PACTS (Program to Assess Ceftolozane/Tazobactam Susceptibility) study in Latin America were used in the model. Results: C/T+M and C/T obtained incremental cost-effectiveness ratios (ICER) that were below the Colombian cost-effectiveness threshold (3 GDP per capita) in most comparisons, and were dominated by meropenem, considering only gram-negative microorganisms. Sensitivity assessments were also carried out, in which only the population with P. aeruginosa infections was considered, showing positive results for C/T+M and C/T (cost-effective or dominant with regards to all comparators). Conclusions: C/T+M and C/T could be cost-effective alternatives in the treatment of CIAI and CUTI in Colombia, when there is an adequate and rational use of antibiotics. The results of the sensitivity analyses showed dominance and cost-effectiveness with regards to every comparator in patients infected with P. aeruginosa

Ceftazidime-Avibactam versus Meropenem for the Treatment of Complicated Intra-Abdominal Infections.

This study reports an integrated analysis of three randomized controlled trials to compare the clinical efficacies and safety of the ceftazidime–avibactam (CAZ–AVI) combination and meropenem in the treatment of adult patients with complicated intra-abdominal infections (cIAIs). Overall, a total of 1677 patients (CAZ–AVI: 835 patients; meropenem: 842 patients) were included in this analysis. CAZ–AVI had a clinical cure rate at test of cure in the clinically evaluable (CE) population similar to that of meropenem (OR, 0.88; 95% CI, 0.58–1.32; I2 = 0%). Similar trends were also observed in the modified intent-to-treat (MITT) population (OR, 0.80; 95% CI, 0.59–1.09; I2 = 0%) and microbiological evaluable (ME) population (OR, 0.73; 95% CI, 0.32–1.68; I2 = 0%). In terms of clinical cure rate at the end of treatment, the efficacy of CAZ–AVI was comparable to that of meropenem in the CE population (OR, 0.77; 95% CI, 0.47–1.25; I2 = 0%), MITT population (OR, 0.70; 95% CI, 0.47–1.06; I2 = 5%), and ME population (OR, 1.26; 95% CI, 0.39–4.08; I2 = 0%). CAZ–AVI had a similar risk of (i) treatment emergent adverse events (TEAEs) (OR, 1.03; 95% CI, 0.79–1.36; I2 = 38%), (ii) any serious adverse events (OR, 0.97; 95% CI, 0.67–1.40; I2 = 0%), (iii) discontinuation of study drug due to TEAE (OR, 2.14; 95% CI, 1.00–4.57), and iv) all-cause mortality (OR, 1.66; 95% CI, 0.78–3.53; I2 = 0%) when compared with meropenem. In conclusion, CAZ–AVI had comparable efficacy and safety profile to those of meropenem in the treatment of cIAI.

The use of ceftolozane-tazobactam in the treatment of complicated intra-abdominal infections and complicated urinary tract infections—A meta-analysis of randomized controlled trials

ObjectiveThe aim of this study was to assess the clinical efficacy and safety of ceftolozane-tazobactam in the treatment of complicated intra-abdominal infections (cIAIs) and complicated urinary tract infections (cUTIs) in adult patients through meta-analysis. MethodsPubMed, Embase and Cochrane databases were searched up to June 2019. Only randomized controlled trials (RCTs) that evaluated ceftolozane-tazobactam and comparators for treating cIAIs and cUTIs in adult patients were included. Primary outcome was clinical cure rate; secondary outcomes were clinical failure rate, microbiological eradication rate, and risk of an adverse event (AE). ResultsThree RCTs were included. Overall, ceftolozane-tazobactam had a clinical cure rate similar to comparators in the microbiological intent-to-treat (mITT) population (odds ratio [OR], 0.87; 95% confidence interval [CI], 0.43–1.79; I2 = 73%) and in the clinically evaluable (CE) population (OR, 1.22; 95% CI, 0.79–1.88; I2 = 0%). Furthermore, ceftolozane-tazobactam had a similar microbiological eradication rate for pathogens (OR, 1.31; 95% CI, 0.42–4.10; I2 = 37%). There were no significant differences in the risks of treatment-emergent AEs (OR, 1.04; 95% CI, 0.87–1.23; I2 = 0%), serious AEs (OR, 1.16; 95% CI, 0.67–1.99; I2 = 37%), discontinuation of study drug due to an AE (OR, 0.77; 95% CI, 0.17–3.47) and mortality (OR, 1.62; 95% CI, 0.69–3.77, I2 = 0%) between ceftolozane-tazobactam and comparators. ConclusionsThe clinical efficacy of ceftolozane-tazobactam is as high as that of comparators in the treatment of cIAIs and cUTIs in adult patients, and this antibiotic is well tolerated.

PIN76 BUDGET IMPACT OF CEFTAZIDIME AVIBACTAM (CAZ-AVI) FOR COMPLICATED INTRA-ABDOMINAL INFECTION, COMPLICATED URINARY TRACT INFECTION AND HOSPITAL-ACQUIRED PNEUMONIA IN SINGAPORE

Antimicrobial resistance is a major public health threat in Singapore. Access to quality medicine is critical to address risk of antimicrobial resistance. CAZ-AVI was developed for treatment of a broad range of gram-negative bacterial infections. This study aimed to find budget impact from the perspective of Singapore healthcare with CAZ-AVI and currently available antibiotics in the treatment of complicated intra-abdominal (cIAI), complicated urinary tract (cUTI), hospital-acquired pneumonia (HAP) and aerobic Gram-negative infections with limited treatment options (Infections w/ LTO) A budget Impact Model was developed with 3-year-time horizon. Cost data were from Singapore statistics, public surveillance and literature reviews. Costs were estimated based on prevalence of diseases, type of medication, period of treatment, length of hospital stay, rate of adverse event, market competition and monitoring costs. Based on the assumption of CAZ-AVI introduction, overall budget was calculated by estimating costs of treatment options of cIAI, cUTI, HAP and Infections with LTO reflecting proportion of patients for 3 years comparing with current available options. Total eligible population for 3 years was estimated around 22,000 and 3-year-total costs including CAZ-AVI were around 340 million SGD. When CAZ-AVI included as a new treatment, 1.5% or 240 SGD per patient was increased for 3 years. Due to drug cost of CAZ-AVI, treatment costs of 6 million SGD (17%) were increased. Hospital stay were decreased from around 349,000 days with current available options to around 348,000 days when CAZ-AVI was included. Impact of CAZ-AVI inclusion for 3 years by cIAI, cUTI, HAP and Infections with LTO are 138 SGD (1%), 115 SGD (1%), 205 SGD (1%), 827 SGD (3.5%), respectively. Impact on new options of CAZ-AVI in the treatment of cIAI, cUTI, HAP and infections with LTO can be marginal on the total Singapore healthcare budget.

Polycaprolactone based nano-carrier for co-administration of moxifloxacin and rutin and its In-vitro evaluation for sepsis

Clinically, complicated intra-abdominal infections (cIAIs) covers a broad spectrum peritonitis to acute appendicitis mainly associated with perforations in ischemic bowel. Antibiotics involved in treatment of cIAIs, possibly involved in pathophysiological initiation of sepsis by destructing the cell wall of microorganism and liberation of lipopolysaccharides (LPS) from bacterial cell. The present work is designed for fabrication of polycaprolactone (PCL) nanoparticles (NPs) for delivery of moxifloxacin (MOX) as antibiotic and rutin (RT) as adjuvant co-administered using PCL by nano-precipitation technique, followed by lyophilisation and In-vitro evaluation in J774 cell line. Preparation of polymeric NPs was by using certain modifications in nano-precipitation technique and certain process parameters were optimized. Stable NPs were then analysed for In-vitro cell line studies. Stable NPs had 173.63 nm ± 3.90 mean particle size, 0.107 ± 0.004 polydispersity, −22.63 ± 0.55 mV zeta potential, 7.49 ± 0.31% and 72.64 ± 1.06% drug loading and entrapment efficiency and sustained In-vitro release for 48 h. Antimicrobial activity of free MOX and PCL NPs of MOX against E. coli had correlation with In-vitro release studies. Cell viability studies on J774, THP1 and RAW 264.7 cell lines at various concentrations of PCL loaded NPs had more than 96.0% of cell viability. Cell uptake studies on J774 cell line confirmed phagocytosis mechanism of prepared PCL loaded nanoparticles. In-vitro cell line studies concluded that PCL loaded NPs of MOX and RT are safer for administration and In-vitro cellular uptake studies have provided a brief on potential of NPs for cellular uptake.

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.

The role of new antibiotics in intra-abdominal infections in the era of multi-resistant bacteria

Complicated intra-abdominal infections (cIAI) are asubstantial cause of morbidity at intensive care units. cIAI are frequently caused by multidrug-resistant strains of Enterobacteriaceae and Pseudomonas aeruginosa. In 592 cIAI patients from the First Department of Surgery, General University Hospital in Prague, we found an alarming increase in resistance of Escherichia coli to amoxicillin/clavulanic acid, piperacillin/tazobactam and third-generation cephalosporins in 2014-2017 (from 28.7% in 2014 to 37.5% in 2017, from25% to 32% and from2.3% to 5.6%, respectively). Ceftolozane/tazobactam and ceftazidime/avibactam are novel cephalosporins available for the treatment of cIAI. Ceftolozane/tazobactam is highly active against multidrug-resistant strains of P. aeruginosa, including carbapenem-resistant isolates. The new non-b-lactam b-lactamase inhibitor avibactam plus ceftazidime is active against carbapenemases-producing strains of Enterobacteriaceae. Both antibiotics are included in the new WSES guidelines for the management of cIAI.

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.

New and Emerging Antibiotics for Complicated Intra-Abdominal Infections.

The purpose of this review is to evaluate the efficacy and safety of ceftazidime/avibactam and ceftolozane/tazobactam in patients with complicated intra-abdominal infections (cIAI), and review eravacycline and other agents in the pipeline for management of cIAI. The increasing incidence of multidrug resistant strains of bacteria has led to the need for additional antibiotics with activity against these organisms. There are 2 newly approved antibiotics, ceftazidime/avibactam and ceftolazane/tazobactam for treatment of cIAI. Both agents have been shown to exert activity against resistant bacteria, including extended-spectrum beta-lactamase-producing organisms. Several other antibiotics are currently under investigation for this indication. Included in the pipeline of agents is a new tetracycline, an aminoglycoside, 2 new fluroquinolones, and 2 new beta-lactamase inhibitor combinations with carbapenems. Although the mechanisms for these new agents are not novel, promising data have shown their ability to overcome class resistance. The passing of the Generating Antibiotic Incentives Now Act has led to an increasing number of fast tracked antibiotic approvals. In addition to recent approval of ceftazidime/avibactam and ceftolazane/tazobactam, several other emerging antibiotics are under investigation which will aid in the management of resistant cIAI.

Cost-effectiveness of ceftolozane/tazobactam plus metronidazole compared with piperacillin/tazobactam as empiric therapy for the treatment of complicated intra-abdominal infections based on the in-vitro surveillance of bacterial isolates in the UK

Aims: An increase in the prevalence of antimicrobial resistance among gram-negative pathogens has been noted recently. A challenge in empiric treatment of complicated intra-abdominal infection (cIAI) is identifying initial appropriate antibiotic therapy, which is associated with reduced length of stay and mortality compared with inappropriate therapy. The objective of this study was to assess the cost-effectiveness of ceftolozane/tazobactam + metronidazole compared with piperacillin/tazobactam (commonly used in this indication) in the treatment of patients with cIAI in UK hospitals.Methods: A decision-analytic Monte Carlo simulation model was used to compare costs (antibiotic and hospitalization costs) and quality-adjusted life years (QALYs) of patients infected with gram-negative cIAI and treated empirically with either ceftolozane/tazobactam + metronidazole or piperacillin/tazobactam. Bacterial isolates were randomly drawn from the Program to Assess Ceftolozane/Tazobactam Susceptibility (PACTS) database, a surveillance database of non-duplicate bacterial isolates collected from patients in the UK infected with gram-negative pathogens. Susceptibility to initial empiric therapy was based on the measured susceptibilities reported in the PACTS database.Results: Ceftolozane/tazobactam + metronidazole was cost-effective when compared with piperacillin/tazobactam, with an incremental cost-effectiveness ratio (ICER) of £4,350/QALY and 0.36 hospitalization days/patient saved. Costs in the ceftolozane/tazobactam + metronidazole arm were £2,576/patient, compared with £2,168/patient in the piperacillin/tazobactam arm. The ceftolozane/tazobactam + metronidazole arm experienced a greater number of QALYs than the piperacillin/tazobactam arm (14.31/patient vs 14.21/patient, respectively). Ceftolozane/tazobactam + metronidazole remained cost-effective in one-way sensitivity and probabilistic sensitivity analyses.Conclusions: Economic models can help to identify the appropriate choice of empiric therapy for the treatment of cIAI. Results indicated that empiric use of ceftolozane/tazobactam + metronidazole is cost-effective vs piperacillin/tazobactam in UK patients with cIAI at risk of resistant infection. This will be valuable to commissioners and clinicians to aid decision-making on the targeting of resources for appropriate antibiotic therapy under the premise of antimicrobial stewardship.

Analysis of patients with diabetes and complicated intra-abdominal infection or complicated urinary tract infection in phase 3 trials of ceftolozane/tazobactam

BackgroundDiabetes mellitus and hyperglycemia are associated with increased susceptibility to bacterial infections and poor treatment outcomes. This post hoc evaluation of the treatment of complicated intra-abdominal infections (cIAI) and complicated urinary tract infections (cUTI) aimed to evaluate baseline characteristics, efficacy, and safety in patients with and without diabetes treated with ceftolozane/tazobactam and comparators. Ceftolozane/tazobactam is an antibacterial with potent activity against Gram-negative pathogens and is approved for the treatment of cIAI (with metronidazole) and cUTI (including pyelonephritis).MethodsPatients from the phase 3 ASPECT studies with (n = 245) and without (n = 1802) diabetes were compared to evaluate the baseline characteristics, efficacy, and safety of ceftolozane/tazobactam and active comparators.ResultsSignificantly more patients with than without diabetes were 65 years of age or older; patients with diabetes were also more likely to weigh ≥75 kg at baseline (57.1% vs 44.5%), to have renal impairment (48.5% vs 30.2%), or to have APACHE II scores ≥10 (33.8% vs 17.0%). More patients with diabetes had comorbidities and an increased incidence of complicating factors in both cIAI and cUTI. Clinical cIAI and composite cure cUTI rates across study treatments were lower in patients with than without diabetes (cIAI, 75.4% vs 86.1%, P = 0.0196; cUTI, 62.4% vs 74.7%, P = 0.1299) but were generally similar between the ceftolozane/tazobactam and active comparator treatment groups. However, significantly higher composite cure rates were reported with ceftolozane/tazobactam than with levofloxacin in patients without diabetes with cUTI (79.5% vs 69.9%; P = 0.0048). Significantly higher rates of adverse events observed in patients with diabetes were likely due to comorbidities because treatment-related adverse events were similar between groups.ConclusionsIn this post hoc analysis, patients with diabetes in general were older, heavier, and had a greater number of complicating comorbidities. Patients with diabetes had lower cure rates and a significantly higher frequency of adverse events than patients without diabetes, likely because of the higher rates of medical complications in this subgroup. Ceftolozane/tazobactam was shown to be at least as effective as comparators in treating cUTI and cIAI in this population.Trial registrationcIAI, NCT01445665 and NCT01445678 (both trials registered prospectively on September 26, 2011); cUTI, NCT01345929 and NCT01345955 (both trials registered prospectively on April 28, 2011).

Ceftazidime-avibactam for the treatment of complicated intra-abdominal infections

ABSTRACTIntroduction: The treatment of complicated intra-abdominal infections (cIAI) is increasingly challenging due to increased resistance of Gram-negative organisms. These multidrug resistant organisms lead to an increase in morbidity and mortality. This has led to renewed interest in use of older β-lactam antibiotics in combination with newer β-lactamase inhibitors. Ceftazidime-avibactam is one of the newest such combination antibiotics, which has been released for treatment of complicated intra-abdominal infections in combination with metronidazole.Areas covered: In this drug evaluation manuscript cIAI along with the chemistry, pharmacodynamics, pharmacokinetics, metabolism and clinical study results of ceftazidime-avibactam are reviewed.Expert opinion: The role of ceftazidime-avibactam in combination with metronidazole in the treatment of cIAI is still to be defined. Patients with cIAI known to be infected with Klebsiella pneumoniae carbapenemase-producing Enterobacteriaceae would be clear candidates for treatment with this agent, as would patients infected with more common types of extended-spectrum β-lactamase producing Gram-negative pathogens if a carbapenem alternative were desired. At present, it is difficult to establish a clear group of patients with cIAI for whom initial empiric therapy with this agent would be warranted.

Optimal Treatment for Complicated Intra-abdominal Infections in the Era of Antibiotic Resistance: A Systematic Review and Meta-Analysis of the Efficacy and Safety of Combined Therapy With Metronidazole

Background. Carbapenem-resistant Enterobacteriaceae has increased dramatically in the last decade, resulting in infections that are difficult to treat and associated with high mortality rates. To prevent further antibacterial resistance, it is necessary to use carbapenem selectively. A combination of metronidazole with an antimicrobial agent active against aerobes is an alternative effective treatment for patients with complicated intra-abdominal infections (cIAIs). This study aimed to compare efficacy and safety of metronidazole combination therapies and carbapenem and to provide clinical evidence regarding the optimal treatment of cIAI. Methods. A systematic review and a meta-analysis of randomized clinical trials in the treatment of cIAI were conducted. The systematic review with PubMed, Embase, and the Cochrane Database of Systematic Reviews followed the Cochrane Handbook's recommended methodology, and the meta-analysis used a Mantel-Haenszel random-effects model with RevMan, version 5.3. Primary endpoints were clinical success and bacteriological eradication, and secondary endpoints were all-cause mortality and drug-related adverse events. Results. Eight studies comparing metronidazole combination therapies and carbapenem were included in the meta-analysis. No difference was found between combined therapy with metronidazole and carbapenem regarding clinical success (odds ratio [OR] = 1.31; 95% confidence interval [CI], .75-2.31), bacteriological eradication (OR = 1.27; 95% CI, .84-1.91), all-cause mortality (OR = 0.61; 95% CI, .37-1.00), or drug-related adverse events (OR = 0.58; 95% CI, .18-1.88). Sensitivity analyses found similar results. Conclusions. Combined therapy with metronidazole is as effective and safe as carbapenem in treatment of cIAI. Therefore, combined therapy with metronidazole offers an effective alternative to carbapenem with low risk of drug resistance.

A review of the health economic and resource utilization literature for the use of tigecycline treatment of complicated intra-abdominal infections

Objectives:Complicated intra-abdominal infections (cIAIs) infect deep soft tissues requiring surgical interventions and often result in decreased quality of life due to hospitalization. In addition to tigecycline, treatment of cIAI includes other drugs such as ceftriaxone, ciprofloxacin, imipenem, and levofloxacin. In this study, we conducted a literature review using publically-available databases focusing on the health economic and resource utilization estimates of tigecycline and the other agents as first-line treatment of cIAIs. Methods:The databases used in this systematic review included PubMed and 42 unique HTA organizations. Search terms included “tigecycline” in combination with “Health Economics,” “Resource Utilization,” “Cost-Effectiveness,” and “Length of Stay.” The search criteria excluded articles with the following characteristics: without abstracts, published over 10 years ago, or not in English. Articles were then determined for eligibility using four additional inclusion criteria: 1) Indication, 2) Bacteria Type, 3) Qualitative Assessment, 4) Technicality. Studies were analyzed independently and not pooled because this was not a meta-analysis. Results:After applying our filters to the search criteria, we identified 9 unique papers on the health economics and resource utilization of using tigecycline as first-line treatment of cIAIs. Though the health economic search resulted in only a few number papers on the cost-effectiveness of tigecycline, the messaging was consistent: tigecycline showed competitive clinical effectiveness and economic resource utilization versus several different comparators despite higher acquisition expenses. Several studies established that in terms of length of stay (LoS), total costs of hospitalization and other resource utilization parameters tigecycline was not inferior and thus the results do not favor one treatment over another.Conclusion:The health economics literature estimates tigecycline to have comparable total cost per patient with respect to comparators. The broad spectrum activity of the drug avoids inappropriate treatments which are associated with increased resource utilization and result in higher costs. In view of the alarming spread in antibiotic resistance, the addition of another treatment option offers a valuable tool to counteract a mono-culture of therapies applied against cIAIs.

Clinical characteristics of ceftriaxone plus metronidazole in complicated intra-abdominal infection

PurposeEmpirical antibiotics in complicated intra-abdominal infection (c-IAI), such as secondary peritonitis are a first step of treatment. Empirical antibiotic regimen is very diverse. Ceftriaxone plus metronidazole regimen (CMR) is one of the empirical antibiotic regimens used in treatment of c-IAI. However, although CMR is a widely used empirical antibiotic regimen, study regarding success, failure or efficacy of CMR has been poorly understood. This retrospective study is conducted to compare the clinical efficacy of this regimen in c-IAI according to clinical characteristics.MethodsThe subjects were patients in this hospital who were diagnosed as secondary peritonitis between 2009 and 2013. Retrospective analysis was performed based on the records made after surgery regarding clinical characteristics including albumin level, blood pressure, pulse rate, respiration rate, smoking, age, sex, body mass index, hemoglobin, coexisting disease, leukocytosis, and APACHE (acute physiology and chronic health evaluation) II score.ResultsA total of 114 patients were enrolled. In univariated analysis, the success and failure of CMR showed significant association with preoperative low albumin, old age, and preoperative tachycardia. In multivariated analysis, low albumin and preoperative tachycardia were significant.ConclusionIt is thought that an additional antibiotic treatment plan is necessary in patients with low albumin and tachycardia when the empirical antibiotic regimen is CMR in c-IAI. Conduct of research through well-designed prospective randomized clinical study is also necessary in order to evaluate the appropriateness of CMR and decide on a proper empirical antibiotic regimen between many regimens in c-IAI based on our country.

Ceftolozane/Tazobactam: A Novel Cephalosporin/β-Lactamase Inhibitor Combination with Activity Against Multidrug-Resistant Gram-Negative Bacilli

Ceftolozane is a novel cephalosporin currently being developed with the β-lactamase inhibitor tazobactam for the treatment of complicated urinary tract infections (cUTIs), complicated intra-abdominal infections (cIAIs), and ventilator-associated bacterial pneumonia (VABP). The chemical structure of ceftolozane is similar to that of ceftazidime, with the exception of a modified side-chain at the 3-position of the cephem nucleus, which confers potent antipseudomonal activity. As a β-lactam, its mechanism of action is the inhibition of penicillin-binding proteins (PBPs). Ceftolozane displays increased activity against Gram-negative bacilli, including those that harbor classical β-lactamases (e.g., TEM-1 and SHV-1), but, similar to other oxyimino-cephalosporins such as ceftazidime and ceftriaxone, it is compromised by extended-spectrum β-lactamases (ESBLs) and carbapenemases. The addition of tazobactam extends the activity of ceftolozane to include most ESBL producers as well as some anaerobic species. Ceftolozane is distinguished from other cephalosporins by its potent activity versus Pseudomonas aeruginosa, including various drug-resistant phenotypes such as carbapenem, piperacillin/tazobactam, and ceftazidime-resistant isolates, as well as those strains that are multidrug-resistant (MDR). Its antipseudomonal activity is attributed to its ability to evade the multitude of resistance mechanisms employed by P.aeruginosa, including efflux pumps, reduced uptake through porins and modification of PBPs. Ceftolozane demonstrates linear pharmacokinetics unaffected by the coadministration of tazobactam; specifically, it follows a two-compartmental model with linear elimination. Following single doses, ranging from 250 to 2,000mg, over a 1-h intravenous infusion, ceftolozane displays a mean plasma half-life of 2.3h (range 1.9-2.6h), a steady-state volume of distribution that ranges from 13.1 to 17.6L, and a mean clearance of 102.4mL/min. It demonstrates low plasma protein binding (20%), is primarily eliminated via urinary excretion (≥92%), and may require dose adjustments in patients with a creatinine clearance <50mL/min. Time-kill experiments and animal infection models have demonstrated that the pharmacokinetic-pharmacodynamic index that is best correlated with ceftolozane's in vivo efficacy is the percentage of time in which free plasma drug concentrations exceed the minimum inhibitory concentration of a given pathogen (%fT >MIC), as expected of β-lactams. Two phaseII clinical trials have been conducted to evaluate ceftolozane±tazobactam in the settings of cUTIs and cIAIs. One trial compared ceftolozane 1,000mg every 8h (q8h) versus ceftazidime 1,000mg q8h in the treatment of cUTI, including pyelonephritis, and demonstrated similar microbiologic and clinical outcomes, as well as a similar incidence of adverse effects after 7-10days of treatment, respectively. A second trial has been conducted comparing ceftolozane/tazobactam 1,000/500mg and metronidazole 500mg q8h versus meropenem 1,000mg q8h in the treatment of cIAI. A number of phaseI and phaseII studies have reported ceftolozane to possess a good safety and tolerability profile, one that is consistent with that of other cephalosporins. In conclusion, ceftolozane is a new cephalosporin with activity versus MDR organisms including P.aeruginosa. Tazobactam allows the broadening of the spectrum of ceftolozane versus β-lactamase-producing Gram-negative bacilli including ESBLs. Potential roles for ceftolozane/tazobactam include empiric therapy where infection by a resistant Gram-negative organism (e.g., ESBL) is suspected, or as part of combination therapy (e.g., with metronidazole) where a polymicrobial infection is suspected. In addition, ceftolozane/tazobactam may represent alternative therapy to the third-generation cephalosporins after treatment failure or for documented infections due to Gram-negative bacilli producing ESBLs. Finally, the increased activity of ceftolozane/tazobactam versus P.aeruginosa, including MDR strains, may lead to the treatment of suspected and documented P.aeruginosa infections with this agent. Currently, ceftolozane/tazobactam is being evaluated in three phaseIII trials for the treatment of cUTI, cIAI, and VABP.