Cost-effectiveness analysis of ceftazidime/avibactam compared to imipenem as empirical treatment for complicated urinary tract infections

Ceftazidime/avibactam (CAZ-AVI) is a novel, fixed-dose combination antibiotic that has been approved in Europe and the United States for patients with complicated urinary tract infections (cUTIs) based on results of a Phase III, randomized, comparative study (RECAPTURE study). The present analysis evaluated cost-effectiveness of CAZ-AVI as an empirical treatment for hospitalized patients with cUTIs from the Italian publicly funded healthcare (third-party payer) perspective. A sequential, patient-level simulation model was developed that followed the clinical course of cUTI and generated 5000 pairs of identical patients (CAZ-AVI or imipenem as empirical treatment). The model included additional impact of resistant pathogens; patients who did not respond to empirical treatment were switched to second-line treatment of colistin+high dose carbapenem in both groups. The time horizon of the model was five years, with an annual discount rate of 3% applied to both costs and quality-adjusted life-years (QALYs). The analysis demonstrated that an intervention sequence (CAZ-AVI followed by colistin+high dose carbapenem) compared with a comparator sequence (imipenem followed by colistin+high dose carbapenem) was associated with a net incremental cost of €1015 per patient but provided better health outcomes in terms of clinical cure (97.65% vs. 91.08%; ∆ = 6.57%), shorter hospital stays (10.65 vs. 12.55 days; ∆ = 1.90 days), and QALYs gained per patient (4.190 vs. 4.063; ∆ = 0.126). The incremental cost-effectiveness ratio was €8039/QALY, which is well below the willingness-to-pay threshold of €30 000/QALY in Italy. The results showed that CAZ-AVI is expected to be a cost-effective treatment compared with imipenem for cUTI in Italy

Weight-based antibiotic dosing in a real-world European study of complicated skin and soft-tissue infections due to methicillin-resistant <i>Staphylococcus aureus</i>

AbstractWe aimed to characterize real-world dosing of weight-based intravenous (IV) antibiotic therapy in patients hospitalized for methicillin-resistant Staphylococcus aureus (MRSA) complicated skin and soft-tissue infections (cSSTIs). This was a subgroup analysis of a retrospective chart review that captured data from 12 European countries. The study included patients ≥18 years old, hospitalized with an MRSA cSSTI between 1 July 2010 and 30 June 2011 and discharged alive by 31 July 2011. Patients treated with IV vancomycin, teicoplanin or daptomycin at any stage during hospitalization were included in this analysis. Analyses were conducted at the regimen level (dosing in mg/kg or in mg, frequency, and total daily dose (TDD)), with potentially multiple regimens per patient, and the patient level, categorizing patients into low, standard (labelled) and high dosing groups according to their initial MRSA-targeted regimen. Among the 1502 patients in the parent study, 998 patients contributed a total of 1050 daptomycin, teicoplanin or vancomycin regimens. Across all regimens, the mean initial TDDs were 6.3 ± 1.9 mg/kg for daptomycin, 10.5 ± 4.9 mg/kg for teicoplanin and 28.5 ± 11.5 mg/kg for vancomycin. A total of 789 patients received first-line therapy with one of the above antibiotics. The majority of patients receiving first-line teicoplanin and daptomycin (96% and 80%, respectively) received higher than labelled cSSTI doses, whereas vancomycin doses were lower than labelled doses in >40% of patients. These real-world data reveal significant deviation from labelled antibiotic dosing in 12 European countries and the potential for suboptimal outcomes in patients with MRSA cSSTIs

Comparison of vancomycin and linezolid in patients with peripheral vascular disease and/or diabetes in an observational European study of complicated skin and soft-tissue infections due to methicillin-resistant <i>Staphylococcus aureus</i>

AbstractSuboptimal antibiotic penetration into soft tissues can occur in patients with poor circulation due to peripheral vascular disease (PVD) or diabetes. We conducted a real-world analysis of antibiotic treatment, hospital resource use and clinical outcomes in patients with PVD and/or diabetes receiving linezolid or vancomycin for the treatment of methicillin-resistant Staphylococcus aureus complicated skin and soft-tissue infections (MRSA cSSTIs) across Europe. This subgroup analysis evaluated data obtained from a retrospective, observational medical chart review study that captured patient data from 12 European countries. Data were obtained from the medical records of patients ≥ 18 years of age, hospitalized with an MRSA cSSTI between 1 July 2010 and 30 June 2011 and discharged alive by 31 July 2011. Hospital length of stay and length of treatment were compared between the treatment groups using inverse probability of treatment weights to adjust for clinical and demographic differences. A total of 485 patients had PVD or diabetes and received treatment with either vancomycin (n = 258) or linezolid (n = 227). After adjustment, patients treated with linezolid compared with vancomycin respectively had significantly shorter hospital stays (17.9 ± 13.6 vs. 22.6 ± 13.6 days; p < 0.001) and treatment durations (12.9 ± 7.9 vs. 16.4 ± 8.3 days; p < 0.001). The proportions of patients prescribed oral, MRSA-active antibiotics at discharge were 43.2% and 12.4% of patients in the linezolid and vancomycin groups, respectively (p < 0.001). The reduction in resource use may result in lower hospital costs for patients with PVD and/or diabetes and MRSA cSSTIs if treated with linezolid compared with vancomycin

Implementing criteria-based early switch/early discharge programmes:a European perspective

AbstractEarly switch (ES) from intravenous (IV) to oral antibiotic therapy programmes is increasingly included as a component of hospital antimicrobial stewardship initiatives that aim to optimize antimicrobial therapy while limiting toxicity and resistance. In terms of prioritizing the most cost-effective stewardship interventions, ES has been seen as a ‘low-hanging fruit’, which refers to selecting the most obtainable targets rather than confronting more complicated issues. Administration of highly bioavailable oral antibiotics should be considered for nearly all non-critically ill patients and has been recommended as an effective and safe strategy for over two decades. However, to accrue the most benefit from ES, it should be combined with an early discharge (ED) plan, protocol, or care pathway. Benefits of this combined approach include improved patient comfort and mobility, reduced incidence of IV-line-related adverse effects, reduced IV antimicrobial preparation time, decreased hospital stays, reduced antimicrobial purchasing and administration costs, decreased patient deconditioning, and shortened recovery times. Results from published studies document decreases in healthcare resource use and costs following implementation of ES programmes, which in most studies facilitate the opportunity for ED and ED programmes. Barriers to the implementation of these programmes include clinician misconceptions, practical considerations, organizational factors, and a striking lack of awareness of IV to oral switch guidance. These and other barriers will need to be addressed to maximize the effectiveness of ES and ED programmes. As national antimicrobial stewardship programmes dictate the inclusion of ES and ED programmes within healthcare facilities, programmes must be developed and success must be documented

Cost-effectiveness analysis comparing ceftazidime/avibactam (CAZ-AVI) as empirical treatment comparing to ceftolozane/tazobactam and to meropenem for complicated intra-abdominal infection (cIAI)

Background: The rising incidence of resistance to currently available antibiotics among pathogens, particularly Gram-negative pathogens, in complicated intra-abdominal infections (cIAIs) has become a challenge for clinicians. Ceftazidime/avibactam (CAZ-AVI) is a fixed-dose antibiotic approved in Europe and the United States for treating (in combination with metronidazole) cIAI in adult hospitalised patients who have limited or no alternative treatment options. The approval was based on the results of RECLAIM, a Phase III, parallel-group, comparative study (RECLAIM 1 [NCT01499290] and RECLAIM 2 [NCT01500239]). The objective of our study was to assess the cost-effectiveness of CAZ-AVI plus metronidazole compared with 1) ceftolozane/tazobactam plus metronidazole and 2) meropenem, as an empiric treatment for the management of cIAI in Italy. Methods: A sequential, patient-level simulation model, with a 5-year time horizon and 3% annual discount rate (applied to both costs and health benefits), was developed using Microsoft Excel\uae to demonstrate the clinical course of the disease. The impact of resistant pathogens was included as an additional factor. Results: In the base-case analysis, the CAZ-AVI sequence (CAZ-AVI plus metronidazole followed by a colistin + tigecycline + high-dose meropenem combination after treatment failure), when compared to sequences for ceftolozane/tazobactam (ceftolozane/tazobactam plus metronidazole followed by colistin + tigecycline + high-dose meropenem after treatment failure) and meropenem (meropenem followed by colistin + tigecycline + high-dose meropenem after treatment failure), had better clinical outcomes with higher cure rates (93.04% vs. 91.52%; 92.98% vs. 90.24%, respectively), shorter hospital stays (\ue2'\u2020 =-0.38 and \ue2'\u2020 =-1.24 days per patient, respectively), and higher quality-adjusted life years (QALYs) gained per patient (4.021 vs. 3.982; 4.019 vs. 3.960, respectively). The incremental cost effectiveness ratio in the CAZ-AVI sequence was 4099 and 15,574 per QALY gained versus each comparator sequence, respectively, well below the willingness-to-pay threshold of 30,000 per QALY accepted in Italy. Conclusions: The model results demonstrated that CAZ-AVI plus metronidazole could be a cost-effective alternative when compared with other antibiotic treatment options, as it is expected to provide better clinical benefits in hospitalised patients with cIAI in Italy

Review of ceftazidime-avibactam for the treatment of infections caused by pseudomonas aeruginosa

Pseudomonas aeruginosa is an opportunistic Gram-negative pathogen that causes a range of serious infections that are often challenging to treat, as this pathogen can express multiple resistance mechanisms, including multidrug-resistant (MDR) and extensively drug-resistant (XDR) pheno-types. Ceftazidime–avibactam is a combination antimicrobial agent comprising ceftazidime, a third-generation semisynthetic cephalosporin, and avibactam, a novel non-β-lactam β-lactamase inhibitor. This review explores the potential role of ceftazidime–avibactam for the treatment of P. aeruginosa infections. Ceftazidime–avibactam has good in vitro activity against P. aeruginosa relative to com-parator β-lactam agents and fluoroquinolones, comparable to amikacin and ceftolozane–tazobactam. In Phase 3 clinical trials, ceftazidime–avibactam has generally demonstrated similar clinical and microbiological outcomes to comparators in patients with complicated intra-abdominal infections, complicated urinary tract infections or hospital-acquired/ventilator-associated pneumonia caused by P. aeruginosa. Although real-world data are limited, favourable outcomes with ceftazidime–avibactam treatment have been reported in some patients with MDR and XDR P. aeruginosa infections. Thus, ceftazidime–avibactam may have a potentially important role in the management of serious and complicated P. aeruginosa infections, including those caused by MDR and XDR strains. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

Safety and Efficacy of Tigecycline to Treat Multidrug-resistant Infections in Pediatrics: An Evidence Synthesis.

BACKGROUND: The need for antimicrobial therapies effective against multidrug resistant organisms for children remains unmet. Tigecycline shows antibacterial activity across a broad spectrum of bacteria and is approved for treating complicated skin and skin-structure infections, complicated intra-abdominal infections and, in the United States, community-acquired bacterial pneumonia for adult patients. No blinded, randomized phase 3 tigecycline clinical trials on neonates or children have been completed or planned. This review aimed to provide a comprehensive synthesis of all the existing data sources, both on-label and off-label, for tigecycline use in children. METHODS: Data on tigecycline use in children were identified from published and unpublished sources including clinical trials, expanded access and compassionate use programs, databases of healthcare records and patient safety monitoring. RESULTS: Pharmacokinetic simulations predicted that tigecycline 1.2 mg/kg (maximum dose 50 mg) every 12 hours (q12h) in children 8-11 years and 50 mg q12h in children 12 to <18 years would achieve exposure similar to adults receiving 50 mg q12h. Available phase 2 pediatric clinical trial data and data from other sources demonstrated similar clinical efficacy between adult and pediatric patients treated with tigecycline. These data showed no new or unexpected safety concerns with tigecycline in children. CONCLUSIONS: Information presented here may help guide the appropriate use of tigecycline in children with multidrug resistant infections. Continued pharmacovigilance from real-world observational studies may also further refine appropriate use of tigecycline

Antibiotic research and development: business as usual?

The global burden of antibiotic resistance is tremendous and, without new anti-infective strategies, will continue to increase in the coming decades. Despite the growing need for new antibiotics, few pharmaceutical companies today retain active antibacterial drug discovery programmes. One reason is that it is scientifically challenging to discover new antibiotics that are active against the antibiotic-resistant bacteria of current clinical concern. However, the main hurdle is diminishing economic incentives. Increased global calls to minimize the overuse of antibiotics, the cost of meeting regulatory requirements and the low prices of currently marketed antibiotics are strong deterrents to antibacterial drug development programmes. New economic models that create incentives for the discovery of new antibiotics and yet reconcile these incentives with responsible antibiotic use are long overdue. DRIVE-AB is a €9.4 million public–private consortium, funded by the EU Innovative Medicines Initiative, that aims to define a standard for the responsible use of antibiotics and to develop, test and recommend new economic models to incentivize investment in producing new anti-infective agents

Antibiotic research and development: business as usual?

The global burden of antibiotic resistance is tremendous and, without new anti-infective strategies, will continue to increase in the coming decades. Despite the growing need for new antibiotics, few pharmaceutical companies today retain active antibacterial drug discovery programmes. One reason is that it is scientifically challenging to discover new antibiotics that are active against the antibiotic-resistant bacteria of current clinical concern. However, the main hurdle is diminishing economic incentives. Increased global calls to minimize the overuse of antibiotics, the cost of meeting regulatory requirements and the low prices of currently marketed antibiotics are strong deterrents to antibacterial drug development programmes. New economic models that create incentives for the discovery of new antibiotics and yet reconcile these incentives with responsible antibiotic use are long overdue. DRIVE-AB is a \u20ac9.4 million public-private consortium, funded by the EU Innovative Medicines Initiative, that aims to define a standard for the responsible use of antibiotics and to develop, test and recommend new economic models to incentivize investment in producing new anti-infective agents