Fight Against Antimicrobial Resistance: We Always Need New Antibacterials but for Right Bacteria.

Antimicrobial resistance in bacteria is frightening, especially resistance in Gram-negative Bacteria (GNB). In 2017, the World Health Organization (WHO) published a list of 12 bacteria that represent a threat to human health, and among these, a majority of GNB. Antibiotic resistance is a complex and relatively old phenomenon that is the consequence of several factors. The first factor is the vertiginous drop in research and development of new antibacterials. In fact, many companies simply stop this R&D activity. The finding is simple: there are enough antibiotics to treat the different types of infection that clinicians face. The second factor is the appearance and spread of resistant or even multidrug-resistant bacteria. For a long time, this situation remained rather confidential, almost anecdotal. It was not until the end of the 1980s that awareness emerged. It was the time of Vancomycin-Resistance Enterococci (VRE), and the threat of Vancomycin-Resistant MRSA (Methicillin-Resistant Staphylococcus aureus). After this, there has been renewed interest but only in anti-Gram positive antibacterials. Today, the threat is GNB, and we have no new molecules with innovative mechanism of action to fight effectively against these bugs. However, the war against antimicrobial resistance is not lost. We must continue the fight, which requires a better knowledge of the mechanisms of action of anti-infectious agents and concomitantly the mechanisms of resistance of infectious agents.

Impact of an infectious diseases specialist-led antimicrobial stewardship programmes on antibiotic use and antimicrobial resistance in a large Korean hospital.

The aim of this study was to evaluate the impact of an infectious diseases specialist (IDS)-led antimicrobial stewardship programmes (ASPs) in a large Korean hospital. An interrupted time series analysis assessing the trends in antibiotic use and antimicrobial resistance rate of major pathogens between September 2015 and August 2017 was performed in an 859-bed university-affiliated hospital in Korea. The restrictive measure for designated antibiotics led by an IDS reduced carbapenems usage by -4.57 days of therapy (DOT)/1,000 patient-days per month in general wards (GWs) (95% confidence interval [CI], -6.69 to -2.46; P < 0.001), and by -41.50 DOT/1,000 patient-days per month in intensive care units (ICUs) (95% CI, -57.91 to -25.10; P < 0.001). Similarly, glycopeptides usage decreased by -2.61 DOT/1,000 patient-days per month in GWs (95% CI, -4.43 to -0.79; P = 0.007), and -27.41 DOT/1,000 patient-days per month in ICUs (95% CI, -47.03 to -7.79; P = 0.009). Use of 3rd generation cephalosporins, beta-lactam/beta-lactamase inhibitors, and fluoroquinolones in GWs showed change comparable with that of carbapenems or glycopeptides use. Furthermore, trends of antimicrobial resistance rate of Staphylococcus aureus to gentamicin in GWs, Staphylococcus aureus to ciprofloxacin and oxacillin in ICUs, and Pseudomonas aeruginosa to imipenem in ICUs decreased in slope in the intervention period. The in-hospital mortality rate per 1,000 patient-days among ICU patients remained stable between the pre-intervention and intervention periods. In conclusion, an IDS-led ASPs could enact a meaningful reduction in antibiotic use, and a decrease in antibiotic resistance rate, without changing mortality rates in a large Korean hospital.

Newer glycopeptide antibiotics for treatment of complicated skin and soft tissue infections: systematic review, network meta-analysis and cost analysis.

OBJECTIVES: Skin and soft tissue infections (SSTIs) carry significant economic burden, as well as morbidity and mortality, especially when caused by methicillin-resistant Staphylococcus aureus (MRSA). Several new MRSA-active antibiotics have been developed, including semisynthetic glycopeptides (telavancin, dalbavancin and oritavancin). Of these, dalbavancin and oritavancin offer extended dosing intervals. METHODS: We performed a systematic review, network meta-analysis and cost analysis to compare the newer glycopeptides to standard care and to each other for the treatment of complicated SSTIs (cSSTI). A search for randomized controlled trials (RCTs) was conducted in Medline, Embase and the Cochrane Central Register of Controlled Trials. We also developed a model to evaluate the costs associated with dalbavancin and oritavancin from the third-party payer perspective. RESULTS: Seven RCTs met the inclusion criteria. Network meta-analyses suggested that the clinical response to telavancin, dalbavancin and oritavancin was similar to standard care (odds ratio (OR) 1.09, 95% confidence interval (CI) 0.90-1.33; OR 0.78, 95% CI 0.52-1.18; and OR 1.06, 95% CI 0.85-1.33, respectively). Head-to-head comparisons showed no difference in clinical response between oritavancin and dalbavancin (OR 1.36; 95% CI 0.85-2.18), oritavancin and telavancin (OR 0.98; 95% CI 0.72-1.31) or dalbavancin and telavancin (OR 0.72; 95% CI 0.45-1.13). Telavancin had a higher incidence of overall adverse events compared to standard care (OR 1.33; 95% CI 1.10-1.61). Compared to telavancin, there were fewer overall adverse events with dalbavancin (OR 0.58; 95% CI 0.45-0.76) and oritavancin (OR 0.71; 95% CI 0.55-0.92). Studies were of high quality overall. Our cost analyses demonstrated that dalbavancin and oritavancin were less costly compared to standard care under baseline assumptions and many scenarios evaluated. The use of dalbavancin could save third-party payers $1442 to $4803 per cSSTI, while the use of oritavancin could save $3571 to $6932 per cSSTI. CONCLUSIONS: Dalbavancin and oritavancin demonstrate efficacy and safety comparable to standard care in well-designed RCTs and result in cost savings when standard care is treatment that covers MRSA.

New Gram Positive Agents to Treat Acute Bacterial Skin and Skin Structure Infections.

The FDA guidance published in 2013 provided requirements for conducting ABSSSI trials. In 2014, dalbavancin, oritavancin, and tedizolid were introduced into the market after phase III noninferiority clinical trials against vancomycin (for the lipoglycopeptides) and linezolid (for tedizolid), demonstrating clinical efficacy for the treatment of ABSSSI. Great interest exists for these agents because of the postulated financial impact. Due to favorable pharmacokinetics which allow for less frequent medication administration and shorter treatment durations, these agents may prove to reduce hospital admissions and length of stay.

Use of Oritavancin in Moderate-to-Severe ABSSSI Patients Requiring IV Antibiotics: A U.S. Payer Budget Impact Analysis.

BACKGROUND: It is estimated that acute bacterial skin and skin structure infections (ABSSSI) account for nearly 10% of hospital admissions and 3.4-3.8 million emergency department visits per year in the United States. Analyses of hospital discharge records indicate 74% of ABSSSI admissions involve empiric treatment with methicillin-resistant Staphylococcus aureus (MRSA) active antibiotics. Analysis has shown that payer costs could be reduced if moderate-to-severe ABSSSI patients were treated to a greater extent in the observational unit followed by discharge to outpatient parenteral antibiotic therapy (OPAT). Oritavancin is a lipoglycopeptide antibiotic with bactericidal activity against gram-positive bacteria, including MRSA. OBJECTIVE: To estimate the impact on a U.S. payer's budget of using single-dose oritavancin in ABSSSI patients with suspected MRSA involvement who are indicated for intravenous antibiotics. METHODS: A decision analytic model based on current clinical practice was developed to estimate the economic value of decreased hospital resource consumption by using single-dose oritavancin over a 1-year time horizon. Use of antibiotics was informed by an analysis of the Premier Research Database. Demographic and clinical data were derived from a targeted literature review. Emergency department, observation, laboratory, and administration costs used were Medicare National Limitation amounts. Drug costs were 2014 wholesale acquisition costs. RESULTS: For a hypothetical U.S. payer with 1,000,000 members, it is expected that approximately 14,285 members per year will be diagnosed with ABSSSI severe enough to indicate intravenous antibiotics with MRSA activity. Based on this simulation, use of single-dose oritavancin in 26% of these patients was estimated to reduce the number of inpatient admissions, reduce length of stay for patients requiring admission, and reduce the number of days a patient needs to receive daily infusions in the OPAT clinic. The total patient days decreased from 171,125 to 133,435 with a total annual budget impact of -$12,550,000 or -$1.05 per member per month (PMPM). Total inpatient and outpatient costs were reduced by $9,970,000 (19.7%) and $2,580,000 (4.2%), respectively. Inpatient cost savings were derived from a reduction in admissions, length of stay, and lower drug administration burden. Outpatient costs were reduced by lower drug administration burden in the OPAT setting. A sensitivity analysis demonstrated that the model was most sensitive to population estimates. CONCLUSIONS: Use of single-dose oritavancin in moderate-to-severe ABSSSI patients, including those with suspected MRSA, was projected to deliver an estimated cost reduction to U.S. payers of $1.05 PMPM by avoiding hospitalization in appropriate patients and reducing outpatient costs associated with multiday parenteral antibiotic therapy. DISCLOSURES: This work was funded by The Medicines Company. Jensen, Wu, and Cyr are employees of ICON Health Economics, which provides consulting services to the biopharmaceutical industry, including The Medicines Company. Fan and Sulman are employees and shareholders of The Medicines Company. Dufour and Lodise have provided consulting services to The Medicines Company. Nicolau provided model input but did not receive an honorarium for contributions on this project. Nicolau is a speaker for The Medicines Company. Study concept and design were contributed by Jensen and Wu, along with the other authors. Jensen, Wu, Fan, and Sulham collected the data, with assistance from Cyr. Data interpretation was performed by Sulham, Jensen, Wu, and Fan, assisted by Lodise, Nicolau, and Dufour. The manuscript was written by Jensen, Wu, and Sulham, with assistance from Cyr, and revised by Lodise, Nicolau, and Dufour, with assistance from the other authors.

Use of Oritavancin in Acute Bacterial Skin and Skin Structure Infections Patients Receiving Intravenous Antibiotics: A US Hospital Budget Impact Analysis.

BACKGROUND AND OBJECTIVE: Nearly 10% of all US hospital admissions are attributed to acute bacterial skin and skin structure infections (ABSSSIs). While most antibacterials used to treat these infections require multi-day and multi-dose regimens, a single-dose treatment is now available. The objective of this analysis is to estimate the annual budget impact of using single-dose oritavancin in patients with moderate to severe ABSSSIs receiving intravenous methicillin-resistant Staphylococcus aureus (MRSA)-active antibacterials from a US hospital perspective. METHODS: A decision-analytic model based on current clinical practice was developed to estimate the economic impact of oritavancin. Utilization of antibacterials and rates of hospital admission were derived from the Premier Research Database. Demographic and clinical data were informed by the published literature and 2014 wholesale drug acquisition costs were used. Other costs were based on the published literature and Medicare National Limitation amounts. All costs were inflated to 2014 US dollars. Two base-case scenarios were considered: one for hospitals with ambulatory services and one for hospitals without ambulatory services. RESULTS: For a US hospital with ambulatory services with 1000 ABSSSI patients receiving intravenous MRSA antibiotics annually, use of oritavancin in 26% of patients is estimated to reduce the total annual budget by 12.9% (US$1.23 million), or approximately US$1234.67 per patient. Total inpatient costs will be reduced by 22.3% (US$1.40 million) and outpatient costs will increase slightly by 1.7% (US$55,310). Pharmaceutical cost increases are offset by savings in the inpatient setting from fewer hospital admissions. Hospitals without ambulatory services are estimated to receive overall cost savings of 9.3% (US$0.63 million). CONCLUSION: Use of single-dose oritavancin in select ABSSSI patients with suspected or confirmed MRSA involvement is estimated to save US hospitals approximately 9.3-12.9% per year by reducing hospital admissions and lowering drug administration burden.

Economic Impact of Oritavancin for the Treatment of Acute Bacterial Skin and Skin Structure Infections in the Emergency Department or Observation Setting: Cost Savings Associated with Avoidable Hospitalizations.

PURPOSE: Data indicate that acute bacterial skin and skin structure infection (ABSSSI) patients without major comorbidities can be managed effectively in the outpatient setting. Because most patients with ABSSSIs present to the emergency department, it is essential that clinicians identify candidates for outpatient treatment given the substantially higher costs associated with inpatient care. We examined the potential cost avoidance associated with shifting care from inpatient treatment with vancomycin to outpatient treatment with oritavancin for ABSSSI patients without major complications or comorbidities. METHODS: A decision analytic, cost-minimization model was developed to compare costs of inpatient vancomycin versus outpatient oritavancin treatment of ABSSSI patients with few or no comorbidities (Charlson Comorbidity Index score ≤1) and no life-threatening conditions presenting to emergency department. Hospital discharge data from the Premier Research Database was used to determine the costs associated with inpatient vancomycin treatment. FINDINGS: Mean costs for inpatient treatment with vancomycin ranged from $5973 to $9885, depending on Charlson Comorbidity Index score and presence of systemic symptoms. Switching an individual patient from inpatient vancomycin treatment to outpatient oritavancin treatment was estimated to save $1752.46 to $6475.87 per patient, depending on Charlson Comorbidity Index score, presence of systemic symptoms, and use of observation status. Assuming some patients may be admitted to the hospital after treatment with oritavancin, it is estimated that up to 38.12% of patients could be admitted while maintaining budget neutrality. IMPLICATIONS: This cost-minimization model indicates that use of oritavancin in the emergency department or observation setting is associated with substantial cost savings compared with inpatient treatment with vancomycin.

[Antibiotic consumption and its costs of purchase in Polish neonatology networks units]. / Zuzycie antybiotyków i koszty ich zakupu w oddzialach Polskiej sieci neonatologicznej.

AIM: The study presents the results of the analysis of antibiotic consumption and its direct costs in selected neonatal units. MATERIAL AND METHODS: Data were collected retrospectively (the year 2007) in five hospitals, during the pilot phase of the Polish Neonatal Network . Antibiotic consumption was assessed using the Defined Daily Dose (DDD). The costs were assessed as the costs of purchase of one DDD. RESULTS: The study included 11 922 children hospitalized in the period from 1.01 to 31.12.2007. In this group, 731 infants have birth weight < 1500 grams (from 2.2% to 64.2% in individual units, median--7.3%). The mean consumption of antibacterial drugs was 48.52 DDD/1 000 person-days (P-D) of stay among the entire study population (median--42,52), and varied from 23.13 to 85.82 DDD/1,000 P-D. However, this difference has not been statistically significant. The most commonly used group of antibiotics were beta-lactams--in four out of five units the percentage of its usage ranged from 48.71% to 74.67%. Next group were aminoglicosides--in one unit its usage reached 56.97% and in other ranged from 5.01% to 22.53%. Glycopeptides and macrolides were also used in every unit of the studied group. The usage of glycopeptides ranged from 1.7% to 10.81% and of macrolides from 1.32% to 15.71%. Different kinds of antibiotics were used occasionally. The differences of costs of purchase of one DDD between hospitals were greater and varied from 17,64 PLN/ DDD to 84,58 PLN/ DDD (average costs). A considerable range of costs index values was also noted for different groups of antibiotics. The costs of purchase of one DDD of beta-lactams varied from 19.54 PLN/ DDD to 68.35 PLN/ DDD; for aminoglicosides the cost varied from 4.61 PLN/ DDD to 122.9 PLN/ DDD, for glycopeptides--from 31.40 PLN/ DDD to 283.13 PLN/ DDD and in case of macrolides: from 12.05 PLN/ DDD to 90.77 PLN/ DDD. This differentiation of the cost of purchasing a single defined daily dose, taking into account the specific groups of antibiotics, did not have the characteristics of statistical significance. CONCLUSIONS: As expected, the antibiotic regimens in the studied wards were similar. This is due to a homogeneous population of hospitalized patients. However, the differences of costs of purchase of antibiotics observed in the study, indicate the considerable variety of the treatment patterns in Polish neonatology units and the need to develop and implement recommendations of effective pharmacotherapy for patients in intensive neonatal care units and the implementation of a unified model of infections surveillance.

Effects of legal antibiotic restrictions on consumption of broad-spectrum beta-lactam antibiotics, glycopeptides and amphotericin B.

In 2002, antimicrobial drugs were the most frequently prescribed drugs in Turkey. On February 15, 2003, the Turkish Government implemented a new Budget Application Instruction (BAI) to promote rational antibiotic usage in order to decrease the costs. This BAI restricted the reimbursement of certain antibiotics without prescription or approval by the infectious diseases specialists (IDS). The purpose of this study is to evaluate the effect of BAI on antibiotic consumption for the 3 years before and 2 years after its implementation, according to IMS Health Office findings. Based on the data of the IMS Health Turkey Office, the amount of some broad-spectrum antibiotics (piperacillin/tazobactam, imipenem, meropenem, cefoperazone/sulbactam, ceftazidime, cefepime, teicoplanin, vancomycin, and amphotericin B) that were prescribed by IDS between 2000 and 2002 and between 2003 and 2004 are determined. The Anatomical Therapeutic Chemical classification and the defined daily dose (DDD)/1,000 methodology are used to calculate antibiotic consumption. Total antibiotic consumption before BAI, in 2000, 2001 and 2002 was 0.091, 0.107 and 0.119 DDD/1,000 inhabitant-days, respectively, and after BAI, in 2003 and 2004, 0.137 and 0.135 DDD/1,000 inhabitant-days, respectively. Average utilization of antibiotics before the implementation of BAI was 0.105 DDD and increased to 0.136 DDD after BAI. Antibiotic consumption has increased 1.3-fold after the implementation of BAI. However, the effect of restricted antibiotic utilization was revealed especially in the second year after BAI. The consumption of antimicrobials decreased to 0.135 in 2004 while it was 0.137 in 2003.

An economic model for the prevention of MRSA infections after surgery: non-glycopeptide or glycopeptide antibiotic prophylaxis?

AIM: Surgical site infection is commonly caused by Staphylococcus aureus. The multiresistant strains (MRSA) are resistant to most antibiotic prophylaxis regimens. Our aim was to explore whether there is a threshold of MRSA prevalence at which switching to routine glycopeptide-based antibiotic prophylaxis becomes cost-effective. METHODS: An indicative model was designed to explore the cost-effectiveness of vancomycin, cephalosporin or a combination, in patients undergoing primary hip arthroplasty. RESULTS: If the MRSA infection rate is equal to or above 0.25% and the rate of other infections with cephalosporin prophylaxis is equal to or above 0.2%, use of the combination antibiotic prophylaxis is optimal. DISCUSSION: Modelling the cost-effectiveness of interventions for MRSA prevention is complex due to uncertainty around resistance and effectiveness of glycopeptides. CONCLUSIONS: The indicative model provides a framework for evaluation. More work is needed to understand the impact of antibiotic resistance over time in these currently effective antibiotics.

Are glycopeptides still appropriate and convenient for empiric use?

The glycopeptides vancomycin and teicoplanin are widely used, and indeed recommended for, the treatment of severe or resistant Gram-positive infections. Therapeutic drug monitoring is widely used for vancomycin but less commonly for teicoplanin, and remains controversial. We report the cost savings of a formulary decision to replace teicoplanin with daptomycin for the empiric treatment of complicated skin and soft tissue infections (CSSTIs), staphylococcal bacteraemia and hospital-acquired Gram-positive sepsis. In the Intensive Therapy Unit (ITU) we optimised treatment of serious Gram-positive infections by substituting teicoplanin with vancomycin administered by continuous infusion. Costs were calculated using British National Formulary (BNF) prices and costs for therapeutic drug monitoring. Daptomycin (350 mg/d) use was associated with a cost saving per 7 days of treatment of 86 pounds and vancomycin with 51 pounds (4 g/d) to 276 pounds (2 g/d) compared to the 600 mg teicoplanin dose. Our own formulary re-positioning of glyco/lipopeptides, i.e. the preferential use of vancomycin in the ITU and substitution of teicoplanin with daptomycin, is cost-effective and provides better therapeutic alternatives. Continuous vancomycin infusion in the ITU setting guarantees optimal dosing for severely ill patients. Daptomycin use on surgical and medical wards, apart from being marginally cheaper than teicoplanin, guarantees optimal dosing without the need for drug monitoring.

A systematic review and economic model of switching from non-glycopeptide to glycopeptide antibiotic prophylaxis for surgery.

OBJECTIVES: To determine whether there is a level of methicillin-resistant Staphylococcus aureus (MRSA) prevalence at which a switch from non-glycopeptide to glycopeptide antibiotics for routine prophylaxis is indicated in surgical environments with a high risk of MRSA infection. DATA SOURCES: Major electronic databases were searched up to September 2005. REVIEW METHODS: The effectiveness review included controlled clinical trials comparing a glycopeptide with an alternative antibiotic regimen that reported effectiveness and/or adverse events. Controlled observational studies were also included for adverse events. The cost-effectiveness review included economic evaluations comparing glycopeptide prophylaxis with any alternative comparator. Study validity was assessed using standard checklists. The supplementary economic reviews assessed evaluations of non-glycopeptide antibiotic prophylaxis; evaluations where antibiotic resistance is a problem; methods of modelling resistance in infectious diseases; and developing a conceptual framework. An indicative decision analytic model was developed to compare vancomycin with a cephalosporin and with a combination of vancomycin and cephalosporin, using hip arthroplasty as an exemplar. Available data on, for example, surgical site infection (SSI) rates, MRSA rates, effectiveness of the antibiotics, were incorporated into the model. Costs were estimated from the perspective of the NHS. RESULTS: The effectiveness review included 16 randomised controlled trials, with a further three studies included for adverse events only. There was no evidence that glycopeptides were more effective than non-glycopeptides in preventing SSIs. Most of the trials did not report either the baseline prevalence of MRSA at the participating surgical units or MRSA infections as an outcome. The cost-effectiveness review included five economic evaluations of glycopeptide prophylaxis. Only one study incorporated health-related quality of life and undertook a cost-utility analysis. None of the studies was undertaken in the UK and none explicitly modelled antibiotic resistance. The supplementary reviews provided few insights into how to assess cost-effectiveness in the context of resistance. No studies modelled cost-effectiveness alongside epidemiological models of resistance. There was little information regarding the impact of surgical infections on costs post-discharge and patient quality of life. The lack of available clinical evidence limited the development of the cost-effectiveness model and meant that the modelling could only be indicative in nature. The model can be used to show the threshold baseline risk at which the use of vancomycin as prophylaxis might be cost-effective (the model did not include teicoplanin). The indicative model suggests that the baseline risk of MRSA can be fairly modest at below the national average and it would still appear cost-effective to use glycopeptide prophylaxis. The model indicates that the use of glycopeptides as a form of prophylaxis in addition to a treatment for MRSA infections is unlikely to decrease the total usage and hence reduce the risk of future problems with glycopeptide-resistant bacteria. CONCLUSIONS: There is insufficient evidence to determine whether there is a threshold prevalence of MRSA at which switching from non-glycopeptide to glycopeptide antibiotic prophylaxis might be clinically effective and cost-effective. Future research needs to address the complexities of decision-making relating to the prevention of MRSA and infection control in general. Research including evidence synthesis and decision modelling comparing a full range of interventions for infection control, which extends to other infections, not just MRSA, is needed. A long-term research programme to predict the pattern of drug resistance and its implications for future costs and health is also needed.

The decrease in healthcare-associated methicillin-resistant Staphylococcus aureus infections and savings from glycopeptide use.

We evaluated changes in the rate of healthcare-associated methicillin-resistant Staphylococcus aureus (MRSA) infections and healthcare-associated S. aureus infections after implementation of infection control precautions and the effect of this on glycopeptide use and expenditures for glycopeptides in a private medical center in Turkey in the years 2000-2005. A striking decrease was obtained in the number of MRSA infections, and the expenditure for glycopeptide use also decreased.