Fast and expensive (PCR) or cheap and slow (culture)? A mathematical modelling study to explore screening for carbapenem resistance in UK hospitals.

BACKGROUND: Enterobacteriaceae are a common cause of hospital infections. Carbapenems are a clinically effective treatment of such infections. However, resistance is on the rise. In particular, carbapenemase-producing carbapenem-resistant Enterobacteriaceae (CP-CRE) are increasingly common. In order to limit spread in clinical settings, screening and isolation is being recommended, but many different screening methods are available. We aimed to compare the impact and costs of three algorithms for detecting CP-CRE carriage. METHODS: We developed an individual-based simulation model to compare three screening algorithms using data from a UK National Health Service (NHS) trust. The first algorithm, "Direct PCR", was highly sensitive/specific and quick (half a day), but expensive. The second, "Culture + PCR", was relatively sensitive/specific but slower, requiring 2.5 days. A third algorithm, "PHE", repeated the "Culture + PCR" three times with an additional PCR. Scenario analysis was used to compare several levels of CP-CRE prevalence and coverage of screening, different specialities as well as isolation strategies. Our outcomes were (1) days that a patient with CP-CRE was not detected and hence not isolated ("days at risk"), (2) isolation bed days, (3) total costs and (4) mean cost per CP-CRE risk day averted per year. We also explored limited isolation bed day capacity. RESULTS: We found that although a Direct PCR algorithm would reduce the number of CP-CRE days at risk, the mean cost per CP-CRE risk day averted per year was substantially higher than for a Culture + PCR algorithm. For example, in our model of an intensive care unit, during a year with a 1.6% CP-CRE prevalence and 63% screening coverage, there were 508 (standard deviation 15), 642 (14) and 655 (14) days at risk under screening algorithms Direct PCR, Culture + PCR and PHE respectively, with mean costs per risk day averted of £192, £61 and £79. These results were robust to sensitivity analyses. CONCLUSIONS: Our results indicate that a Culture + PCR algorithm provides the optimal balance of cost and risk days averted, at varying isolation, prevalence and screening coverage scenarios. Findings from this study will help clinical organisations determine the optimal screening approach for CP-CRE, balancing risk and resources.

Carbapenem resistance, inappropriate empiric treatment and outcomes among patients hospitalized with Enterobacteriaceae urinary tract infection, pneumonia and sepsis.

BACKGROUND: Drug resistance among gram-negative pathogens is a risk factor for inappropriate empiric treatment (IET), which in turn increases the risk for mortality. We explored the impact of carbapenem-resistant Enterobacteriaceae (CRE) on the risk of IET and of IET on outcomes in patients with Enterobacteriaceae infections. METHODS: We conducted a retrospective cohort study in Premier Perspective database (2009-2013) of 175 US hospitals. We included all adult patients with community-onset culture-positive urinary tract infection (UTI), pneumonia, or sepsis as a principal diagnosis, or as a secondary diagnosis in the setting of respiratory failure, treated with antibiotics within 2 days of admission. We employed regression modeling to compute adjusted association of presence of CRE with risk of receiving IET, and of IET on hospital mortality, length of stay (LOS) and costs. RESULTS: Among 40,137 patients presenting to the hospital with an Enterobacteriaceae UTI, pneumonia or sepsis, 1227 (3.1%) were CRE. In both groups, the majority of the cases were UTI (51.4% CRE and 54.3% non-CRE). Those with CRE were younger (66.6+/-15.3 vs. 69.1+/-15.9 years, p < 0.001), and more likely to be African-American (19.7% vs. 14.0%, p < 0.001) than those with non-CRE. Both chronic (Charlson score 2.0+/-2.0 vs. 1.9+/-2.1, p = 0.009) and acute (by day 2: ICU 56.3% vs. 30.4%, p < 0.001, and mechanical ventilation 35.8% vs. 11.7%, p < 0.001) illness burdens were higher among CRE than non-CRE subjects, respectively. CRE patients were 3× more likely to receive IET than non-CRE (46.5% vs. 11.8%, p < 0.001). In a regression model CRE was a strong predictor of receiving IET (adjusted relative risk ratio 3.95, 95% confidence interval 3.5 to 4.5, p < 0.001). In turn, IET was associated with an adjusted rise in mortality of 12% (95% confidence interval 3% to 23%), and an excess of 5.2 days (95% confidence interval 4.8, 5.6, p < 0.001) LOS and $10,312 (95% confidence interval $9497, $11,126, p < 0.001) in costs. CONCLUSIONS: In this large US database, the prevalence of CRE among patients with Enterobacteriaceae UTI, pneumonia or sepsis was comparable to other national estimates. Infection with CRE was associated with a four-fold increased risk of receiving IET, which in turn increased mortality, LOS and costs.

Cost-effectiveness analysis of polymyxin B versus colistin for treating patients with carbapenem-resistant gram-negative bacterial infections.

The prevalence of carbapenem-resistant gram-negative bacterial (CRGNB) infection is continuously increasing, and polymyxin B and colistin are considered last-resort drugs. This study compared the cost-effectiveness of polymyxin B with that of colistin for the treatment of intensive care unit patients with CRGNB infection from the Chinese healthcare perspective. A decision-analytic Markov model was constructed to assess the cost-effectiveness of polymyxin B compared with colistin over a period of 5 years using evidence from phase trials and other publicly available studies. The model was developed in Treeage Pro 2022 and comprises a decision tree depicting initial hospitalization and a Markov model with four states projecting long-term health and economic impacts following discharge. Uncertainty was tested with one-way sensitivity analyses and probabilistic sensitivity analyses. The quality-adjusted life years (QALYs), direct medical costs, and incremental cost-effectiveness ratio (ICER) were estimated at willingness-to-pay (WTP) thresholds of $12,674 to $38,024 per QALY. According to the base analyses, the cost incurred by patients receiving colistin treatment was $12,244.77, leading to a gain of 1.35 QALYs. In contrast, patients treated with polymyxin B had a lower cost of $7,306.71 but yielded 1.07 QALYs. The ICRE of colistin was $18032.25/QALY. At a $12,674/QALY threshold, the results were sensitive to several variables, including the probability of cure with polymyxin B, the cost of drugs, the utility of discharge to home, the utility of discharge to long-term care, and the cost of nephrotoxicity with renal replacement therapy. After all model inputs varied across a wide range of reasonable values, only the probability of being cured with polymyxin B resulted in an ICER above the $38,024/QALY threshold. According to the probabilistic sensitivity analyses, colistin was the optimal strategy in 38.2% and 62.8% of the simulations, at $12,674/QALY and $38,024/QALY, respectively. Our study findings suggest that, when considering the Chinese healthcare perspective, colistin is likely to be more cost-effective than polymyxin B for patients with CRGNB infection, especially when the WTP threshold is set at one-time the per capita GDP. However, as the WTP threshold increases from one to three times the per capita GDP, the cost-effectiveness acceptability of colistin improves, increasing from 38.2 to 62.8%.

A permission system for carbapenem use reduced incidence of drug-resistant bacteria and cost of antimicrobials at a general hospital in Japan.

Some drug management systems have been established in Japanese hospitals to reduce medical costs and regulate drug usage. Among the many available prescription drugs, antimicrobials should be given special attention because their inappropriate use often leads to sudden outbreaks of resistant bacteria. As drug specialists, pharmacists should monitor the use of all drugs, particularly antimicrobials. Carbapenems are a class of broad-spectrum antimicrobials that are widely used to treat infections worldwide. However, their inappropriate use has led to an increase in the incidence of drug-resistant bacteria and consequently, medical costs, at hospitals. To reduce inappropriate use and drug resistance, we have established a permission system to control the use of carbapenems at the Japanese Red Cross Nagoya Daiichi Hospital. In this study, we retrospectively evaluated the applicability of the new permission system compared to that of the notification system and the non control system for 14 months each. The two management systems were able to maintain total antibiotic use density and control the outbreak of drug-resistant bacteria (P. aeruginosa, E. coli, and K. pneumoniae). The number of carbapenem prescriptions was decreased dramatically when this permission system was enforced. Compared to the non control system, the cost of antimicrobials was reduced by $757,470 for the 14-month study period using the permission system. These results suggest that our system to control the use of antimicrobials can efficiently suppress the incidence of drug-resistant bacteria and medical costs at hospitals.

Multiresistant bacteria and current therapy - the economical side of the story.

UNLABELLED: Severe infections with multiresistant bacteria (MRB) are a medical challenge and a financial burden for hospitals. The adequate antibiotic therapy is a key issue in multiresistant bacteria management. Several major cost drivers have been identified. Remarkably drug acquisition costs are not necessarily included. Most significant are the length of stay in hospital, the hours of mechanical ventilation and the time treated on an intensive care unit. - In a systematic review of the literature the following aspects were investigated: - Do generic treatment strategies contribute in cost savings? - Are there specific results for recent antibiotics? - Early adequate and effective antimicrobial treatment, switch from i.v. to oral therapy, adjusted duration of therapy and adherence to guidelines have been found to be successful strategies. - Looking at specific antibiotics, the best evidence for cost-effectiveness is found for Linezolid in treatment of cSSTI as well as in HAP. Daptomycin shows good economic results in bloodstream infections, so possibly being a cost-effective alternative to vancomycin. Looking at tigecycline the published data show neither higher costs nor savings compared to imipeneme. Doripenem as one of the newest therapy options has proven to be highly cost-saving in HAP when compared with imipenem. However, most analyses are based on pharmacoeconomic modelling rather than on directly analysing trial data or real life clinical populations. - CONCLUSION: Using modern antibiotics in whole is not more expensive than using established therapies. Modern antibiotics are cost-effective and sometimes even cost-saving. This is especially true if an effective therapy is initiated as early as possible.

Clinical and economic consequences of ventilator-associated pneumonia.

Increasing drug resistance rates among gram-negative pathogens that frequently cause ventilator-associated pneumonia have resulted in increased hospital mortality, longer hospital stays, and higher inpatient health care costs. There is an urgent need for effective therapies that lessen the clinical and economic consequences of this nosocomial infection. In a randomized, multicenter, prospective, phase 3 trial, medical resource use associated with doripenem was compared with that associated with imipenem for the treatment of ventilator-associated pneumonia. Analysis of medical resource use revealed that patients who received doripenem had a significantly shorter duration of hospital stay (22 vs. 27 days; P = .01)and duration of mechanical ventilation use (7 vs. 10 days; P = .03) than did patients who received imipenem. In addition, the duration of intensive care unit stay tended to be shorter for patients who received doripenem. The reduced medical resource use achieved with use of doripenem for treatment of ventilator-associated pneumonia may provide not only clinical benefits to patients but also economic benefits to hospitals and health care systems.

Doripenem monohydrate, a broad-spectrum carbapenem antibiotic.

BACKGROUND: Doripenem monohydrate, a broad-spectrum carbapenem antibiotic, has been approved by the US Food and Drug Administration for the treatment of complicated intra-abdominal infections (cIAIs) and complicated urinary tract infections (cUTIs). OBJECTIVE: This article reviews available information on doripenem in the management of patients with complicated bacterial infections, including its chemistry, spectrum of activity, resistance mechanisms, pharmacokinetics, pharmacodynamics, drug interactions, therapeutic efficacy, tolerability, and dosing and administration. Also discussed are pharmacoeconomic considerations associated with doripenem. METHODS: Pertinent English-language literature was identified from searches of MEDLINE (1996-October 2008) and BIOSIS (1993-October 2008). Search terms included, but were not limited to, doripenem, S-4661, spectrum of activity, resistance, pharmacology, pharmacokinetics, pharmacodynamics, adverse events, and therapeutic use. Additional publications were found by searching the reference lists of identified articles and reviewing abstracts from meetings of the Interscience Conference on Antimicrobial Agents and Chemotherapy (2003-2007). RESULTS: Doripenem is a parenteral carbapenem antibiotic with in vitro activity against gram-positive, gram-negative, and anaerobic organisms. It is stable against a wide variety of beta-lactamases, including extended-spectrum and AmpC beta-lactamases; it is, however, inactivated by organisms that produce class A enzymes, KPC enzymes, class B metallo-beta-lactamases, and class D enzymes. Doripenem is eliminated primarily in the urine (68%-80% unchanged). It should be used cautiously in patients receiving valproic acid, as combined use may lead to a precipitous decline in serum concentrations of valproic acid. A large Phase III study in the treatment of cIAIs found doripenem noninferior to meropenem (clinical cure rates, 83.9% and 85.9%, respectively; difference, -2.1; 95% CI, -9.8 to 5.6). A Phase III study in the treatment of cIAIs, including pyelonephritis, found doripenem non-inferior to levofloxacin (clinical cure rates, 95.1% and 90.2%, respectively; 95% CI, 0.2 to 9.6). With respect to the treatment of nosocomial pneumonia, one Phase III study found doripenem noninferior to imipenem (clinical cure rates, 68.3% and 64.8%, respectively; difference, 3.5%; 95% CI, -9.1 to 16.1), and another found it noninferior to piperacillin/tazobactam (clinical cure rates, 81.3% and 79.8%, respectively; difference, 1.5%; 95% CI, -9.1 to 12.1). Adverse events with doripenem were similar to those of other antibiotics with which it has been compared. Adverse events in clinical trials of doripenem have included anaphylaxis and rash (l%-5%), gastrointestinal effects (25%-32%, including nausea [1.1%-12.0%], diarrhea [1.9%-11.0%], and vomiting [1.5%-6.6%]), and central nervous system effects (headache [2.1%-16.0%], insomnia [3.7%], anxiety [2.9%], and, rarely, seizures). CONCLUSIONS: In Phase III studies, doripenem was noninferior to meropenem in the treatment of cIAIs; noninferior to levofloxacin in the treatment of cUTIs; and noninferior to imipenem and piperacillin/tazobactam in the treatment of nosocomial pneumonia. As with all new antibiotics, because of the risk of selecting for resistant organisms, use of doripenem should be reserved for infections in which a multidrug-resistant gram-negative organism, polymicrobial infection, or Pseudomonas aeruginosa is suspected.

Educational ICU Antimicrobial Stewardship model: the daily activities of the AMS team over a 10-month period.

The emergence of antibiotic resistance as a consequence of inappropriate use results in higher mortality rates and has become a major public health challenge worldwide. Antimicrobial stewardship programs (ASPs) aim to ensure proper use of antimicrobials and reduce health care costs. We assessed the impact of using a behavioral approach during a persuasive ASP on antibiotic appropriateness, consumption and costs. We conducted a prospective interventional cohort before-and-after study in the intensive care unit (ICU) of a 554-bed, university teaching hospital in Terni, Italy, 14 of which are located in the ICU. We describe a 10-month persuasive ASP intervention model used in a referral ICU with daily rounds. The aim of the study was to improve medication appropriateness through educational action and reduce the consumption of carbapenems and echinocandins by conducting post-prescription reviews, prescribing reviews and holding daily discussions with the ICU team. We analyzed the prescribing appropriateness of the ICU team in accordance with the decisions made by the Antimicrobial Stewardship (AMS) team to improve the quality of antibiotic prescribing during the first five months and the last five months of the surveillance period. The results were expressed as the defined daily dose (DDD) per 100 occupied bed-days and costs. The data were compared with those previously obtained during the pre-educational period (the year before ASP implementation). Comparisons were made between the decisions taken to improve antimicrobial treatments administered during the first half of the surveillance period (March-July) and those administered during the second half (August-December). In all, 116 decisions were made from March to July while only 65 were made from August to December (p-value 0.00001). A significant reduction was observed in the consumption of carbapenems and echinocandins (11.15% and 25.62%, respectively). Total antibiotic cost savings amounted to 57,541.16 euros. The persuasive ASP strategy positively influenced the prescribing behavior of physicians, thus improving the appropriateness of antibiotic therapy and reducing antimicrobial consumption.

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.

Societal willingness to pay to avoid mortality and morbidity from Clostridioides difficile and carbapenem-resistant Enterobacteriaceae infections in the United States.

BACKGROUND: Clostridioides difficile infection (CDI) is among the most common health care-associated infections in the United States and is increasingly affecting the elderly. Although carbapenem-resistant Enterobacteriaceae (CRE) infections are still relatively uncommon, there are reported increases in the rate of infection for certain strains, such as Klebsiella pneumoniae. This study examines the burden of mortality and morbidity for CDI and CRE infections in the United States and estimates the societal willingness to pay to avoid them. METHODS: We use an analytic model to estimate the number of incident cases and associated health outcomes for CDI and CRE infections. RESULTS: The number of CDI and CRE infection incident cases in the United States in 2016, is estimated at 468,567 and 9,620, respectively. These infections result in a total of 17,630 estimated deaths and 8,624 lost quality-adjusted life years among patients who survive per year. CONCLUSIONS: Given the significant mortality and morbidity from these infections, the estimated societal willingness to pay to avoid them is high at $176.7 billion per year, of which 93.9% ($166.0 billion) is for CDI. Our estimates far exceed the medical care costs for CDIs and CRE infections reported in the literature despite not capturing the additional costs borne by third-party payers. As incident cases increase or resistant strains develop, the societal willingness to pay is also expected to increase.

Hospital resource utilization with doripenem versus imipenem in the treatment of ventilator-associated pneumonia.

BACKGROUND: Ventilator-associated pneumonia (VAP) is a common nosocomial infection that is associated with prolonged length of stay (LOS) and significant mortality. OBJECTIVE: The aim of this study was to compare resource utilization with doripenem, an investigational carbapenem, versus imipenem from a hospital perspective among patients with VAP. METHODS: This analysis was based on data from a Phase III, randomized, open-label, noninferiority study that compared clinical cure of VAP with doripenem 500 mg q8h i.v. (4-hour infusion) with imipenem 500 mg q6h (30-minute infusion) or 1000 mg q8h i.v. (1-hour infusion). Total hospital LOS, intensive care unit (ICU) LOS, and time on mechanical ventilation for doripenem and imipenem were compared in a clinical modified intent-to-treat population. P values were determined using the generalized Wilcoxon test, which compared treatments in a time-to-event analysis, censoring patients at the late follow-up visit (28-35 days after the end of i.v. therapy). RESULTS: Patients in the doripenem and imipenem groups had similar baseline clinical characteristics. Median hospital LOS was significantly shorter with doripenem versus imipenem (22 vs 27 days; P=0.010); median time on mechanical ventilation was significantly shorter for doripenem (7 vs 10 days; P=0.034); median ICU LOSs were similar between the 2 groups (12 vs 13 days). Clinical cure and mortality rates were similar. CONCLUSIONS: Of the 3 primary end points in this analysis, hospital LOS and time on mechanical ventilation were significantly shorter with doripenem compared with imipenem; no statistical significance was observed in ICU LOS. These findings suggest that doripenem use may be associated with an economic and clinical benefit to patients and hospitals.

Clinical review: balancing the therapeutic, safety, and economic issues underlying effective antipseudomonal carbapenem use.

Antipseudomonal carbapenems have played a useful role in our antimicrobial armamentarium for 20 years. However, a review of their use during that period creates concern that their clinical effectiveness is critically dependent on attainment of an appropriate dosing range. Unfortunately, adequate carbapenem dosing is missed for many reasons, including benefit/risk misconceptions, a narrow therapeutic window for imipenem and meropenem (due to an increased rate of seizures at higher doses), increasingly resistant pathogens requiring higher doses than are typically given, and cost containment issues that may limit their use. To improve the use of carbapenems, several initiatives should be considered: increase awareness about appropriate treatment with carbapenems across hospital departments; determine optimal dosing regimens for settings where multidrug resistant organisms are more likely encountered; use of, or combination with, an alternative antimicrobial agent having more favorable pharmacokinetic, pharmacodynamic, or adverse event profile; and administer a newer carbapenem with lower propensity for resistance development (for example, reduced expression of efflux pumps or greater stability against carbapenemases).

Enumerating the economic cost of antimicrobial resistance per antibiotic consumed to inform the evaluation of interventions affecting their use.

Background: Antimicrobial resistance (AMR) poses a colossal threat to global health and incurs high economic costs to society. Economic evaluations of antimicrobials and interventions such as diagnostics and vaccines that affect their consumption rarely include the costs of AMR, resulting in sub-optimal policy recommendations. We estimate the economic cost of AMR per antibiotic consumed, stratified by drug class and national income level. Methods: The model is comprised of three components: correlation coefficients between human antibiotic consumption and subsequent resistance; the economic costs of AMR for five key pathogens; and consumption data for antibiotic classes driving resistance in these organisms. These were used to calculate the economic cost of AMR per antibiotic consumed for different drug classes, using data from Thailand and the United States (US) to represent low/middle and high-income countries. Results: The correlation coefficients between consumption of antibiotics that drive resistance in S. aureus, E. coli, K. pneumoniae, A. baumanii, and P. aeruginosa and resistance rates were 0.37, 0.27, 0.35, 0.45, and 0.52, respectively. The total economic cost of AMR due to resistance in these five pathogens was $0.5 billion and $2.9 billion in Thailand and the US, respectively. The cost of AMR associated with the consumption of one standard unit (SU) of antibiotics ranged from $0.1 for macrolides to $0.7 for quinolones, cephalosporins and broad-spectrum penicillins in the Thai context. In the US context, the cost of AMR per SU of antibiotic consumed ranged from $0.1 for carbapenems to $0.6 for quinolones, cephalosporins and broad spectrum penicillins. Conclusion: The economic costs of AMR per antibiotic consumed were considerable, often exceeding their purchase cost. Differences between Thailand and the US were apparent, corresponding with variation in the overall burden of AMR and relative prevalence of different pathogens. Notwithstanding their limitations, use of these estimates in economic evaluations can make better-informed policy recommendations regarding interventions that affect antimicrobial consumption and those aimed specifically at reducing the burden of AMR.

The impact of earlier intervention by an antimicrobial stewardship team for specific antimicrobials in a single weekly intervention.

OBJECTIVE: The objective of this study was to evaluate the effects of earlier intervention by an antimicrobial stewardship team (AST) on antimicrobial use, antimicrobial resistance rates, and the clinical outcomes, without changing the weekly intervention schedule. METHODS: A retrospective study was conducted at Fukuoka University Hospital between April 2013 and March 2016. The effects were compared among three study periods (SP): SP1 (patients receiving anti-methicillin-resistant Staphylococcus aureus agents and carbapenems for ≥14 days), SP2 (patients receiving specific antimicrobials for ≥14 days), and SP3 (patients receiving specific antimicrobials regardless of the duration of treatment). RESULTS: The timing of AST intervention was shortened from an average of 15.5days after administration in SP1 to 4.2 days in SP3. The antimicrobial use density (AUD) of carbapenems and piperacillin-tazobactam decreased significantly (SP2 vs. SP3, p<0.05), and the costs of specific antimicrobials decreased (SP1, US$ 1080000; SP2, US$ 944000; SP3, US$ 763000). The rates of carbapenem resistance among Pseudomonas aeruginosa isolates showed a significant reduction from 16.2% in SP2 to 8.7% in SP3 (p<0.05). The mortality rate and length of stay did not change during the study period. CONCLUSIONS: Earlier intervention by an AST could contribute to the proper use of antimicrobials without adversely affecting patient outcomes.

Antimicrobial consumption in five adult intensive care units: a 33-month surveillance study.

Background: Estimating the baseline antimicrobial consumption is extremely important to monitor the impact of antimicrobial stewardship activities that aim to reduce the burden and cost of antimicrobial consumption. Objectives: To quantify service-specific antimicrobial consumption using different metrics. Methods: A surveillance study was conducted at King Abdulaziz Medical City, Riyadh, Saudi Arabia, between October 2012 and June 2015 in five adult intensive care units (ICUs). Consumption data were collected manually on a daily basis by infection control practitioners. Data were presented as defined daily dose (DDD), days of therapy (DOT) per 1000 patient days, and frequency of daily consumption. Results: A total of 43,970 DDDs and 46,940 DOTs were monitored during 54,116 patient-days. For the most frequently consumed antimicrobials, the consumption of carbapenems, piperacillin/tazobactam, vancomycin, and colistin (respectively) in all ICUs combined were 255.9, 134.3, 98.2, and 13.6 DDDs per 1000 patient-days and 235.7, 145.9, 129.5, and 117.5 DOTs per 1000 patient-days. For the frequency of daily consumption, carbapenems were the most frequently consumed antimicrobial group in medical/surgical, burn, and step-down ICUs while piperacillin/tazobactam was the most frequently consumed antimicrobial in neuro-surgical and cardio-thoracic ICUs. Conclusion: High consumption of broad-spectrum antimicrobial agents such as meropenem and piperacillin/tazobactam is observed in multiple ICUs in a tertiary care hospital. Meropenem consumption is considerably higher than similar ICUs internationally. Future studies focusing on concurrent monitoring of antimicrobial resistance and identifying patient and physician characteristics associated with specific prescription patterns may help in improving judicious antimicrobial consumption.

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.

Carbapenems in the treatment of severe community-acquired pneumonia in hospitalized elderly patients: a comparative study against standard therapy.

In this open, prospective, study were enrolled 204 hospitalized elderly patients with severe (88 males, 116 females, age range 70-94). Patients were randomized to receive one of the following antibiotic treatment regimens: meropenem 500 mg i.v. t.i.d. (52); imipenem/cilastatin 500 mg i.v. t.i.d. (51), clarithromycin 500 mg + ceftriaxone 1 g i.v. b.i.d. (52), clarithromycin 500 mg + amikacin 250 mg i.v. b.i.d. (49). In 99 cases causative germs were isolated (24 meropenem, 26 imipenem, 23 clarithromycin + ceftriaxone, 26 ceftriaxone + amikacin). A satisfactory clinical, bacteriological response was achieved respectively in 86.5% 77% in meropenem; 86.3% 71% in imipenem/cilastatin; 69% 61% in ceftriaxone + clarithromycin and in 85.7% 77% in clarithromycin + amikacin. The mean total cost for each patient was $1,560; $1,620; $1,760 and $1,792 in meropenem, imipenem/cilastatin, clarithromycin + ceftriaxone and clarithromycin + amikacin respectively. This study shows that treatment with either meropenem or imipenem is as efficacious as conventional therapy in the treatment of community acquired pneumonia (CAP), and that meropenem is the most cost-effective.

Impact of an antimicrobial stewardship program on the use of carbapenems in a tertiary women's and children's hospital, Singapore.

OBJECTIVES: Antimicrobial stewardship programs (ASPs) promote the judicious use of antimicrobials by limiting inappropriate use. This article evaluates the impact of a prospective-audit-and-feedback ASP implementation on the appropriate utilization of carbapenems in a tertiary pediatrics and obstetrics/gynecology hospital in Singapore (KKH) after the establishment of an ASP in July 2011. METHODS: This was a prospective, single-center, pre-post intervention study designed to analyze the appropriate prescribing of carbapenems pre-ASP (October 2009 to June 2011) and post-ASP (July 2011 to December 2013). Utilization of carbapenems was evaluated by daily defined doses (DDDs), days of therapy (DOTs), prescriptions, as well as cost per 100 patient-days pre-ASP and post-ASP using a segmented regression of interrupted time series analysis. RESULTS: Of 404 prescriptions for carbapenems reviewed post-ASP, 70.3% were appropriate compared with those prescribed pre-ASP (55.9%; p=0.027). Reasons for inappropriate prescribing included inappropriate choice (36.1%) and duration (31.3%). A total of 61.2% of the interventions (213 of 348) were accepted. For pediatrics, there was a significant decrease in DDDs per 100 patient-days by 55.6% from a baseline of 0.9-0.4 (p=0.013) post-ASP and a reduction in DOTs per 100 patient-days by 46.7% from a baseline of 1.5-0.8 (p=0.06) post-ASP without significant changes in prescription rates. Pediatrics utilization cost increased from a pre-ASP mean of $175 per 100 patient-days to a peak of $238 (p<0.001) and decreased significantly post-ASP to a mean of $149 (p=0.01). For obstetrics/gynecology, there were no significant changes in DDDs (0.3 vs 0.3, p=0.99), DOTs (0.2 vs 0.3, p=0.36), prescriptions (0.03 vs 0.04, p=0.38), or cost ($45 vs $52, p=0.63) per 100 patient-days pre- versus post-ASP. CONCLUSIONS: ASPs improved the appropriateness of carbapenems prescribing overall and reduced utilization in pediatrics. Identification of areas of inappropriate prescribing will be valuable in guiding future ASP efforts.

When pharmacodynamics trump costs: an antimicrobial stewardship program's approach to selecting optimal antimicrobial agents.

BACKGROUND: Treatment of Pseudomonas aeruginosa infections is increasingly challenging because of escalating resistance. Antimicrobial stewardship programs provide guidance for clinicians regarding use of the most appropriate antimicrobial at the right dose, duration, and route in addition to being cost-effective. Optimizing antimicrobial therapy by using pharmacokinetic/pharmacodynamic principles such as extending time above the MIC is 1 stewardship strategy to reduce antimicrobial resistance. OBJECTIVE: The goal of this study was to evaluate our current dosing strategy for cefepime and the formulary carbapenem (imipenem) compared with meropenem and doripenem to determine the best dosing strategy for achieving maximal pharmacodynamic activity against an institution-specific population of P aeruginosa isolates. METHODS: Consecutive, nonduplicate, blood (n = 39) or bronchial alveolar lavage (n = 25) isolates of P aeruginosa from adult, hospitalized (2009-2010) critically ill patients underwent MIC testing by using broth microdilution. A pharmacokinetic model was developed and used with Monte Carlo simulation to evaluate the ability of imipenem, meropenem, doripenem, and cefepime to achieve optimal bactericidal activity as varying doses infused over standard infusions (SIs; 0.5-1 hour) or prolonged infusions (PIs; 3-4 hours). A regimen was defined as optimal if the cumulative fraction response (CFR) was ≥90%. RESULTS: None of the imipenem regimens modeled as SI or PI achieved a CFR ≥90%. Meropenem at 1 to 2 g q8h PI achieved a CFR ≥90%. Doripenem 0.5, 1, or 2 g q8h PI achieved a CFR ≥90%. The only cefepime regimen that achieved a CFR ≥90% was 2 g q8h PI. Overall susceptibility rates to P aeruginosa were highest with cefepime (91%), followed by meropenem (83%), doripenem (78%), and imipenem (72%). Our antimicrobial stewardship programs recommended switching from imipenem to doripenem 0.5g q8h PI, which was 36% more costly in drug acquisition costs. Cefepime dosing was increased from 2 g q12h SI to 2 g q8h PI, a 52% increase in drug acquisition cost. CONCLUSIONS: Antimicrobial stewardship programs should consider pharmacodynamic modeling to select the optimal dosing strategies to guide therapy in an era of escalating antimicrobial resistance. Using the percent susceptibility alone can be misleading and ultimately the most expensive if the patient fails to respond.