Clinical and Economic Value of Reducing Antimicrobial Resistance in the Management of Hospital-Acquired Infections with Limited Treatment Options in Greece.

INTRODUCTION: Antimicrobial resistance (AMR) is a major public health threat worldwide. Greece has the highest burden of infections due to antibiotic-resistant bacteria among European Union/European Economic Area (EU/EEA) countries. One of the most serious AMR threats in Greece is hospital-acquired infections (HAIs) with limited treatment options (LTO) caused by resistant gram-negative pathogens. Thus, this study sought to estimate the current AMR burden in Greece and the value of reducing AMR to gram-negative pathogens for the Greek healthcare system. METHODS: The current model was adapted from a previously published and validated model of AMR to investigate the overall and AMR-specific burden of treating the most common HAIs with LTO in Greece and scenarios to demonstrate the benefits associated with reducing AMR levels from a third-party payer perspective. Clinical and economic outcomes were estimated over a 10-year time horizon; life years (LYs) and quality-adjusted life years (QALYs) were calculated over a lifetime (based on the annual number of infections over 10 years) at a willingness-to-pay of €30,000 per QALY gained and a 3.5% discount rate. RESULTS: In Greece, the current AMR levels in HAIs with LTO caused by four gram-negative pathogens account for > 316,000 hospital bed days, €73 million in hospitalisation costs, and > 580,000 LYs and 450,000 QALYs lost over 10 years. The monetary burden is estimated at €13.9 billion. A reduction in current AMR levels by 10-50% results in clinical and economic benefit; 29,264-151,699 bed days may be saved, leading to decreased hospitalisation costs (€6.8 million-€35.3 million) and a gain in LYs (85,328-366,162) and QALYs (67,421-289,331), associated with a monetary benefit of between €2.0 billion and €8.7 billion. CONCLUSION: This study shows the substantial clinical and economic burden AMR represents to the Greek healthcare system and the value that can be achieved by effectively reducing AMR levels.

Estimating the Clinical and Economic Impact of Introducing a New Antibacterial into Greek Clinical Practice for the Management of Hospital-Acquired Infections with Limited Treatment Options.

INTRODUCTION: Hospital-acquired infections (HAIs) and growing antimicrobial resistance (AMR) represent a significant healthcare burden globally. Especially in Greece, HAIs with limited treatment options (LTO) pose a serious threat due to increased morbidity and mortality. This study aimed to estimate the clinical and economic value of introducing a new antibacterial for HAIs with LTO in Greece. METHODS: A previously published and validated dynamic model of AMR was adapted to the Greek setting. The model estimated the clinical and economic outcomes of introducing a new antibacterial for the treatment of HAIs with LTO in Greece. The current treatment pathway was compared with introducing a new antibacterial to the treatment sequence. Outcomes were assessed from a third-party payer perspective, over a 10-year transmission period, with quality-adjusted life years (QALYs) and life years (LYs) gained considered over a lifetime horizon. RESULTS: Over the next 10 years, HAIs with LTO in Greece account for approximately 1.4 million hospital bed days, hospitalisation costs of more than €320 million and a loss of approximately 403,000 LYs (319,000 QALYs). Introduction of the new antibacterial as first-line treatment provided the largest clinical and economic benefit, with savings of up to 93,000 bed days, approximately €21 million in hospitalisation costs and an additional 286,000 LYs (226,000 QALYs) in comparison to the current treatment strategy. The introduction of a new antibacterial was linked to a monetary benefit of €6.8 billion at a willingness to pay threshold of €30,000 over 10 years. CONCLUSION: This study highlights the considerable clinical and economic benefit of introducing a new antibacterial for HAIs with LTO in Greece. This analysis shows the additional benefit when a new antibacterial is introduced to treatment sequences. These findings can be used to inform decision makers to implement policies to ensure timely access to new antibacterial treatments in Greece.

Antimicrobial resistance is a major issue for the Greek healthcare system. The overuse of antibacterial agents contributes to the growing resistance levels, making currently available treatment options less effective. As a result, there is an imperative need to address antimicrobial resistance in Greece. This study developed a mathematical model to investigate the clinical and economic benefits of introducing a new antibacterial to current treatment practice. The model uses regression equations to describe the relationships between inputs and outputs from a published and validated model, which describes the transmission and treatment of infections. The model is used to estimate the impact of a new treatment in Greece, considering differing treatment sequence scenarios. The largest health and financial benefits were seen when a new antibacterial was introduced at first line prior to currently used treatments. Over 10 years, savings of up to 93,000 hospital bed days and €21 million in hospitalisation costs could be achieved, as well as a gain of 286,000 patient life years and 226,000 patient quality-adjusted life years (QALYs), a measure of a patient's quality and length of life, over their remaining lifetime. The introduction of a new antibacterial into the current treatment pathway resulted in an overall monetary benefit of €6.8 billion over 10 years, when additional QALYs are valued at €30,000. This study demonstrates considerable health economic benefits of introducing a new antibacterial in Greece and can help inform decision makers when developing a national action plan to combat resistance and improve access to treatments.

Impact of a non-compulsory antifungal stewardship program on overuse and misuse of antifungal agents in a tertiary care hospital.

OBJECTIVES: To assess the impact of an antifungal stewardship (AFS) program on appropriate use, consumption and acquisition costs of antifungals, and on clinical outcomes (in-hospital-mortality, in-hospital-length-of-stay). METHODS: The study was conducted at a 535-bed tertiary-care hospital and had three consecutive periods. A) Observational period (10 months): all antifungal prescriptions were prospectively evaluated. B) Educational intervention to increase the awareness on proper antifungals use. C) Implementation of a non-compulsory AFS program (10 months) based on prospective audit and feedback. Interrupted time series analysis has been used to assess the impact of the intervention. RESULTS: During the pre-interventional period 198 AF prescriptions for 147 patients, have been evaluated compared to 181 prescriptions in 138 patients during the AFS period. Statistical analysis showed a significant immediate drop of inappropriate prescriptions after intervention with a significantly declining trend thereafter, and a significant drop of the total consumption of antifungals immediately after the intervention with a significant declining trend thereafter. All-cause, in-hospital- mortality was stable during the pre-intervention period with a significant declining trend after the AFS program implementation, although no immediate intervention effect could be established. Comparison of pre-and post-interventional periods showed significant reduction in acquisition costs (-26.8%, p<0.001) but no difference regarding the total number of bed-days (107,654 vs. 102,382), and mean length of hospital-stay (5.19 vs. 4.96 days, p=NS). CONCLUSIONS: The implementation of a non-compulsory AFS program resulted in significant improvement in the quality of prescriptions and reduction in antifungals consumption and acquisitions costs, without affecting the overall in-hospital-mortality and mean in-hospital-length-of-stay.

Exploring colistin pharmacodynamics against Klebsiella pneumoniae: a need to revise current susceptibility breakpoints.

Objectives: Because the pharmacokinetic/pharmacodynamic (PK/PD) characteristics of colistin against Enterobacteriaceae are not well explored, we studied the activity of colistin against K. pneumoniae in an in vitro PK/PD model simulating different dosing regimens. Methods: Three clinical isolates of K. pneumoniae with MICs of 0.5, 1 and 4 mg/L were tested in an in vitro PK/PD model following a dose-fractionation design over a period of 24 h. A high and low inoculum of 107 and 104 cfu/mL with and without a heteroresistant subpopulation, respectively, were used. PK/PD indices associated with colistin activity were explored and Monte Carlo analysis was performed in order to determine the PTA for achieving a bactericidal effect (2 log kill). Results: The fAUC/MIC (R2 = 0.64-0.68) followed by fCmax/MIC (R2 = 0.55-0.63) best described colistin's 24 h log10 cfu/mL reduction for both low and high inocula. Dosing regimens with fCmax/MIC ≥6 were always associated with a bactericidal effect (P = 0.0025). However, at clinically achievable concentrations, usually below fCmax/MIC = 6, an fAUC/MIC ≥25 was more predictive of a bactericidal effect. Using a dosing regimen of 9 MU/day, the PTA for this pharmacodynamic target was 100%, 5%-70% and 0%, for isolates with MICs of ≤0.5, 1 and ≥2 mg/L, respectively. Dosing regimens that aim for a trough level of 1 mg/L achieve coverage of strains up to 0.5 mg/L (target trough/MIC = 2 mg/L). Conclusions: Characterization of the pharmacodynamics of colistin against Enterobacteriaceae in an in vitro model of infection indicates that a revision of current susceptibility breakpoints is needed. Therapeutic drug monitoring of colistin to achieve pharmacodynamic targets in individual patients is highly recommended.

Pharmacokinetic-pharmacodynamic modelling of meropenem against VIM-producing Klebsiella pneumoniae isolates: clinical implications.

VIM-producing Klebsiella pneumoniae isolates are usually associated with high MICs to carbapenems. Preclinical studies investigating the pharmacokinetic-pharmacodynamic (PK-PD) characteristics of carbapenems against these isolates are lacking. The in vitro antibacterial activity of meropenem against one WT and three VIM-producing K. pneumoniae clinical isolates (median MICs 0.031, 8, 16 and 128 mg l- 1) was studied in a dialysis-diffusion PK-PD model and verified in a thigh infection neutropenic animal model by testing selected strains and exposures. The in vitro PK-PD target associated with bactericidal activity was estimated and the target attainment for different dosing regimens was calculated with Monte Carlo analysis. The in vitro model was correlated with the in vivo data, with log10CFU/ml reduction of < 1 for the VIM-producing (MIC 16 mg l- 1) and >2 for the WT (MIC 0.031 mg l- 1) isolates, with %f T >MIC 25 and 100%, respectively. The in vitro bactericidal activity for all isolates was associated with 40 % f T>MIC and attained in >90% of cases with the standard 1 g q8 0.5 h infusion dosing regimen only for isolates with MICs up to 1 mg l- 1. For isolates with MICs of 2-8 mg l- 1, prolonged infusion regimens (4 h infusion q8 or 2 h infusion q4) of standard (1 g) and higher (2 g) doses or continuous infusion regimens (3-6 g) are required. For isolates with a MIC of 16 mg l- 1 the unconventional dosing regimen of 2 g as 2 h infusion q4 or 12 g continuous infusion will be required. Prolonged and continuous infusion regimens of meropenem may increase efficacy against VIM-producing K. pneumoniae isolates.

The Additive Value of Femoral Ultrasound for Subclinical Atherosclerosis Assessment in a Single Center Cohort of 962 Adults, Including High Risk Patients with Rheumatoid Arthritis, Human Immunodeficiency Virus Infection and Type 2 Diabetes Mellitus.

BACKGROUND: Presence of femoral atheromatic plaques, an emerging cardiovascular disease (CVD) biomarker additional to carotid plaques, is poorly investigated in conditions associating with accelerated atherosclerosis such as Rheumatoid Arthritis (RA), Human Immunodeficiency Virus (HIV) infection and Type 2 Diabetes Mellitus (T2DM). OBJECTIVE/METHODS: To assess the frequency of femoral/carotid subclinical atheromatosis phenotypes in RA, HIV and T2DM and search for each disease-specific probability of either femoral and/or carotid subclinical atheromatosis, we examined by ultrasound a single-center cohort of CVD-free individuals comprised of consecutive non-diabetic patients with RA (n=226) and HIV (n=133), T2DM patients (n=109) and non-diabetic individuals with suspected/known hypertension (n=494) who served as reference group. RESULTS: Subclinical atheromatosis--defined as local plaque presence in at least on arterial bed--was diagnosed in 50% of the overall population. Among them, femoral plaques only were found in 25% of either RA or HIV patients, as well as in 16% of T2DM patients and 35% of reference subjects. After adjusting for all classical CVD risk factors, RA and HIV patients had comparable probability to reference group of having femoral plaques, but higher probability (1.75; 1.17-2.63 (odds ratio; 95% confidence intervals), 2.04; 1.14-3.64, respectively) of having carotid plaques, whereas T2DM patients had higher probability to have femoral and carotid plaques, albeit, due to their pronounced dyslipidemic profile. CONCLUSION: RA and HIV accelerate predominantly carotid than femoral. A "two windows" carotid/femoral, rather than carotid alone ultrasound, screening improves substantially subclinical atheromatosis detection in patients at high CVD risk.

Assessment of prealbumin in hemodialysis and renal-transplant patients.

OBJECTIVE: This study assessed prealbumin in hemodialysis (HD) and renal-transplant (RT) patients, and compared it with other biochemical and anthropometric markers, clinical conditions, and treatment variables. DESIGN: We used a research design. PATIENTS: Serum prealbumin was measured in 84 HD patients with a mean age of 60.47 +/- 17.81 years and a mean body mass index (BMI) of 24.38 +/- 4.87 kg/m(2), and in 154 RT patients with a mean age of 44.08 +/- 13.59 years and a mean BMI of 24.97 +/- 3.87 kg/m(2). Renal-transplant patients were divided into three groups, based on year of renal transplantation (first year, first to second year, and third to tenth year). Serum albumin, creatinine, cholesterol, glucose, triglycerides, white blood cells, BMI, midarm circumference, and triceps and biceps skinfolds were measured. RESULTS: Prealbumin levels were significantly higher in HD patients compared with RT patients. Both groups had prealbumin levels <30 mg/dL, but almost all RT patients in our study had prealbumin levels <20 mg/dL. Gender, age, and presence of anemia, hypertension, and diabetes did not significantly affect prealbumin levels in the two groups. Prealbumin levels were significantly positively correlated with duration of dialysis in the HD group and with albumin in the RT group. CONCLUSIONS: Hemodialysis patients have higher levels of prealbumin compared with RT patients. Prealbumin levels are below normal range in both groups of patients. Prealbumin reflects nutritional status in RT patients, but is also affected by other factors.

Medical and nursing students with suboptimal protective immunity against vaccine-preventable diseases.

OBJECTIVES: Medical and nursing students (hereafter referred to as "healthcare students") are at risk of contracting and transmitting infectious diseases in a hospital setting. The aim of our study was to evaluate the vaccination history of healthcare students and their serologic immunity against vaccine-preventable diseases. DESIGN: Prospective cohort study. SETTING: A tertiary care children's hospital in Athens, Greece, which is affiliated with the University of Athens. METHODS: Healthcare students were recruited during April through November 2007. The information obtained from these students during personal interviews included demographics and whether there was a history of varicella, measles, mumps, rubella, and/or hepatitis A or B virus infection. Vaccination history and documentation of disease were abstracted from available medical records. Serum antibodies against the above-mentioned viral agents were determined by use of an enzyme-linked immunosorbent assay. Seronegative students and those with immunization gaps were referred to local vaccination clinics, and compliance was assessed 3 months later. RESULTS: A total of 187 healthcare students were recruited, 131 (70.1%) of whom provided complete documentation of vaccination history. Adequate immunity against diphtheria and tetanus was documented for 55 (37.2%) and 73 (49.3%) of the 148 participants, respectively, whereas age-appropriate vaccination against pertussis, diphtheria, tetanus, and poliomyelitis was noted for 138 (93.2%), 147 (99.3%), 147 (99.3%), and 147 (99.3%) healthcare students, respectively. Of 185 healthcare students, 171 (92.4%) were immune to varicella. Of 182 healthcare students, 179 (98.4%) were immune to measles, 163 (89.6%) were immune to mumps, and 176 (96.7%) were immune to rubella. Of 179 healthcare students, 151 (84.4%) were immune to hepatitis B virus. Of 178 healthcare students, 26 (14.6%) were immune to hepatitis A virus. Antibodies (10 IU/L or higher) to hepatitis B surface antigen were detected for 151 (84.4%) of 179 healthcare students, and antibodies (10 IU/L or higher) to hepatitis A virus were detected for 26 (14.6%) of 178 healthcare students. Fewer than 30% of participants were in full compliance with recommended vaccinations. CONCLUSIONS: We have determined that there is a certain proportion of healthcare students who are susceptible to certain vaccine-preventable diseases. The development of an appropriate vaccination strategy is required to decrease the risk of transmission in a hospital setting.

Ethical dilemmas encountered during clinical drug trials.

Ethical standards have a basis in antiquity and changes in practice need to be measured by moral considerations that are slower to change. This paper considers present day ethical problems in clinical trials--especially in infection, conflict of interest, financing of scientific studies and publishing (or non-publishing) of the results.

Two doses of a lipid formulation of amphotericin B for the treatment of Mediterranean visceral leishmaniasis.

To evaluate the efficacy of a short course of a lipid formulation of amphotericin B (L-AmB) for the treatment of Mediterranean visceral leishmaniasis (VL), an open prospective study was conducted. Forty-one children with parasitologically confirmed leishmaniasis received L-AmB, 10 mg/kg daily for 2 days. The comparison groups were 30 children who, in a previous study, were treated with L-AmB, 4 mg/kg daily for 5 days, and 52 children who were treated with meglumine antimoniate. At 6 months after completion of treatment, overall treatment success was noted for 40 of 41 children treated with 2 doses of L-AmB, 27 of 30 children treated with 5 doses of L-AmB, and 47 of 52 children treated with meglumine antimoniate. Abatement of fever, reduction in spleen size, and correction of laboratory parameters occurred more quickly among the children who received 2 doses of L-AmB than among the comparison groups, and the total estimated cost of the 2-dose regimen was also lower than that of the other regimens. Two doses of L-AmB, 10 mg/kg each, is cost-effective therapy for Mediterranean VL in children.