gms | German Medical Science

GMS Infectious Diseases

Paul-Ehrlich-Gesellschaft für Infektionstherapie e.V. (PEG) (PEG)

ISSN 2195-8831

Calculated parenteral initial treatment of bacterial infections: Economic aspects of antibiotic treatment

Guideline Calculated parenteral initial therapy

Search Medline for

  • corresponding author Michael Wilke - inspiring-health Dr. Wilke GmbH, Munich, Germany
  • Claudia Hübner - Lehrstuhl für Allgemeine Betriebswirtschaftslehre und Gesundheitsmanagement, Universität Greifswald, Germany
  • Wolfgang Kämmerer - Klinische Pharmazie, Apotheke des Universitätsklinikums Augsburg, Germany

GMS Infect Dis 2020;8:Doc03

doi: 10.3205/id000047, urn:nbn:de:0183-id0000476

This is the English version of the article.
The German version can be found at: http://www.egms.de/de/journals/id/2020-8/id000047.shtml

Published: March 26, 2020

© 2020 Wilke et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. See license information at http://creativecommons.org/licenses/by/4.0/.


Abstract

This is the seventeenth chapter of the guideline “Calculated initial parenteral treatment of bacterial infections in adults – update 2018” in the 2nd updated version. The German guideline by the Paul-Ehrlich-Gesellschaft für Chemotherapie e.V. (PEG) has been translated to address an international audience.

This chapter analyses economic aspects of antiinfective therapy. Any treatment decision is also a cost decision. In this chapter the authors particularly analyse whether or not there is evidence that certain clinically effective strategies as Antimicrobial Stewardship programs (AMS), guideline adherent initial therapy, early diagnostics, De-escalation, sequence therapy or therapeutic drug monitoring also have benficial economic effects. These can be direct savings or shortening of length of stay to free resources.


Introduction

Calculated parenteral initial treatment of bacterial diseases in adults aims at choosing the right antibiotic at the earliest possible moment in order to maximize the chances of curing the infection. In addition, the recommendations for calculated treatment should also contribute to minimizing risk of developing resistance. In the following, the economic aspects of antibiotic treatment will be analyzed and strategies presented that are favorable from an economic point of view. Practically all studies and publications on the economic evaluation of certain antibiotic treatment strategies show that clinical (time to cure, survival, proportion of superinfections) and economic benefits go hand in hand. Thus, none of the economically favorable treatment strategies presented here have a negative impact on the clinical outcome.

In most European countries, including the German-speaking countries, remuneration systems based on the so-called “diagnosis-related groups (DRG)” are in use in hospitals. These systems have in common that they reimburse for a hospital stay on the basis of the principal diagnosis, interventions performed (surgeries and other procedures) and any secondary diagnoses (for example nosocomial infections). In these compensation systems in particular, all diagnostic and therapeutic strategies that lead to a longer hospital stay from the outset are economically unfavorable, since reimbursement usually takes the form of a per-case lump sum based on the average cost of a patient, which in turn is strongly influenced by the average length of stay. If the in-patient stay extends beyond the average length of stay, treatment usually costs more than the reimbursement for the case. In classical pharmacoeconomics, considerations of drug costs are often in the foreground. Since these costs generally only account for about 4% of the costs in a hospital (intensive care wards 10%), they are well below the costs associated with longer stays. Nevertheless, strategies should also be considered that lead to a reduction in the cost of medicines through targeted intervention. Finally, the authors have included a simple guide in this text that readers can use to perform their own analyzes.

Pharmacoeconomic parameters such as cost-effectiveness or costs per quality-adjusted year of age (Cost/QALY) are not considered, since these considerations do not play a major role in German-speaking countries and are only used in some English-speaking countries to decide whether or not certain medicines should be reimbursed.

The aim of this text is to give readers a quick overview of economically advisable strategies in the form of a table, which in addition to the strategies also contains a level of recommendation in order to decide which of them should be used systematically (see Table 1 [Tab. 1]).


Diagnostic and therapeutic strategies in detail

Adequate initial therapy

The selection of the antibiotic at the beginning of treatment – especially in critically ill patients – determines the clinical and economic outcome to a high degree. Inadequate treatment is associated with significantly higher mortality [1], [2], [3], [4], [5] and usually higher costs [1], [6], [7], [8], [9]. However, the term “inadequate treatment” is rather vague. In the following we present aspects, including examples from the literature, which individually or in combination lead to inadequate initial therapy.

Compliance with guidelines

Guidelines and recommendations combine diagnostic and therapeutic strategies designed to ensure that the most common pathogens in certain infections – factoring in the current resistance situation – are included in initial treatment. Thus, adherence to guidelines, including local recommendations based on national and international guidelines, is an important driver of clinical and economic outcomes of treatment. There are examples in the literature of prospective randomized studies [10], [11], [12], case-control studies and so-called “interrupted time series” analyzes – more commonly known as “before and after” [13], [14], [15], [16]. After reviewing the literature and assessing the evidence, the authors strongly recommend (A) adherence to guidelines.

Consideration of the local resistance situation and patient-specific risk regarding the presence of resistant pathogens

Inadequate antibiotic treatment is associated with increased mortality and prolonged hospital stays [2], [9], [17]. Therefore, it is relevant not only from a clinical but also from an economic point of view that adequate antibiotic treatment takes place as soon as possible, ideally starting with calculated initial treatment.

In addition, many studies comparing adequate and inadequate treatment have found in particular that patients who were proven to have infections with multidrug-resistant pathogens often did not received adequate initial treatment [15], [18], [19], [20], [21], [22], [23], [24], [25].

The resistance rate, i.e. the proportion of strains of a bacterial species that is resistant to one or more antimicrobial substances, has been identified as a factor that influences the cost-effectiveness of antibiotics [26]. The effects were investigated in various decision analysis studies using the example of community-acquired pneumonia (CAP) [27], [28], [29]. Sensitivity analyzes showed that taking the resistance rates of Streptococcus pneumoniae and Haemophilus influenzae into account in the selection of active agents resulted in a reduction of the failure rate of first-line treatment (thus removing the need for second-line therapy), hospital admissions and mortality.

In the treatment of life-threatening bacterial infections in which calculated antibiotic treatment is used initially, knowledge of the local, often even ward-specific pathogen spectrum and associated resistance situation is crucial. Therefore, it is essential that the resistance statistics are continuously compiled, evaluated and communicated to the clinicians by the microbiologists (or hospital hygienists). Microbiological diagnostics plays a special role in this. It has two important functions to fulfill:

  • Modification of initially calculated antibiotic treatment through microbiological findings and
  • Providing data for determining the local pathogen and resistance spectrum against which future calculated antibiotic strategies will be targeted.

Especially regarding the first point it is important to obtain microbiological results as soon as possible. Here the use of fast and expensive diagnostic procedures can indeed be justified economically [30], [31]. The aim is to initiate early escalation or de-escalation of calculated initial treatment by quickly determining the resistance status and thus to reduce the duration of possibly inadequate treatment with its associated negative consequences. Cost efficiency has been demonstrated in economic model calculations, for example for PCR-controlled calculated antibiotic treatment [32], [33].

In addition, it is important to consider patient-specific risk factors that indicate infection with a multidrug-resistant pathogen when selecting treatment. These primarily include previous treatment with antibiotics, colonization or infection with an MRE or pathogen with special resistance in the medical history, a hospital-acquired infection or a previous hospital stay, chronic immunosuppression (cancer, COPD, diabetes, MTX therapy with PCP, etc.) as well as stay on an intensive care ward (possibly with ventilation) and acute or chronic renal failure, to name only the most important [34], [35], [36], [37], [38], [39]. The evaluation/weighting of such risk factors is recommended, amongst others, in the selection of appropriate antibiotics for calculated initial treatment of pneumonia [40], [41], [42].

Failure to take account of the risks leads to poorer clinical outcomes and higher treatment costs. In these patients, the choice of an antibiotic which acts against multidrug-resistant pathogens in initial therapy may be the better choice clinically and economically. As soon as the pathogen is known, treatment should be adapted accordingly i.e. de-escalated.

The benefit of early consideration of multidrug-resistant pathogens in high-risk patients has so far only been shown in retrospective case-control studies but the authors nevertheless strongly recommend (A) this strategy.

Rapid diagnostics with modern methods

Precisely because misjudging the risk of a certain pathogen being present often leads to inadequate initial therapy and because pathogen identification by means of culture in clinical practice takes 48 hours or longer, the question arises as to whether newer diagnostic methods such as real-time PCR, MALDI-TOF or the PCR-based electron spray mass spectroscopy (PCR/ESI-MS) [43] can contribute to adequate initial therapy and a reduction in costs. Since these procedures are very expensive compared to conventional diagnostics, the question arises of when they are useful. Various authors have carried out investigations and selected different scientific approaches (expert assessment on the basis of test results [44], [45], modeling [33], before/after [30], [31], [46]). One work showed that rapid testing led to a reduction in the use of vancomycin and shortened the duration of hospital stays [47]. After assessing the evidence for the present work, which deals explicitly with the economic effects of rapid diagnostics, the authors give a medium recommendation for this strategy (B).

Antibiotic stewardship programme (ABS)

Many measures to optimize antibiotic treatment can be subsumed under the term ABS. Here it was analyzed if there is evidence that extensive programs with measures such as

  • creation of in-house recommendations,
  • regular prescription analysis with ward rounds and continuous feedback,
  • advice from ABS experts (such as infectiologists or clinical pharmacists), and
  • restriction of certain antibiotic classes

are clinically and economically sensible. A number of international authors emphasize this clearly [48], [49], [50]. In 2013 a Cochrane Review [51] and an S3 guideline on this topic [52] appeared. Overall, according to the authors, the evidence for the introduction of ABS programs and their clinical and economic benefits is very good and they are strongly recommended (A).

Sequential therapy

Parenteral-oral follow-up treatment (sequential therapy) gives the option to continue treatment initiated parenterally in hospital with oral (out-patient) administration. As a result, the duration of intravenous treatment is reduced without having a negative impact on the success of the treatment [53]. In addition to reducing the risk of infusion-related infection and mobilizing the patient more quickly, there are a number of economic advantages that speak in favor of sequential therapy.

An early move to oral drug forms leads to a significant reduction in hospital stays, which can play a significant role in DRG flat-rate hospital remuneration systems. In a Europe-wide retrospective analysis of the treatment of MRSA-associated skin and soft tissue infections the team led by Nathwani and Eckmann found, for example, that the introduction of sequential therapy shortened hospital stays by 6.2 days on average with resultant potential savings of €2,000 per patient [54]. Similar results were reported by Gray et al. with her study in 5 hospitals in the United Kingdom, where she found savings of £363 per patient [55].

Other reasons for the economic superiority of sequential therapy over continuous parenteral therapy can be lower antibiotic costs and lower personnel costs for the preparation and administration of the parenteral antibiotics. The effects are not only evident in the clinical area but also in pre- and post-inpatient care.

Although there are mainly retrospective studies available on sequential therapy and its economic advantages, from an economic point of view the authors strongly recommend it (A).

De-escalation

In addition to sequential therapy, de-escalation can also contribute to optimizing the clinical economic balance. The aim is to replace calculated initial broad-spectrum antibiotic treatment with a more targeted one, i.e. to replace the initial substance with a similarly effective substance that however has a narrower spectrum. Prerequisites for this are:

  • presence of specific and plausible microbiological findings
  • clinical improvement (patient responded well to initial treatment)

By reducing the treatment spectrum and thus the antibiotic load, the development of resistances should be influenced favorably by minimizing the selection pressure. Patient safety is improved through fewer adverse drug reactions and superinfections [52]. From an economic point of view this will result in (sometimes significant) savings in drug expenditure, not least by reducing the duration of treatment [56].

As with sequential therapy, the publications on the economic effects of de-escalation are predominantly either retrospective analyzes or secondary evaluations of clinical studies. Nevertheless, once again the authors express a strong recommendation (A).

Therapeutic drug monitoring (TDM)

It is important to determine drug levels, particularly in the case of antibiotics with a narrow therapeutic range, such as vancomycin but also in the case of prolonged treatment with beta-lactam antibiotics. For TDM in vancomycin it has been shown repeatedly that using TDM significantly reduces nephrotoxic complications and thus, despite the costs, leads to considerable savings through avoiding complications [57], [58].

An analysis of 200 intensive care patients with severe infections investigated various therapeutic strategies with piperacillin/tazobactam. With an average total cost of €90.64 for a 7-day treatment with piperacillin/tazobactam, in spite of the additional costs of therapeutic drug monitoring (TDM, €26.68) continuous administration of an individual dose was below the cost of intermittent bolus administration in line with the package insert recommendations of 3x 4.5 g (for complicated urinary tract infection, intra-abdominal infections, skin and soft tissue infections, €112.11) or 4x 4.5 g (for severe pneumonia, neutropenic adults with fever, in cases of suspected bacterial infection, €148.49). Reduced drug costs contributed to this result – €36.75 [3x 4.5 g]/€49.00 [4x 4.5 g] bolus application versus €24.50 [8 g (2–16 g), median (min, max)] continuous application with TDM – about 30–50%. Plus on the other hand the lower process costs (disposable items and working time for preparation and continuous application (€46.11/€61.48 bolus application versus €24.42 continuous application) [59].

Although one of the studies on vancomycin was a randomized clinical study, overall there are relatively few studies on the economic aspects of TDM, the authors recommendation is a B-grade.

Importance of process costs

At the latest with the introduction of DRG, the analysis of their process costs and the resulting process optimization became imperative for hospitals. Here, it is important to consider the process of drug treatment from drug procurement through to administering it to a patient.

An important instrument for process optimization is the establishment of clinical treatment pathways and the creation of standard operating procedures (SOPs). With the help of these treatment paths/process descriptions it is possible to document and ensure cost and quality of treatment. Part of the treatment pathways are standards in drug therapy. Anti-infective agents are an important drug group because of their major importance in terms of cost and also their significance for the quality and success of treatment. These treatment standards are also an important part of ABS programs.

An important criterion for the selection of appropriate anti-infective agents in the treatment pathways/processes will be the economic-pharmacoeconomic analysis of alternative treatments from the perspective of a hospital. In addition to the purchase prices of drugs, consumption of other resources must also be taken into account.

It should also be questioned to what extent the anti-infective agent used satisfies aspects of quality management, quality assurance, process management, patient orientation and employee orientation. The following parameters are therefore included in such an analysis:

  • Personnel costs per application: under DRG conditions (increased output rates, reduced headcount), a reduction in the frequency of application should be considered positive. Also, the personnel costs incurred per application are an important criterion: they are given in the literature as being €2–4 or US$ per application [60], [61];
  • the costs of the associated application aids such as syringes, cannulas, infusion sets, etc. In the literature, these costs are given depending on the type of application as being €1–4 [61];
  • a lower error rate: Investigations and the resulting recommendations from English-speaking countries showed that the number of drug application errors decreases with the reduction of the frequency of application and the simplicity of preparation [62]. The required number of steps in preparation must also be taken into account. So, whenever possible, ready-made preparations should be used;
  • the possible likelihood of confusion;
  • the cost of required monitoring but also the reduction in the use of anti-infective agents through monitoring.

The aim of this process and process cost analysis is to improve quality while optimizing costs. Cost optimization in this sense means that with the help of the described analysis, an anti-infective agent is chosen from amongst equally good active ingredients that has the lowest resource consumption. Due to the small number of studies that deal explicitly with litigation costs and error costs in antibiotic treatment, the authors give a Grade B recommendation.

Economic consequences with increasing frequency of resistance

From a clinical and ecological point of view, the risk of selection of antibiotic-resistant microorganisms should be minimized, as infections caused by multidrug-resistant or even pan-resistant bacteria are associated with a (considerably) increased mortality risk for patients. A number of publications on the health threat posed by antibiotic-resistant pathogens have also studied the associated costs. According to the State of the World’s Antibiotics report, the 23,000 patients who died as a result of an infection with resistant pathogens in the US led to health care costs of $20 billion and $35 billion in lost productivity [63]. The 2014 WHO Global Report on Antibiotic Resistance Surveillance includes, amongst other things, a systematic literature review of the cost of infections with resistant microorganisms. This very sophisticated report comes to the conclusion that the increase of resistant pathogens has led to increased costs but that no global extrapolation can be made on the base of existing data [64]. In particular, it is pointed out that the additional costs attributable to infections by resistant strains should be considered economically in comparison with infections by sensitive strains of a pathogen species in the same type of infection. For example there are several papers that have studied MRSA and MSSA infections economically. These gave attributable additional costs of €8,000 to €17,000 and US$13,900 respectively [65], [66], [67], [68], [69]. Based on these amounts, it is easy to understand how the figures in the extrapolation above were reached. They appear quite realistic. Another report concludes that the number of deaths from resistant pathogens will rise from 700,000 worldwide today to 10 million by 2050 if no further action is taken. In total, this would lead to a – global – total economic damage of US$100 billion (100 trillions US-notation in the original) by 2050 [70]. The authors acknowledge that first steps have been taken to tackle this global crisis. Intensified research, actions coordinated by WHO in 194 countries and advances in understanding the genetics of bacteria and, ultimately, the improvements in infection prevention in emerging economies are rays of hope.

In summary, it can be stated that resistance to antibiotics causes considerable direct financial and even greater economic damage. That is precisely why this topic should remain on the agenda in the future when discussing the economic aspects of antibiotic treatment.

Further sources of information and their evaluation

In Medline, there are also increasing indications of health economic works. The journals, which mainly publish articles on health economic issues, include “Health Economics and Quality Management” published by the German Society for Health Economics as well as international English-language journals such as “Health Economics”, “European Journal of Health Economics” and “Value in Health”.

It is a well-known problem that not only approval-related treatment studies but also many pharmacoeconomic studies are carried out in cooperation with the pharmaceutical industry. Such studies tend to present positive results for usually high-priced drug innovations and are often used as marketing tools for external sales visits or at specialist congresses. Also the choice of a method of analysis is often result-oriented or extensive and non-transparent model calculations are used. For the non-economist it is difficult to recognize this publication bias and to classify the significance of such studies. One option is to focus on reports from Health Technology Assessment (HTA) agencies such as the National Institute for Health and Clinical Excellence (http://www.evidence.nhs.uk/), the Institute for Quality and Efficiency in Health (https://www.iqwig.de/) or the Canadian Agency for Drugs and Technologies in Health (http://www.cadth.ca/). In addition to a systematic presentation and qualitative assessment of the available evidence, these also include evaluations of the cost-effectiveness of pharmaceuticals and other medical technologies. These are based partly on existing studies and partly on their own economic studies. The increasing networking of international HTA agencies and a progressive standardization of assessment methods have an additional beneficial influence.

Studies and HTA reports are also presented in great detail in the database of the NHS Center for Review and Dissemination (http://www.crd.york.ac.uk/crdweb/). The NHS Economic Evaluation Database contains studies that can be found under Current Contents, Clinical Medicine, Medline, and CINAHL, as well as manual searches. Based on a scheme of approximately 30 criteria, the study objective, design of the clinical and economic part of the study as well as clinical and economic results are presented clearly and in detail. In addition, there is a brief evaluation of the study quality.


Note

This is the seventeenth chapter of the guideline “Calculated initial parenteral treatment of bacterial infections in adults – update 2018” in the 2nd updated version. The German guideline by the Paul-Ehrlich-Gesellschaft für Chemotherapie e.V. (PEG) has been translated to address an international audience.


Competing interests

The authors declare that they have no competing interests.


References

1.
Shorr AF, Haque N, Taneja C, Zervos M, Lamerato L, Kothari S, Zilber S, Donabedian S, Perri MB, Spalding J, Oster G. Clinical and economic outcomes for patients with health care-associated Staphylococcus aureus pneumonia. J Clin Microbiol. 2010 Sep;48(9):3258-62. DOI: 10.1128/JCM.02529-09 External link
2.
Ibrahim EH, Sherman G, Ward S, Fraser VJ, Kollef MH. The influence of inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the ICU setting. Chest. 2000 Jul;118(1):146-55. DOI: 10.1378/chest.118.1.146 External link
3.
Retamar P, López-Prieto MD, Rodríguez-López F, de Cueto M, García MV, González-Galan V, Del Arco A, Pérez-Santos MJ, Téllez-Pérez F, Becerril-Carral B, Martín-Aspas A, Arroyo A, Pérez-Cortés S, Acosta F, Florez C, León-Ruiz L, Muñoz-Medina L, Rodríguez-Baño J; SAEI/SAMPAC/REIPI Bacteremia Group. Predictors of early mortality in very elderly patients with bacteremia: a prospective multicenter cohort. Int J Infect Dis. 2014 Sep;26:83-7. DOI: 10.1016/j.ijid.2014.04.029 External link
4.
Kollef MH. Inadequate antimicrobial treatment: an important determinant of outcome for hospitalized patients. Clin Infect Dis. 2000 Sep;31 Suppl 4:S131-8. DOI: 10.1086/314079 External link
5.
Kumar A. Optimizing antimicrobial therapy in sepsis and septic shock. Crit Care Clin. 2009 Oct;25(4):733-51, viii. DOI: 10.1016/j.ccc.2009.08.004 External link
6.
Chong YP, Bae IG, Lee SR, Chung JW, Jun JB, Choo EJ, Moon SY, Lee MS, Jeon MH, Song EH, Lee EJ, Park SY, Kim YS. Clinical and economic consequences of failure of initial antibiotic therapy for patients with community-onset complicated intra-abdominal infections. PLoS One. 2015 Apr 24;10(4):e0119956. DOI: 10.1371/journal.pone.0119956 External link
7.
Lodise TP, McKinnon PS, Swiderski L, Rybak MJ. Outcomes analysis of delayed antibiotic treatment for hospital-acquired Staphylococcus aureus bacteremia. Clin Infect Dis. 2003 Jun;36(11):1418-23. DOI: 10.1086/375057 External link
8.
Davey PG, Marwick C. Appropriate vs. inappropriate antimicrobial therapy. Clin Microbiol Infect. 2008 Apr;14 Suppl 3:15-21. DOI: 10.1111/j.1469-0691.2008.01959.x External link
9.
Kuti EL, Patel AA, Coleman CI. Impact of inappropriate antibiotic therapy on mortality in patients with ventilator-associated pneumonia and blood stream infection: a meta-analysis. J Crit Care. 2008 Mar;23(1):91-100. DOI: 10.1016/j.jcrc.2007.08.007 External link
10.
Singh N, Rogers P, Atwood CW, Wagener MM, Yu VL. Short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit. A proposed solution for indiscriminate antibiotic prescription. Am J Respir Crit Care Med. 2000 Aug;162(2 Pt 1):505-11. DOI: 10.1164/ajrccm.162.2.9909095 External link
11.
Marrie TJ, Lau CY, Wheeler SL, Wong CJ, Vandervoort MK, Feagan BG. A controlled trial of a critical pathway for treatment of community-acquired pneumonia. CAPITAL Study Investigators. Community-Acquired Pneumonia Intervention Trial Assessing Levofloxacin. JAMA. 2000 Feb;283(6):749-55. DOI: 10.1001/jama.283.6.749 External link
12.
Menéndez R, Torres A, Reyes S, Zalacain R, Capelastegui A, Aspa J, Borderías L, Martín-Villasclaras JJ, Bello S, Alfageme I, de Castro FR, Rello J, Molinos L, Ruiz-Manzano J. Initial management of pneumonia and sepsis: factors associated with improved outcome. Eur Respir J. 2012 Jan;39(1):156-62. DOI: 10.1183/09031936.00188710 External link
13.
Wawrzeniak IC, Loss SH, Moraes MC, De La Vega FL, Victorino JA. Could a protocol based on early goal-directed therapy improve outcomes in patients with severe sepsis and septic shock in the Intensive Care Unit setting?. Indian J Crit Care Med. 2015 Mar;19(3):159-65. DOI: 10.4103/0972-5229.152759 External link
14.
Rello J, Ulldemolins M, Lisboa T, Koulenti D, Mañez R, Martin-Loeches I, De Waele JJ, Putensen C, Guven M, Deja M, Diaz E; EU-VAP/CAP Study Group. Determinants of prescription and choice of empirical therapy for hospital-acquired and ventilator-associated pneumonia. Eur Respir J. 2011 Jun;37(6):1332-9. DOI: 10.1183/09031936.00093010 External link
15.
Micek ST, Welch EC, Khan J, Pervez M, Doherty JA, Reichley RM, Kollef MH. Empiric combination antibiotic therapy is associated with improved outcome against sepsis due to Gram-negative bacteria: a retrospective analysis. Antimicrob Agents Chemother. 2010 May;54(5):1742-8. DOI: 10.1128/AAC.01365-09 External link
16.
Meyer E, Buttler J, Schneider C, Strehl E, Schroeren-Boersch B, Gastmeier P, Ruden H, Zentner J, Daschner FD, Schwab F. Modified guidelines impact on antibiotic use and costs: duration of treatment for pneumonia in a neurosurgical ICU is reduced. J Antimicrob Chemother. 2007 Jun;59(6):1148-54. DOI: 10.1093/jac/dkm088 External link
17.
Garnacho-Montero J, Ortiz-Leyba C, Herrera-Melero I, Aldabó-Pallás T, Cayuela-Dominguez A, Marquez-Vacaro JA, Carbajal-Guerrero J, Garcia-Garmendia JL. Mortality and morbidity attributable to inadequate empirical antimicrobial therapy in patients admitted to the ICU with sepsis: a matched cohort study. J Antimicrob Chemother. 2008 Feb;61(2):436-41. DOI: 10.1093/jac/dkm460 External link
18.
Mauldin PD, Salgado CD, Hansen IS, Durup DT, Bosso JA. Attributable hospital cost and length of stay associated with health care-associated infections caused by antibiotic-resistant gram-negative bacteria. Antimicrob Agents Chemother. 2010 Jan;54(1):109-15. DOI: 10.1128/AAC.01041-09 External link
19.
Marquet K, Liesenborgs A, Bergs J, Vleugels A, Claes N. Incidence and outcome of inappropriate in-hospital empiric antibiotics for severe infection: a systematic review and meta-analysis. Crit Care. 2015 Feb;19:63. DOI: 10.1186/s13054-015-0795-y External link
20.
MacVane SH, Tuttle LO, Nicolau DP. Impact of extended-spectrum β-lactamase-producing organisms on clinical and economic outcomes in patients with urinary tract infection. J Hosp Med. 2014 Apr;9(4):232-8. DOI: 10.1002/jhm.2157 External link
21.
Cheah AL, Spelman T, Liew D, Peel T, Howden BP, Spelman D, Grayson ML, Nation RL, Kong DC. Enterococcal bacteraemia: factors influencing mortality, length of stay and costs of hospitalization. Clin Microbiol Infect. 2013 Apr;19(4):E181-9. DOI: 10.1111/1469-0691.12132 External link
22.
Micek S, Johnson MT, Reichley R, Kollef MH. An institutional perspective on the impact of recent antibiotic exposure on length of stay and hospital costs for patients with gram-negative sepsis. BMC Infect Dis. 2012 Mar;12:56. DOI: 10.1186/1471-2334-12-56 External link
23.
Shorr AF, Micek ST, Kollef MH. Inappropriate therapy for methicillin-resistant Staphylococcus aureus: resource utilization and cost implications. Crit Care Med. 2008 Aug;36(8):2335-40. DOI: 10.1097/CCM.0b013e31818103ea External link
24.
Hirsch EB, Tam VH. Impact of multidrug-resistant Pseudomonas aeruginosa infection on patient outcomes. Expert Rev Pharmacoecon Outcomes Res. 2010 Aug;10(4):441-51. DOI: 10.1586/erp.10.49 External link
25.
Heyland DK, Cook DJ, Griffith L, Keenan SP, Brun-Buisson C. The attributable morbidity and mortality of ventilator-associated pneumonia in the critically ill patient. The Canadian Critical Trials Group. Am J Respir Crit Care Med. 1999 Apr;159(4 Pt 1):1249-56. DOI: 10.1164/ajrccm.159.4.9807050 External link
26.
Simoens S. Factors affecting the cost effectiveness of antibiotics. Chemother Res Pract. 2011;2011:249867. DOI: 10.1155/2011/249867 External link
27.
Sabes-Figuera R, Segú JL, Puig-Junoy J, Torres A. Influence of bacterial resistances on the efficiency of antibiotic treatments for community-acquired pneumonia. Eur J Health Econ. 2008 Feb;9(1):23-32. DOI: 10.1007/s10198-006-0019-0 External link
28.
Martin M, Quilici S, File T, Garau J, Kureishi A, Kubin M. Cost-effectiveness of empirical prescribing of antimicrobials in community-acquired pneumonia in three countries in the presence of resistance. J Antimicrob Chemother. 2007 May;59(5):977-89. DOI: 10.1093/jac/dkm033 External link
29.
Martin M, Moore L, Quilici S, Decramer M, Simoens S. A cost-effectiveness analysis of antimicrobial treatment of community-acquired pneumonia taking into account resistance in Belgium. Curr Med Res Opin. 2008 Mar;24(3):737-51. DOI: 10.1185/030079908X273336 External link
30.
Perez KK, Olsen RJ, Musick WL, Cernoch PL, Davis JR, Peterson LE, Musser JM. Integrating rapid diagnostics and antimicrobial stewardship improves outcomes in patients with antibiotic-resistant Gram-negative bacteremia. J Infect. 2014 Sep;69(3):216-25. DOI: 10.1016/j.jinf.2014.05.005 External link
31.
Perez KK, Olsen RJ, Musick WL, Cernoch PL, Davis JR, Land GA, Peterson LE, Musser JM. Integrating rapid pathogen identification and antimicrobial stewardship significantly decreases hospital costs. Arch Pathol Lab Med. 2013 Sep;137(9):1247-54. DOI: 10.5858/arpa.2012-0651-OA External link
32.
Brown J, Paladino JA. Impact of rapid methicillin-resistant Staphylococcus aureus polymerase chain reaction testing on mortality and cost effectiveness in hospitalized patients with bacteraemia: a decision model. Pharmacoeconomics. 2010;28(7):567-75. DOI: 10.2165/11533020-000000000-00000 External link
33.
Hübner C, Hübner NO, Kramer A, Fleßa S. Cost-analysis of PCR-guided pre-emptive antibiotic treatment of Staphylococcus aureus infections: an analytic decision model. Eur J Clin Microbiol Infect Dis. 2012 Nov;31(11):3065-72. DOI: 10.1007/s10096-012-1666-y External link
34.
Aliberti S, Di Pasquale M, Zanaboni AM, Cosentini R, Brambilla AM, Seghezzi S, Tarsia P, Mantero M, Blasi F. Stratifying risk factors for multidrug-resistant pathogens in hospitalized patients coming from the community with pneumonia. Clin Infect Dis. 2012 Feb;54(4):470-8. DOI: 10.1093/cid/cir840 External link
35.
American Thoracic Society; Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005 Feb;171(4):388-416. DOI: 10.1164/rccm.200405-644ST External link
36.
Bowman N, Goswami N, Lippincott CK, Vinikoor MJ, Miller WC. Clinical scoring for risk of resistant organisms in pneumonia: right idea, wrong interpretation. Clin Infect Dis. 2012 Sep;55(5):749-50. DOI: 10.1093/cid/cis532 External link
37.
Dalhoff K, Abele-Horn M, Andreas S, Bauer T, von Baum H, Deja M, Ewig S, Gastmeier P, Gatermann S, Gerlach H, Grabein B, Höffken G, Kern WV, Kramme E, Lange C, Lorenz J, Mayer K, Nachtigall I, Pletz M, Rohde G, Rosseau S, Schaaf B, Schaumann R, Schreiter D, Schütte H, Seifert H, Sitter H, Spies C, Welte T; German Society for Anaesthesiology and Intensive Care Medicine; German Society for Infectious Diseases; German Society for Hygiene and Microbiology; German Respiratory Society; Paul-Ehrlich-Society for Chemotherapy. Epidemiologie, Diagnostik und Therapie erwachsener Patienten mit nosokomialer Pneumonie. S-3 Leitlinie der Deutschen Gesellschaft fur Anästhesiologie und Intensivmedizin e.V., der Deutschen Gesellschaft fur Infektiologie e.V., der Deutschen Gesellschaft fur Hygiene und Mikrobiologie e.V., der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin e.V. und der Paul-Ehrlich-Gesellschaft fur Chemotherapie e.V. [Epidemiology, diagnosis and treatment of adult patients with nosocomial pneumonia. S-3 Guideline of the German Society for Anaesthesiology and Intensive Care Medicine, the German Society for Infectious Diseases, the German Society for Hygiene and Microbiology, the German Respiratory Society and the Paul-Ehrlich-Society for Chemotherapy]. Pneumologie. 2012 Dec;66(12):707-65. DOI: 10.1055/s-0032-1325924 External link
38.
Bodmann K-F, Lorenz J, Bauer TT, Ewig S, Trautmann M, Vogel F. Nosokomiale Pneumonie: Prävention, Diagnostik und Therapie: Ein Konsensuspapier der Paul-Ehrlich-Gesellschaft für Chemotherapie (PEG) und der Deutschen Gesellschaft für Pneumologie (DGP) unter Mitarbeit von Experten der Deutschen Gesellschaft für Anästhesiologie und Intensivmedizin (DGAI) – PEG Emfehlungen. Chemother J. 2003;12(2):33-44.
39.
Webb BJ, Dascomb K, Stenehjem E, Vikram HR, Agrwal N, Sakata K, Williams K, Bockorny B, Bagavathy K, Mirza S, Metersky M, Dean NC. Derivation and Multicenter Validation of the Drug Resistance in Pneumonia Clinical Prediction Score. Antimicrob Agents Chemother. 2016 Apr 22;60(5):2652-63. DOI: 10.1128/AAC.03071-15 External link
40.
Wilke M, Grube RF, Bodmann KF. Guideline-adherent initial intravenous antibiotic therapy for hospital-acquired/ventilator-associated pneumonia is clinically superior, saves lives and is cheaper than non guideline adherent therapy. Eur J Med Res. 2011 Jul;16(7):315-23. DOI: 10.1186/2047-783X-16-7-315 External link
41.
Infekt-Liga. Pneumonien. [cited 2017-8-31]. Available from: http://www.infektliga.de/empfehlungen/atemwegsinfektionen/pneumonien/ External link
42.
Shorr AF, Zilberberg MD, Reichley R, Kan J, Hoban A, Hoffman J, Micek ST, Kollef MH. Validation of a clinical score for assessing the risk of resistant pathogens in patients with pneumonia presenting to the emergency department. Clin Infect Dis. 2012 Jan;54(2):193-8. DOI: 10.1093/cid/cir813 External link
43.
Jordana-Lluch E, Giménez M, Quesada MD, Rivaya B, Marcó C, Domínguez MJ, Arméstar F, Martró E, Ausina V. Evaluation of the Broad-Range PCR/ESI-MS Technology in Blood Specimens for the Molecular Diagnosis of Bloodstream Infections. PLoS ONE. 2015;10(10):e0140865. DOI: 10.1371/journal.pone.0140865 External link
44.
Vincent JL, Brealey D, Libert N, Abidi NE, O’Dwyer M, Zacharowski K, Mikaszewska-Sokolewicz M, Schrenzel J, Simon F, Wilks M, Picard-Maureau M, Chalfin DB, Ecker DJ, Sampath R, Singer M; Rapid Diagnosis of Infections in the Critically Ill Team. Rapid Diagnosis of Infection in the Critically Ill, a Multicenter Study of Molecular Detection in Bloodstream Infections, Pneumonia, and Sterile Site Infections. Crit Care Med. 2015 Nov;43(11):2283-91. DOI: 10.1097/CCM.0000000000001249 External link
45.
Bacconi A, Richmond GS, Baroldi MA, Laffler TG, Blyn LB, Carolan HE, Frinder MR, Toleno DM, Metzgar D, Gutierrez JR, Massire C, Rounds M, Kennel NJ, Rothman RE, Peterson S, Carroll KC, Wakefield T, Ecker DJ, Sampath R. Improved sensitivity for molecular detection of bacterial and Candida infections in blood. J Clin Microbiol. 2014 Sep;52(9):3164-74. DOI: 10.1128/JCM.00801-14 External link
46.
Sango A, McCarter YS, Johnson D, Ferreira J, Guzman N, Jankowski CA. Stewardship approach for optimizing antimicrobial therapy through use of a rapid microarray assay on blood cultures positive for Enterococcus species. J Clin Microbiol. 2013 Dec;51(12):4008-11. DOI: 10.1128/JCM.01951-13 External link
47.
Nguyen DT, Yeh E, Perry S, Luo RF, Pinsky BA, Lee BP, Sisodiya D, Baron EJ, Banaei N. Real-time PCR testing for mecA reduces vancomycin usage and length of hospitalization for patients infected with methicillin-sensitive staphylococci. J Clin Microbiol. 2010 Mar;48(3):785-90. DOI: 10.1128/JCM.02150-09 External link
48.
Weber A, Schneider C, Grill E, Strobl R, Vetter-Kerkhoff C, Jauch KW. Interventionen eines Apothekers auf chirurgischen Normalstationen – Auswirkungen auf die Antibiotikatherapie [Interventions by clinical pharmacists on surgical wards – impact on antibiotic therapy]. Zentralbl Chir. 2011 Feb;136(1):66-73. DOI: 10.1055/s-0030-1247469 External link
49.
Geerlings SE, Hulscher M, Prins JM. Goed antibioticagebruik verkort de opnameduur. Ned Tijdschr Geneeskd. 2014;158:A7288.
50.
Cisneros JM, Neth O, Gil-Navarro MV, Lepe JA, Jiménez-Parrilla F, Cordero E, Rodríguez-Hernández MJ, Amaya-Villar R, Cano J, Gutiérrez-Pizarraya A, García-Cabrera E, Molina J; PRIOAM team. Global impact of an educational antimicrobial stewardship programme on prescribing practice in a tertiary hospital centre. Clin Microbiol Infect. 2014 Jan;20(1):82-8. DOI: 10.1111/1469-0691.12191 External link
51.
Davey P, Brown E, Charani E, Fenelon L, Gould IM, Holmes A, Ramsay CR, Wiffen PJ, Wilcox M. Interventions to improve antibiotic prescribing practices for hospital inpatients. Cochrane Database Syst Rev. 2013 Apr 30;(4):CD003543. DOI: 10.1002/14651858.CD003543.pub3 External link
52.
Kern WV. Antibiotic Stewardship – Strategien zur Sicherung eines intelligenten und rationalen Antibiotikaeinsatzes [Antibiotic stewardship – strategies for ensuring an intelligent and rational use of antibiotics]. Drug Res (Stuttg). 2014 Nov;64 Suppl 1:S5. DOI: 10.1055/s-0033-1358027 External link
53.
Mertz D, Koller M, Haller P, Lampert ML, Plagge H, Hug B, Koch G, Battegay M, Flückiger U, Bassetti S. Outcomes of early switching from intravenous to oral antibiotics on medical wards. J Antimicrob Chemother. 2009 Jul;64(1):188-99. DOI: 10.1093/jac/dkp131 External link
54.
Nathwani D, Eckmann C, Lawson W, Stephens JM, Macahilig C, Solem CT, Simoneau D, Chambers R, Li JZ, Haider S. Pan-European early switch/early discharge opportunities exist for hospitalized patients with methicillin-resistant Staphylococcus aureus complicated skin and soft tissue infections. Clin Microbiol Infect. 2014 Oct;20(10):993-1000. DOI: 10.1111/1469-0691.12632 External link
55.
Gray A, Dryden M, Charos A. Antibiotic management and early discharge from hospital: an economic analysis. J Antimicrob Chemother. 2012 Sep;67(9):2297-302. DOI: 10.1093/jac/dks194 External link
56.
Berild D, Mohseni A, Diep LM, Jensenius M, Ringertz SH. Adjustment of antibiotic treatment according to the results of blood cultures leads to decreased antibiotic use and costs. J Antimicrob Chemother. 2006 Feb;57(2):326-30. DOI: 10.1093/jac/dki463 External link
57.
Jelassi ML, Benlmouden A, Lefeuvre S, Mainardi J, Billaud EM. Niveau de preuve pour le suivi thérapeutique pharmacologique de la vancomycine. Thérapie. 2011;66(1):29–37. DOI: 10.2515/therapie/2011005 External link
58.
Fernández de Gatta MD, Calvo MV, Hernández JM, Caballero D, San Miguel JF, Domínguez-Gil A. Cost-effectiveness analysis of serum vancomycin concentration monitoring in patients with hematologic malignancies. Clin Pharmacol Ther. 1996 Sep;60(3):332-40.
59.
Wörmann A. Pharmakoökonomische Überlegungen zur kontinuierlichen Infusion von ß-Lactam Antibiotika unter Serumspiegelkontrolle am Beispiel von Meropenem und Piperacillin/Tazobactam: Masterarbeit zur Erlangung des akademischen Grades Master of Science. Dresden: Dresden International University;2015.
60.
Tice AD, Turpin RS, Hoey CT, Lipsky BA, Wu J, Abramson MA. Comparative costs of ertapenem and piperacillin-tazobactam in the treatment of diabetic foot infections. Am J Health Syst Pharm. 2007 May;64(10):1080-6.
61.
van Zanten AR, Engelfriet PM, van Dillen K, van Veen M, Nuijten MJ, Polderman KH. Importance of nondrug costs of intravenous antibiotic therapy. Crit Care. 2003 Dec;7(6):R184-90. DOI: 10.1186/cc2388 External link
62.
Cheung KC, van Rhijn A, Cousins D, De Smet P. Improving European cooperation on medication errors. Lancet. 2014 Apr 5;383(9924):1209-10. DOI: 10.1016/S0140-6736(14)60603-6 External link
63.
Center for Disease Dynamics, Economics & Policy, editor. The State of the World’s Antibiotics 2015. Washington: CDDEP; 2015. Available from: https://www.cddep.org/wp-content/uploads/2017/06/swa_edits_9.16.pdf External link
64.
World Health Organization. Antimicrobial Resistance: Global Report on Surveillance: Global Report on Surveillance. Geneva: World Health Organization; 2014. Available from: http://apps.who.int/iris/bitstream/10665/112642/1/9789241564748_eng.pdf?ua=1 External link
65.
Robert Koch Institut. Daten und Fakten: Ergebnisse der Studie „Gesundheit in Deutschland aktuell 2012“. Berlin: Robert Koch-Institut; 2014. Kapitel 2: Gesundheitstrends bei Erwachsenen in Deutschland zwischen 2003 und 2012. (Beiträge zur Gesundheitsberichterstattung des Bundes). Available from: https://www.rki.de/DE/Content/Gesundheitsmonitoring/Studien/Geda/kapitel_gesundheitstrends.pdf?__blob=publicationFile External link
66.
Ott E, Bange FC, Reichardt C, Graf K, Eckstein M, Schwab F, Chaberny IF. Costs of nosocomial pneumonia caused by meticillin-resistant Staphylococcus aureus. J Hosp Infect. 2010 Dec;76(4):300-3. DOI: 10.1016/j.jhin.2010.07.007 External link
67.
Aldeyab MA, Kearney MP, McElnay JC, Magee FA, Conlon G, Gill D, Davey P, Muller A, Goossens H, Scott MG; ESAC Hospital Care Subproject Group. A point prevalence survey of antibiotic prescriptions: benchmarking and patterns of use. Br J Clin Pharmacol. 2011 Feb;71(2):293-6. DOI: 10.1111/j.1365-2125.2010.03840.x External link
68.
Resch A, Wilke M, Fink C. The cost of resistance: incremental cost of methicillin-resistant Staphylococcus aureus (MRSA) in German hospitals. Eur J Health Econ. 2009 Jul;10(3):287-97. DOI: 10.1007/s10198-008-0132-3 External link
69.
Engemann JJ, Carmeli Y, Cosgrove SE, Fowler VG, Bronstein MZ, Trivette SL, Briggs JP, Sexton DJ, Kaye KS. Adverse clinical and economic outcomes attributable to methicillin resistance among patients with Staphylococcus aureus surgical site infection. Clin Infect Dis. 2003 Mar;36(5):592-8. DOI: 10.1086/367653 External link
70.
O’Neill J. Antimicrobial Resistance: Tackling a crisis for the health and wealth of nations: The Review on Antimicrobial Resistance. London: HM Government; 2014.