Next Article in Journal
Gram-negative Organisms from Patients with Community-Acquired Urinary Tract Infections and Associated Risk Factors for Antimicrobial Resistance: A Single-Center Retrospective Observational Study in Japan
Next Article in Special Issue
Prescription of Levofloxacin and Moxifloxacin in Select Hospitals in Uganda: A Pilot Study to Assess Guideline Concordance
Previous Article in Journal
Best Helicobacter pylori Eradication Strategy in the Era of Antibiotic Resistance
Previous Article in Special Issue
Substandard Quality of the Antimicrobials Sold in the Street Markets in Haiti
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Antibiotics
Volume 9
Issue 8
10.3390/antibiotics9080437
antibiotics-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Day 10 Post-Prescription Audit Optimizes Antibiotic Therapy in Patients with Bloodstream Infections

by
Rita Murri
1,2,
Claudia Palazzolo
2,3,
Francesca Giovannenze
2,*,
Francesco Taccari
1,2,
Marta Camici
2,3,
Teresa Spanu
1,4,
Brunella Posteraro
4,5,
Maurizio Sanguinetti
1,4,
Roberto Cauda
1,2 and
Massimo Fantoni
1,2
1
Dipartimento di Scienze di Laboratorio e Infettivologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
2
Dipartimento di Sicurezza e Bioetica, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
3
Istituto Nazionale Malattie Infettive Lazzaro Spallanzani, IRCCS, 00149 Rome, Italy
4
Dipartimento di Scienze biotecnologiche di base, cliniche intensivologiche e perioperatorie, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
5
Dipartimento di Scienze Gastroenterologiche, Endocrino-Metaboliche e Nefro-Urologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
*
Author to whom correspondence should be addressed.
Antibiotics 2020, 9(8), 437; https://doi.org/10.3390/antibiotics9080437
Submission received: 3 June 2020 / Revised: 16 July 2020 / Accepted: 17 July 2020 / Published: 23 July 2020
(This article belongs to the Special Issue Antibiotics Use and Antimicrobial Stewardship in Remote Areas – an One Health Perspective)
Browse Figure
Review Reports Versions Notes

Abstract

:
This study aimed to investigate the clinical and organizational impact of an active re-evaluation (on day 10) of patients on antibiotic treatment diagnosed with bloodstream infections (BSIs). A prospective, single center, pre-post quasi-experimental study was performed. Patients were enrolled at the time of microbial BSI confirmation. In the pre-intervention phase (August 2014–August 2015), clinical status and antibiotic regimen were re-evaluated at day 3. In the intervention phase (January 2016–January 2017), clinical status and antibiotic regimen were re-evaluated at day 3 and day 10. Primary outcomes were rate of optimal therapy, duration of antibiotic therapy, length of hospitalization, and 30-day mortality. A total of 632 patients were enrolled (pre-intervention period, n = 303; intervention period, n = 329). Average duration of therapy reduced from 18.1 days (standard deviation (SD), 11.4) in the pre-intervention period to 16.8 days (SD, 12.7) in the intervention period (p < 0.001). Similarly, average length of hospitalization decreased from 24.1 days (SD, 20.8) to 20.6 days (SD, 17.7) (p = 0.001). No inter-group difference was found for the rate of 30-day mortality. In patients with BSI, re-evaluation of clinical status and antibiotic regimen at day 3 and 10 after microbiological diagnosis was correlated with a reduction in the duration of antibiotic therapy and hospital stay. The intervention is simple and has a low impact on overall costs.

1. Introduction

Antibiotic-resistant bacteria represent a major and global public health concern [1]. Inappropriate antibiotic use is a major and modifiable cause of antibiotic resistance [2,3]. Data from multiple clinical settings suggest that antimicrobial stewardship programs are associated with improved antimicrobial use [4,5,6]. One of the cornerstones of antimicrobial stewardship programs is that “shorter is better” [7,8]. In this regard, several studies recently showed that for many diseases, a short course of antimicrobial therapy was just as effective as longer courses. Particularly, this was proven not only for urinary tract infections, pneumonias and intra-abdominal infections, but also for bloodstream infections (BSIs) [9,10,11,12,13,14,15,16,17,18,19]. However, at the present moment, the optimal duration of BSI treatment is controversial and yet to be defined. Despite Infectious Diseases Society of America (IDSA) guidelines for the management of intravascular catheter-related uncomplicated BSIs due to Gram-negative bacilli recommending 7–14 days of therapy, several studies have reported similar clinical outcomes for “short course” (≤10 days) and “long course” (>10 days) antibiotic treatments [14,15,16,17,18,19]. Moreover, with the exception of catheter-related BSIs due to coagulase-negative Staphylococci, data on short course treatment for Gram-positive BSIs are still lacking [20,21,22].
Post-prescription audit has been proposed as an efficacious strategy to optimize antibiotic regimens, especially treatment duration. In an earlier report, the present authors demonstrated that a three-day active re-evaluation of all patients with BSI was correlated with a decrease in both antimicrobial therapy duration and hospital stay [23]. The evaluation at the third day, when the antibiogram of the isolated microorganism is acquired, allows us to de-escalate or discontinue useless antibiotic therapy. The optimal duration of antibiotic therapy is unknown. Moreover, previous studies demonstrated that a 10-day course could be sufficient to optimally treat patients with BSIs [14,15,16,17,18,19]. Therefore, the aim of the present study was to determine whether active day 3 and day 10 re-evaluation of patients with Gram-positive or Gram-negative BSIs leads to a further reduction in the duration of antibiotic therapy and hospital stay.

2. Results

Between August 2014 and January 2017, 632 patients were enrolled (pre-Iintervention Phase, n = 303; Intervention Phase, n = 329). The intervention flow chart is shown in Figure 1.

2.1. Baseline Characteristics

The baseline demographic and clinical characteristics of the cohort are shown in Table 1. The mean age of the cohort was 71 years (standard deviation (SD), 15.2). In total, 385 (60.9%) of the cohort were males, and 424 (67.1%) of BSI cases concerned patients on medical wards. In total, 224 (35%) patients had been hospitalized within the preceding 90 days, and 150 (24%) had been prescribed an antibiotic within the previous 30 days. In total, 238 (38%) of patients had a central venous catheter in place at the time of BSI diagnosis.

2.2. BSI Etiology

BSI etiology across the cohort is shown in Table 2. In total, 104 (16.4%) of the BSI cases were polymicrobial. Of the 528 patients with mono-microbial BSI, a Gram-positive pathogen was isolated from blood cultures in 199 cases (37.7%). Of the 94 BSI cases that were attributable to Staphylococcus aureus, 30 (46.9%) were due to methicillin-resistant Staphylococcus aureus. A Gram-negative pathogen was isolated in 252 cases (47.7%). Of these, 27 (5.1%) were carbapenemase-producing Klebsiella pneumoniae. In 77 cases (12.2%), Candida spp. were isolated from blood cultures.

2.3. IDS Actions and Inter-Group Differences in IDS Actions at Day 3

In the pre-IP, the re-evaluation at day 3 was feasible in 234 patients (77.2%): 165 patients (54.5%) de-escalated or partially discontinued antibiotic therapy, and 69 (22.8%) were prescribed an extension of antibiotic therapy. In 69 patients (22.8%), the intervention was not feasible: in 31 cases (10.2%) patients were too ill, in 38 cases (12.5%) the therapy was already optimal. In the IP, an intervention at day 3 was feasible for 200 patients (60.8%): of these, 146 (44.4%) de-escalated or partially discontinued antibiotic therapy, and 54 (16.4%) were prescribed an extension of antibiotic therapy. In 129 patients (39.2%), the intervention was not feasible: in 39 cases (11.8%) patients were too ill, in 90 cases (27.3%) the therapy was already optimal. At day 3, considering only people for which an intervention was feasible, a higher rate of de-escalation/discontinuation was observed in IP than in pre-IP (146/200 (73%) vs. 165/234 (70.5%); Table 3). Non-feasibility of the study intervention was higher in period 2 (39.2%) than in period 1 (22.8%).

2.4. IDS Interventions at Day 10

In the IP, 153 patients (46.5%) discontinued the ongoing antibiotic therapy at day 10, while 30 patients (9.1%) prolonged the treatment. Indications for an extension of antibiotic therapy comprised the following: persistence of infection and/or a serious clinical condition (19 patients, 63.3%); infections due to a multi-drug resistant organism (MDRO), S. aureus or Candida spp. infection (five patients, 16.7%); endocarditis (three patients, 10%); prosthetic joint infection (two patients, 6.7%); and spondylodiscitis (one patient, 3.3%). Ten-day re-evaluation of polymicrobial infections took into account every single microorganism which grew from blood cultures. In 17 patients, the 10-day intervention was not feasible because of death (six patients, 35.3%), early discharge (six patients, 35.3%) or transfer to other hospitals (four patients, 23.5%); one patient (5.9%) was lost to follow-up.

2.5. Inter-Group Comparison of Clinical and Organizational Outcomes

In the IP, a statistically significant reduction was observed for time to effective therapy and time to optimal therapy. The total duration of therapy was reduced from 18.1 days (SD, 11.4) in pre-IP to 16.8 days (SD, 12.7) in IP (p < 0.001). Similarly, length of hospitalization was reduced from 24.1 days (SD, 20.8) in pre-IP to 20.6 days (SD, 17.7) in IP (p = 0.001). No inter-group difference was observed for the rate of 30-day mortality (Table 4).

3. Discussion

In the present BSI cohort, re-evaluation of clinical status and antibiotic regimen at both three and 10 days after microbiological diagnosis was correlated to better clinical and organizational outcomes. An increased rate of optimal therapy, shorter time between microbiological diagnosis and the beginning of effective therapy, and reduction in both the duration of antibiotic therapy and length of hospital stay were observed during the intervention period. No significant inter-group difference was found in 30-day mortality. In a previous analysis [23], the present authors found that active re-evaluation at day 3 led to an improvement in the rate of optimal therapy and to a reduction in both therapy duration and length of hospitalization, while survival rates were unchanged. After these results, active day 3 re-evaluation of patients diagnosed with BSI was implemented as routine clinical practice by the infectious diseases consultation unit of our hospital. The addition of a 10-day re-evaluation timepoint was correlated with further improvements in these outcomes. The present study involved post-prescription review with feedback.
At the time of writing, the optimal approach to antibiotic stewardship has yet to be defined. Both restrictive and persuasive strategies have been advocated to improve antimicrobial use in the hospital setting [24,25,26]. However, research suggests that “active strategy-based” antibiotic stewardship programs [27], which define care plans with hospital prescribers, might be associated with superior clinical [28] and health-economic [29] outcomes. Several studies have shown that “post-prescription review with feedback” (PPRF) has a greater positive impact in terms of decreasing antibiotic therapy duration than alternative antibiotic stewardship strategies. Tamma et al. [26] compared outcomes for two commonly used antibiotic stewardship strategies: pre-prescription authorization (PPA) and PPRF. Their data indicated that PPRF may have a greater impact on duration of therapy. Further studies have shown that a daily bedside consultation could enhance clinical and health-economic outcomes [30,31,32]. In a recent meta-analysis, bedside consultations were one of the six fundamental strategies to show a significant beneficial effect on at least one outcome [33].
To our knowledge, the present study is the first to evaluate the impact of a day 10, bedside PPRF on clinical and organizational outcomes. Our data confirm that the PPRF approach had a positive impact on BSI management, leading to a reduction in the duration of antibiotic therapy and in the length of hospital stay. Further research is warranted to evaluate the cost-effectiveness of this day 10 strategy in patients with BSI. A PPRF intervention can be implemented by infectious disease specialists, as in our model, or by other physicians trained in antibiotic prescription appropriateness. This kind of intervention is also simple and reproducible in resource-limited or remote settings. The present data suggest that an indirect advantage of this PPRF approach is a general improvement in BSI management.
A previously-published study found that combining antimicrobial stewardship programs with rapid diagnostic tests, such as MALDI-TOF MS, leads to better clinical outcomes [34]. In BSI patients, pathogen identification is crucial in terms of optimizing antimicrobial therapy, and prompt initiation of appropriate antibiotic therapy is associated with improved patient outcomes and decreased healthcare expenditure [35]. In a pre-post quasi-experimental study by Perez et al. [36], MALDI-TOF MS-based organism identification was integrated with an antimicrobial stewardship intervention in patients with Gram-negative bacteremia. The authors demonstrated a non-significant reduction in mortality and a statistically significant reduction in the length of hospitalization. In a pre-post quasi-experimental study by Huang et al. [37], combined MALDI-TOF and antimicrobial stewardship intervention decreased time to organism identification and improved time to both effective antibiotic therapy and optimal antibiotic therapy. Moreover, univariate analysis showed that length of intensive care unit (ICU) stay and recurrent bacteremia were lower in the intervention group, while multivariate analysis showed that the antimicrobial stewardship intervention was associated with a trend toward reduced mortality (odds ratio, 0.55; p = 0.075). Notably, the present study revealed an equally high rate of polymicrobial BSI (16.5%) in both study periods. MALDI-TOF MS detects only the single most prevalent strain, and thus a diagnosis of polymicrobial BSI can only be assigned once the growth culture results are available. Hence, in patients with polymicrobial BSI, time to optimal therapy may be longer than in mono-microbial BSI cases.
In patients with BSI, early initiation of antibiotic therapy has been associated with improved prognosis [38]. In the present study, we found a surprising improvement of “early” outcomes, i.e., time to effective and optimal therapy, in the IP. A possible explanation for this is that implementation of the day 10 intervention led to a global improvement in the management of BSI at the study center, including initial approach to treatment. Other possible reasons may be the lower percentage of patients who had received antibiotics in the previous 30 days and of patients who had a central venous catheter (CVC) in place in the IP compared to the pre-IP.
When possible, reducing the duration of antibiotic therapy is a mainstay of antibiotic stewardship programs [39,40], regardless of the healthcare setting, and has shown to be safe compared to longer treatments in selected patient populations [15]. The present intervention was correlated with a significant reduction of 1.3 mean days in the duration of antibiotic therapy when compared to re-evaluation at day 3 only, with no significant inter-group difference in the rate of 30-day mortality (p = 0.12). Considering a mean of 1000 BSIs in our hospital per year, the amount of antibiotics saving per year seems to be remarkable. In a cluster-randomized intervention study conducted in 15 small hospitals, Stenehjem et al. showed how an intensive antimicrobial stewardship program including audit and feedback has led to a reduction in total and broad spectrum antibiotic use during the intervention period [41]. In a previous study, the present authors reported a significant decrease in total duration of antibiotic therapy when an active re-evaluation of the patient with a BSI was performed on the third day after starting treatment. Despite this early active intervention, the mean duration of therapy in the cohort remained high (18 ± 11 days) [23]. Interestingly, several recent studies suggested that a ≤10-day course of therapy could be as effective as a longer course in selected patients with BSIs [14,15,16,17,18,19]. In a recent systematic review and meta-analysis, Baur et al. showed that antimicrobial stewardship programs reduced the incidence of infections and colonization with multi-drug resistant Gram-negative bacteria, extended spectrum β-lactamase-producing Gram-negative bacteria and methicillin-resistant Staphylococcus aureus, as well as the incidence of Clostridioides difficile infections [42]. Importantly, a significant reduction in the length of hospitalization was observed (from 24.1 to 20.6 days).
The present study has several limitations. First, the study was not randomized, and confounders may not have been completely excluded from the analyses. Second, the single-center design precludes generalization of the results to clinical centers with different patient populations, antibiotic stewardship practices, and rates of antimicrobial resistance. Moreover, although of great relevance for antibiotic stewardship programs, patients in hematological and ICU units were excluded due to the study design. Finally, the study was not designed primarily to demonstrate the efficacy of rapid diagnostic tests in terms of reduced time to effective/optimal therapy, time to IDS consultation, or time to beginning of effective therapy.

4. Materials and Methods

4.1. Study Design and Setting

We conducted a prospective, single-center, pre-post quasi-experimental study. The study was performed at the 1100-bed University Hospital in Rome, Italy (Fondazione Policlinico Gemelli IRCCS, Università Cattolica del Sacro Cuore), where a bedside infectious disease consultancy unit (Unità di Consulenza Infettivologica, UDCI) has been operating since 2012. The UDCI is staffed by four infectious disease specialists (IDSs) and operates from 8 a.m. to 2 p.m. from Monday to Friday. From 2 p.m. to 8 a.m., and on Sunday, an on-call IDS is available. An alert system for blood cultures is active from Monday to Saturday, whereby the microbiologist immediately informs the duty IDS of any positive blood culture result. Patients were enrolled at the time of notification to the IDS of a positive blood culture result (day 0). If not begun before, i.e., at the time of clinical suspicion and blood culture collection, antimicrobial therapy was started at the time of notification to the IDS.

4.2. Study Population

All adult patients newly diagnosed with BSI and evaluated by UDCI staff between August 2014 and January 2017 were included. Patients in hematological and ICU units were excluded for setting-related issues, since the UDCI service is not active in these wards and the blood culture alert system follows a separate workflow (i.e., the microbiology service communicates the detection of a pathogen directly to the ward physician on duty).

4.3. Data Collection and Definitions

BSI was defined as one or more blood cultures positive with a known pathogen in the presence of clinical signs and symptoms, and at least two blood cultures positive for the same microorganism taken from blood samples for the following microorganisms: coagulase-negative staphylococci, Corynebacterium spp., Micrococcus spp., Bacillus spp., Propionibacterium spp., or other similar non-pathogenic microorganisms. Organisms that were non-susceptible to at least one agent in three or more antimicrobial categories were classified as multi-drug resistant (MDR); organisms that were susceptible to only one class in antimicrobial categories were classified as extensively drug resistant (XDR) [43]. Therapy was defined as effective when isolated microorganisms were susceptible to the regimen in vitro. Therapy was defined as optimal when isolated microorganisms showed susceptibility to the ongoing antibiotic regimen and the regimen entailed the following: 1) the narrowest possible spectrum (taking into account allergies to antibiotics and the need for broader coverage due to concomitant infections); and 2) the best possible pharmacokinetic properties. Baseline demographic, epidemiological and clinical data were collected at enrolment. Specifically, we assessed the severity of clinical presentation at BSI onset using the Acute Physiology and Chronic Health Evaluation (APACHE) II score [44].

4.4. Study Periods and Interventions

We compared patients enrolled in the pre-intervention phase (pre-IP) to patients enrolled during the intervention phase (IP). In the pre-IP, from August 2014 to August 2015, all patients enrolled were actively re-evaluated at their bedside 72 h after notification by the microbiology laboratory to IDS (day 3), as part of the aforementioned study [23]. In the IP, from January 2016 to January 2017, all patients enrolled were actively re-evaluated both at day 3 and at day 10 after notification.
Possible actions undertaken at day 3 (i.e., in both study periods) comprised the following: 1) de-escalation, i.e., a shift from an empiric, wide spectrum therapy to a more restricted spectrum therapy on the basis of microbiological results; 2) escalation, i.e., a shift from a restricted spectrum antibiotic to a broader spectrum antibiotic; or 3) partial discontinuation, i.e., a reduction in the number of antibiotics on the basis of microbiological results.
As an intervention (only in the IP), all patients were actively re-evaluated at day 10 and a decision regarding discontinuing or prolonging antibiotic therapy was made. In the latter case, data were collected concerning indications for the extension of antibiotic therapy beyond 10 days.

4.5. Microbiological Analysis

Blood samples were inoculated in aerobic and anaerobic Bactec (Becton Dickinson Instrument Systems, Sparks, MD, USA) and Bact/Alert bottles (bioMérieux, Marcy l’Etoile, France) and incubated at 35 °C in the Bactec FX and BacT/Alert VIRTUO automated blood culture (BC) systems, respectively. When growth was detected, species level identification of the infecting pathogens was conducted in BC broths using MALDI-TOF MS (MALDI BioTyper; Bruker Daltonik GmbH, Leipzig, Germany)) or FilmArray Blood Culture Identification (BCID, bioMérieux) testing according to the procedure previously described [45]). All specimens were also processed according to the standard procedure that includes subcultures on selective and non-selective media, identification by MALDI BioTyper and antimicrobial susceptibility testing by the Vitek 2 system (bioMérieux) or by the microdilution broth method using commercial dehydrated 96-well panels manufactured by MERLIN Diagnostica GmbH (Bornheim, Germany). Results were interpreted in accordance with the European Committee on Antimicrobial Susceptibility Testing (EUCAST) clinical breakpoints [46]. The phenotypic detection of extended spectrum beta-lactamases (ESBLs), and carbapenemases in Enterobacterales isolates was performed according to the EUCAST guidelines [46]. Multi-drug resistance (MDR) and extensive drug resistance (XDR) were defined according to an international expert proposal by Magiorakos et al. [43].

4.6. Outcome Measures

Primary outcomes of the study were: rate of optimal therapy, antibiotic therapy duration, length of hospital stay and 30-day mortality. Secondary outcomes included: time to effective antibiotic therapy (i.e., time between notification of the positive blood culture result and first effective treatment) and time to optimal therapy (i.e., time between notification of the positive blood culture result and start of optimal treatment).

4.7. Statistical Analysis

A required sample size of 300 patients was calculated for each study period. This calculation was based on a possible decrease in the duration of antibiotic therapy of at least 10%, an assumed difference of 20% in outcome measures between the intervention period and the pre-intervention period, and a power of 80% (= 0.20) at a two-sided significance level of 5% (= 0.05). For the descriptive analyses, the mean and standard deviation (SD) were calculated for continuous values, and the median and interquartile range were calculated for nonparametric continuous variables. Student’s t-test was used to determine inter-group differences in mean values. The chi-square test was used to determine inter-group differences for discrete variables. ANOVA was used to compare mean values for continuous variables. A value of p < 0.05 was considered significant. All statistical analyses were performed using SPSS Statistics (IBM SPSS Statistics v23). All analyses were performed in accordance with the Outbreak Reports and Intervention studies Of Nosocomial infection (ORION) statements [47].

4.8. Ethical Approval

The study was approved by the institutional review board of the Fondazione Policlinico Universitario A. Gemelli IRCCS—Università Cattolica del Sacro Cuore. The requirement for written informed consent was waived due to the already implemented 3-day re-evaluation of all patients with BSI and the fact that all data were anonymized prior to analysis. All study procedures were performed in accordance with the principles of the Declaration of Helsinki and its later amendments.

5. Conclusions

In conclusion, the present data suggest that re-evaluation of clinical status and therapeutic regimen at day 3 and day 10 after microbiological identification is an effective intervention to optimize antibiotic therapy and to improve clinical and organizational outcomes in patients with BSI. We believe that the simple feasibility of the intervention makes it easily reproducible in many healthcare settings, including resource-limited or remote areas.
Improvement of antimicrobial stewardship programs and interventions remains a key healthcare priority, as it will lead to improved clinical outcomes, optimal resource allocation, and improved control of the spread of MDR bacteria. Further studies are needed, especially randomized clinical trials, to assess the impact of PPRF on the duration of therapy for BSIs.

Author Contributions

Conceptualization, R.M.; Data curation, C.P., F.G., F.T. and M.C.; Formal analysis, R.M.; Methodology, R.M.; Software, R.M.; Supervision, T.S., M.S., R.C. and M.F.; Visualization, B.P.; Writing—original draft, C.P.; Writing—review and editing, R.M., F.G. and M.F. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Acknowledgments

We thank Leonida Passeri for technical assistance with data management.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Tackling Drug-Resistant Infections Globally: Final Report and Recommendations the Review on Antimicrobial Resistance Chaired by Jim O’neill. Available online: https://amr-review.org/sites/default/files/160518_Final%20paper_with%20cover.pdf (accessed on 29 May 2020).
  2. Marston, H.D.; Dixon, D.M.; Knisely, J.M.; Palmore, T.N.; Fauci, A.S. Antimicrobial resistance. JAMA J. Am. Med. Assoc. 2016. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Antibiotic Consumption in Europe. Available online: http://drive-ab.eu/wp-content/uploads/2014/09/WP1A_Final-QMs-QIs_final.pdf (accessed on 29 May 2020).
  4. Barlam, T.F.; Cosgrove, S.E.; Abbo, L.M.; Macdougall, C.; Schuetz, A.N.; Septimus, E.J.; Srinivasan, A.; Dellit, T.H.; Falck-Ytter, Y.T.; Fishman, N.O.; et al. Executive summary: Implementing an antibiotic stewardship program: Guidelines by the infectious diseases society of America and the society for healthcare epidemiology of America. Clin. Infect. Dis. 2016, 62, e51–e77. [Google Scholar] [CrossRef]
  5. Honda, H.; Murakami, S.; Tagashira, Y.; Uenoyama, Y.; Goto, K.; Takamatsu, A.; Hasegawa, S.; Tokuda, Y. Efficacy of a Postprescription Review of Broad-Spectrum Antimicrobial Agents With Feedback: A 4-Year Experience of Antimicrobial Stewardship at a Tertiary Care Center. Open Forum Infect. Dis. 2018. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  6. Sikkens, J.J.; Van Agtmael, M.A.; Peters, E.J.G.; Lettinga, K.D.; Van Der Kuip, M.; Vandenbroucke-Grauls, C.M.J.E.; Wagner, C.; Kramer, M.H.H. Behavioral approach to appropriate antimicrobial prescribing in hospitals the Dutch unique method for antimicrobial stewardship (DUMAS) participatory intervention study. JAMA Intern. Med. 2017. [Google Scholar] [CrossRef] [PubMed]
  7. Royer, S.; DeMerle, K.M.; Dickson, R.P.; Prescott, H.C. Shorter versus longer courses of antibiotics for infection in hospitalized patients: A systematic review and meta-analysis. J. Hosp. Med. 2018, 13, 336–342. [Google Scholar] [CrossRef] [Green Version]
  8. Hanretty, A.M.; Gallagher, J.C. Shortened courses of antibiotics for bacterial infections: A systematic review of randomized controlled trials. Pharmacotherapy 2018, 38, 674–687. [Google Scholar] [CrossRef]
  9. Sandberg, T.; Skoog, G.; Hermansson, A.B.; Kahlmeter, G.; Kuylenstierna, N.; Lannergård, A.; Otto, G.; Settergren, B.; Ekman, G.S. Ciprofloxacin for 7 days versus 14 days in women with acute pyelonephritis: A randomised, open-label and double-blind, placebo-controlled, non-inferiority trial. Lancet 2012, 380, 484–490. [Google Scholar] [CrossRef]
  10. Peterson, J.; Kaul, S.; Khashab, M.; Fisher, A.C.; Kahn, J.B. A double-blind, randomized comparison of levofloxacin 750 mg once-daily for five days with ciprofloxacin 400/500 mg twice-daily for 10 days for the treatment of complicated urinary tract infections and acute pyelonephritis. Urology 2008, 71, 17–22. [Google Scholar] [CrossRef]
  11. Uranga, A.; España, P.P.; Bilbao, A.; Quintana, J.M.; Arriaga, I.; Intxausti, M.; Lobo, J.L.; Tomás, L.; Camino, J.; Nuñez, J.; et al. Duration of antibiotic treatment in community-acquired pneumonia: A multicenter randomized clinical trial. JAMA Intern. Med. 2016, 176, 1257–1265. [Google Scholar] [CrossRef] [Green Version]
  12. Capellier, G.; Mockly, H.; Charpentier, C.; Annane, D.; Blasco, G.; Desmettre, T.; Roch, A.; Faisy, C.; Cousson, J.; Limat, S.; et al. Early-onset ventilator-associated pneumonia in adults randomized clinical trial: Comparison of 8 versus 15 days of antibiotic treatment. PLoS ONE 2012, 7, e41290. [Google Scholar] [CrossRef] [Green Version]
  13. Sawyer, R.G.; Claridge, J.A.; Nathens, A.B.; Rotstein, O.D.; Duane, T.M.; Evans, H.L.; Cook, C.H.; O’Neill, P.J.; Mazuski, J.E.; Askari, R.; et al. Trial of short-course antimicrobial therapy for intraabdominal infection. N. Engl. J. Med. 2015, 372, 1996–2005. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Mermel, L.A.; Allon, M.; Bouza, E.; Craven, D.E.; Flynn, P.; O’Grady, N.P.; Raad, I.I.; Rijnders, B.J.; Sherertz, R.J.; Warren, D.K. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 update by the Infectious Disease Society of America. Clin. Infect. Dis. 2009, 49, 1–45. [Google Scholar] [CrossRef] [PubMed]
  15. Yahav, D.; Franceschini, E.; Koppel, F.; Turjeman, A.; Babich, T.; Bitterman, R.; Neuberger, A.; Ghanem-Zoubi, N.; Santoro, A.; Eliakim-Raz, N.; et al. Bacteremia Duration Study Group. Seven versus fourteen days of antibiotic therapy for uncomplicated gram-negative bacteremia: A non-inferiority randomized controlled trial. Clin. Infect. Dis. 2018. [Google Scholar] [CrossRef]
  16. Nelson, A.N.; Justo, J.A.; Bookstaver, P.B.; Kohn, J.; Albrecht, H.; Al-Hasan, M.N. Optimal duration of antimicrobial therapy for uncomplicated Gram-negative bloodstream infections. Infection 2017, 45, 613–620. [Google Scholar] [CrossRef]
  17. Sousa, A.; Pérez-Rodríguez, M.T.; Suárez, M.; Val, N.; Martínez-Lamas, L.; Nodar, A.; Longueira, R.; Crespo, M. Short- versus long-course therapy in gram-negative bacilli bloodstream infections. Eur. J. Clin. Microbiol. Infect. Dis. 2019. [Google Scholar] [CrossRef] [PubMed]
  18. Chotiprasitsakul, D.; Han, J.H.; Cosgrove, S.E.; Harris, A.D.; Lautenbach, E.; Conley, A.T.; Tolomeo, P.; Wise, J.; Tamma, P.D. Antibacterial Resistance Leadership Group. Comparing the Outcomes of Adults with Enterobacteriaceae Bacteremia Receiving Short-Course Versus Prolonged-Course Antibiotic Therapy in a Multicenter, Propensity Score-Matched Cohort. Clin. Infect. Dis 2018. [Google Scholar] [CrossRef]
  19. Tansarli, G.S.; Andreatos, N.; Pliakos, E.E.; Mylonakis, E. A Systematic Review and Meta-analysis of Antibiotic Treatment Duration for Bacteremia Due to Enterobacteriaceae. Antimicrob. Agents Chemother. 2019. [Google Scholar] [CrossRef] [Green Version]
  20. San-Juan, R.; Martínez-Redondo, I.; Fernández-Ruiz, M.; Ruiz-Ruigómez, M.; Corbella, L.; Hernández-Jiménez, P.; Tiago Silva, J.; López-Medrano, F.; Recio, R.; Orellana, M.A.; et al. A short course of antibiotic treatment is safe after catheter withdrawal in catheter-related bloodstream infections due to coagulase-negative staphylococci. Eur. J. Clin. Microbiol. Infect. Dis 2019. [Google Scholar] [CrossRef]
  21. Corey, G.R.; Stryjewski, M.E.; Everts, R.J. Short-course therapy for bloodstream infections in immunocompetent adults. Int. J. Antimicrob. Agents. 2009. [Google Scholar] [CrossRef]
  22. Chong, Y.P.; Moon, S.M.; Bang, K.M.; Park, H.J.; Park, S.Y.; Kim, M.N.; Park, K.H.; Kim, S.H.; Lee, S.O.; Choi, S.O.; et al. Treatment duration for uncomplicated Staphylococcus aureus bacteremia to prevent relapse: Analysis of a prospective observational cohort study. Antimicrob. Agents Chemother. 2013. [Google Scholar] [CrossRef] [Green Version]
  23. Murri, R.; Taccari, F.; Spanu, T.; D’Inzeo, T.; Mastrorosa, I.; Giovannenze, F.; Scoppettuolo, G.; Ventura, G.; Palazzolo, C.; Camici, M.; et al. A 72-h intervention for improvement of the rate of optimal antibiotic therapy in patients with bloodstream infections. Eur. J. Clin. Microbiol. Infect. Dis. 2018, 37. [Google Scholar] [CrossRef] [PubMed]
  24. Mehta, J.M.; Haynes, K.; Wileyto, E.P.; Gerber, J.S.; Timko, D.R.; Morgan, S.C.; Binkley, S.; Fishman, N.O.; Lautenbach, E.; Zaoutis, T. Comparison of Prior Authorization and Prospective Audit with Feedback for Antimicrobial Stewardship. Infect. Control. Hosp. Epidemiol. 2014. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  25. Okumura, L.M.; Riveros, B.S.; da Silva, M.M.G.; Veroneze, I. Strategies of hospital antimicrobial stewardship associated with different health outcomes. Lancet Infect. Dis. 2016. [Google Scholar] [CrossRef]
  26. Tamma, P.D.; Avdic, E.; Keenan, J.F.; Zhao, Y.; Anand, G.; Cooper, J.; Dezube, R.; Hsu, S.; Cosgrove, S.E. What is the more effective antibiotic stewardship intervention: Preprescription authorization or postprescription review with feedback? Clin. Infect. Dis. 2017, 64, 537–543. [Google Scholar] [PubMed]
  27. Hurst, A.L.; Child, J.; Pearce, K.; Palmer, C.; Todd, J.K.; Parker, S.K. Handshake stewardship: A highly effective rounding-based antimicrobial optimization service. Pediatr. Infect. Dis. J. 2016. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  28. Okumura, L.M.; da Silva, M.M.G.; Veroneze, I. Effects of a bundled Antimicrobial Stewardship Program on mortality: A cohort study. Braz. J. Infect. Dis. 2015. [Google Scholar] [CrossRef] [Green Version]
  29. Okumura, L.M.; Riveros, B.S.; Gomes-da-Silva, M.M.; Veroneze, I. A cost-effectiveness analysis of two different antimicrobial stewardship programs. Braz. J. Infect. Dis. 2016. [Google Scholar] [CrossRef] [Green Version]
  30. Forsblom, E.; Ruotsalainen, E.; Ollgren, J.; Järvinen, A. Telephone consultation cannot replace bedside infectious disease consultation in the management of staphylococcus aureus bacteremia. Clin. Infect. Dis. 2013. [Google Scholar] [CrossRef] [Green Version]
  31. Emberger, J.; Tassone, D.; Stevens, M.P.; Markley, J.D. The Current State of Antimicrobial Stewardship: Challenges, Successes, and Future Directions. Curr. Infect. Dis. Rep. 2018, 20, 31. [Google Scholar] [CrossRef]
  32. Schmitt, S.; Macintyre, A.T.; Bleasdale, S.C.; Ritter, J.T.; Nelson, S.B.; Berbari, E.F.; Burdette, S.D.; Hewlett, A.; Miles, M.; Robinson, P.A.; et al. Early Infectious Diseases Specialty Intervention Is Associated with Shorter Hospital Stays and Lower Readmission Rates: A Retrospective Cohort Study. Clin. Infect. Dis. 2019. [Google Scholar] [CrossRef] [Green Version]
  33. Schuts, E.C.; Hulscher, M.E.J.L.; Mouton, J.W.; Verduin, C.M.; Stuart, J.W.T.C.; Overdiek, H.W.P.M.; van der Linden, P.D.; Natsch, S.; Hertogh, C.M.P.M.; Wolfs, T.F.W.; et al. Current evidence on hospital antimicrobial stewardship objectives: A systematic review and meta-analysis. Lancet Infect. Dis. 2016. [Google Scholar] [CrossRef]
  34. Fiori, B.; D’Inzeo, T.; Di Florio, V.; De Maio, F.; De Angelis, G.; Giaquinto, A.; Campana, L.; Tanzarella, E.; Tumbarello, M.; Antonelli, M.; et al. Performance of two resin-containing blood culture media in detection of bloodstream infections and in direct matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) broth assays for isolate identification: Clinical comp. J. Clin. Microbiol. 2014. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Barenfanger, J.; Graham, D.R.; Kolluri, L.; Sangwan, G.; Lawhorn, J.; Drake, C.A.; Verhulst, S.J.; Peterson, R.; Moja, L.B.; Ertmoed, M.M.; et al. Decreased mortality associated with prompt gram staining of blood cultures. Am. J. Clin. Pathol. 2008. [Google Scholar] [CrossRef] [PubMed]
  36. Perez, K.K.; Olsen, R.J.; Musick, W.L.; Cernoch, P.L.; Davis, J.R.; Land, G.A.; Peterson, L.E.; Musser, J.M. Integrating rapid pathogen identification and antimicrobial stewardship significantly decreases hospital costs. Arch. Pathol. Lab. Med. 2013. [Google Scholar] [CrossRef] [Green Version]
  37. Huang, A.M.; Newton, D.; Kunapuli, A.; Gandhi, T.N.; Washer, L.L.; Isip, J.; Collins, C.D.; Nagel, J.L. Impact of rapid organism identification via matrix-assisted laser desorption/ionization time-of-flight combined with antimicrobial stewardship team intervention in adult patients with bacteremia and candidemia. Clin. Infect. Dis. 2013. [Google Scholar] [CrossRef]
  38. Ferrer, R.; Martin-Loeches, I.; Phillips, G.; Osborn, T.M.; Townsend, S.; Dellinger, R.P.; Artigas, A.; Schorr, C.; Levy, M.M. Empiric antibiotic treatment reduces mortality in severe sepsis and septic shock from the first hour: Results from a guideline-based performance improvement program. Crit. Care Med. 2014. [Google Scholar] [CrossRef]
  39. Onakpoya, I.J.; Walker, A.S.; Tan, P.S.; Spencer, E.A.; Gbinigie, O.A.; Cook, J.; Llewelyn, M.J.; Butler, C.C. Overview of systematic reviews assessing the evidence for shorter versus longer duration antibiotic treatment for bacterial infections in secondary care. PLoS ONE 2018, 13, e0194858. [Google Scholar] [CrossRef] [Green Version]
  40. Timsit, J.F.; Bassetti, M.; Cremer, O.; Daikos, G.; de Waele, J.; Kallil, A.; Kipnis, E.; Kollef, M.; Laupland, K.; Paiva, J.A.; et al. Rationalizing antimicrobial therapy in the ICU: A narrative review. Intensive Care Med. 2019, 45, 172–189. [Google Scholar] [CrossRef]
  41. Stenehjem, E.; Hersh, A.L.; Buckel, W.R.; Jones, P.; Sheng, X.; Evans, R.S.; Burke, J.P.; Lopansri, B.K.; Srivastava, R.; Greene, T.; et al. Impact of Implementing Antibiotic Stewardship Programs in 15 Small Hospitals: A Cluster-Randomized Intervention. Clin. Infect. Dis 2018. [Google Scholar] [CrossRef]
  42. Baur, D.; Gladstone, B.P.; Burkert, F.; Carrara, E.; Foschi, F.; Döbele, S.; Tacconelli, E. Effect of antibiotic stewardship on the incidence of infection and colonisation with antibiotic-resistant bacteria and Clostridium difficile infection: A systematic review and meta-analysis. Lancet Infect. Dis. 2017. [Google Scholar] [CrossRef]
  43. Magiorakos, A.P.; Srinivasan, A.; Carey, R.B.; Carmeli, Y.; Falagas, M.E.; Giske, C.G.; Harbarth, S.; Hindler, J.F.; Kahlmeter, G.; Olsson-Liljequist, B.; et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: An international expert proposal for interim standard definitions for acquired resistance. Clin. Microbiol. Infect. 2012. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Knaus, W.A.; Draper, E.A.; Wagner, D.P.; Zimmerman, J. APACHE II: A severity of disease classification system. Crit. Care Med. 1985, 13, 818–829. [Google Scholar] [CrossRef] [PubMed]
  45. Fiori, B.; D’Inzeo, T.; Giaquinto, A.; Menchinelli, G.; Liotti, F.M.; De Maio, F.; De Angelis, G.; Quaranta, G.; Nagel, D.; Tumbarello, M.; et al. Optimized Use of the MALDI BioTyper System and the FilmArray BCID Panel for Direct Identification of Microbial Pathogens from Positive Blood Cultures. J. Clin. Microbiol. 2016. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. The European Committee on Antimicrobial Susceptibility Testing—EUCAST Home Page. Available online: http://www.eucast.org (accessed on 22 July 2020).
  47. University College London—UCL Home >> UCL Antimicrobial Resistance >> Reporting Guidelines >> ORION statement. Available online: https://www.ucl.ac.uk/amr/Reporting_Guidelines/ORION (accessed on 22 July 2020).
Antibiotics 09 00437 g001 550
Figure 1. Flow diagram of interventions at day 3 and day 10 in the two study periods. Type and number of interventions implemented in the pre-IP and IP are shown respectively in (a) and (b).
Figure 1. Flow diagram of interventions at day 3 and day 10 in the two study periods. Type and number of interventions implemented in the pre-IP and IP are shown respectively in (a) and (b).
Antibiotics 09 00437 g001
Table
Table 1. Baseline demographic and clinical characteristics of the study cohort.
Table 1. Baseline demographic and clinical characteristics of the study cohort.
CharacteristicTotal
n = 632		Pre-IP
n = 303		IP
n = 329		p
Age, mean, years (SD)71 (15.2)67.7 (15.6)69.7 (14.8)0.15
Males (%)385 (60.9)123 (40.6)124 (37.7)0.49
Number of comorbidities (SD)1.00 (0.9)1.2 (0.9)0.7 (0.8)<0.001
Ward (%)
Medical424 (67.1)204 (67.3)220 (66.9)
Surgical208 (32.9)99 (32.7)109 (33.1)0.01
Hospitalization in the previous 90 days (%)224 (35.4)116 (38.3)108 (32.8)0.08
Antibiotic therapy in the previous 30 days (%)150 (23.7)89 (29.4)61 (18.5)0.002
Central venous catheter238 (37.6)139 (45.9)99 (30.1)0.001
APACHE II score, mean (SD)11.8 (5.9)12.5 (6.2)10.2 (5.0)<0.001
Septic shock (%)28 (4.4)14 (5.1)14 (5.6)0.95
Polymicrobial (%)104 (16.5)66 (21.8)38 (11.6)<0.001
Multi-drug resistant BSI (%)194 (30.7)100 (33.0)99 (30.1)<0.001
APACHE, Acute Physiology and Chronic Health Evaluation; BSI, bloodstream infection; SD: standard deviation. Student’s t-test and Chi-square test were used respectively to compare continuous and categorical variables.
Table
Table 2. BSI etiology in the study cohort.
Table 2. BSI etiology in the study cohort.
Gram-Positive Bacterian of Samples
Staphylococci
Coagulase-negative43
Methicillin-sensitive Staphylococcus aureus64
Methicillin-resistant Staphylococcus aureus30
Enterococci
Enterococcus faecalis29
Enterococcus faecium9
Streptococcus pneumoniae6
Streptococcus spp.18
Gram-negative bacteria
Escherichia coli69
ESBL-producing48
Klebsiella spp.26
K. aerogenes
K. pneumoniae26
ESBL-producing5
Carbapenemase-producing27
Acinetobacter XDR320
Proteus mirabilis8
MDR5
Pseudomonas aeruginosa19
MDR9
Stenotrophomonas maltophilia2
BSI, bloodstream infection; ESBL, extended-spectrum beta lactamases; XDR, extensively drug resistant; MDR, multi-drug resistant.
Table
Table 3. Interventions at day 3 and day 10.
Table 3. Interventions at day 3 and day 10.
InterventionTotal
n = 632		Pre-IP
n = 303		IP
n = 329		p
Intervention done (%)434 (68.6)234 (77.2)200 (60.8)<0.001
De-escalation or partial discontinuation (%) at day 3 165 (70.5)146 (73)
Escalation (%) at day 3 69 (29.4)54 (27)
Discontinuation of therapy after 10 days re-evaluation -153 (62.7)
Study intervention not feasible (%)198 (31.3)69 (22.8)129 (39.2)<0.001
Patient too ill (%) 31 (44.9)39 (30.2)
Optimal therapy already ongoing (%) 38 (55)90 (69.7)
Pre-IP, pre-intervention phase; IP, intervention phase. Chi-square test was used respectively to compare pre-IP and IP.
Table
Table 4. Primary study outcomes.
Table 4. Primary study outcomes.
OutcomeTotal
n = 632		Pre-IP
n = 303		IP
n = 329		p
Time to start of antibiotic therapy, mean, days (SD)0.5 (0.9)0.5 (1.0)0.49 (0.86)0.002
Time to start of effective antibiotic therapy, mean, days (SD)1.0 (1.5)1.51 (1.8)0.89 (1.2)<0.0001
Time to start of optimal antibiotic therapy, mean, days (SD)2.0 (2.3)3.03 (2.5)2.29 (2.1)<0.0001
Number of effective therapy cases (%)96.1 (13.2)89.8 (14.6)93.3 (11.6)<0.0001
Number of patients receiving effective therapy (%)629 (99.5)301 (99.3)328 (99.7)0.01
Number of optimal therapy cases (%)97 (24.5)87.2 (28.0)92.9 (20.5)<0.0001
Number of patients receiving optimal therapy (%)589 (93.1)275 (90.8)314 (95.4)<0.0001
Duration of antibiotic therapy, mean, days (SD)17.40 (14.5)18.1 (11.4)16.8 (12.7)<0.0001
Length of hospitalization, mean, days (SD)16 (19.3)24.1 (20.8)20.6 (17.7)0.001
Number of deaths at 30 days (%)105 (16.6)64 (21.1)64 (19.5)0.12
Pre-IP, pre-intervention phase; IP, intervention phase. Student’s t-test and Chi-square test were used respectively to compare continuous and categorical variables.

Share and Cite

MDPI and ACS Style

Murri, R.; Palazzolo, C.; Giovannenze, F.; Taccari, F.; Camici, M.; Spanu, T.; Posteraro, B.; Sanguinetti, M.; Cauda, R.; Fantoni, M. Day 10 Post-Prescription Audit Optimizes Antibiotic Therapy in Patients with Bloodstream Infections. Antibiotics 2020, 9, 437. https://doi.org/10.3390/antibiotics9080437

AMA Style

Murri R, Palazzolo C, Giovannenze F, Taccari F, Camici M, Spanu T, Posteraro B, Sanguinetti M, Cauda R, Fantoni M. Day 10 Post-Prescription Audit Optimizes Antibiotic Therapy in Patients with Bloodstream Infections. Antibiotics. 2020; 9(8):437. https://doi.org/10.3390/antibiotics9080437

Chicago/Turabian Style

Murri, Rita, Claudia Palazzolo, Francesca Giovannenze, Francesco Taccari, Marta Camici, Teresa Spanu, Brunella Posteraro, Maurizio Sanguinetti, Roberto Cauda, and Massimo Fantoni. 2020. "Day 10 Post-Prescription Audit Optimizes Antibiotic Therapy in Patients with Bloodstream Infections" Antibiotics 9, no. 8: 437. https://doi.org/10.3390/antibiotics9080437

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop